Evaluation of the Clinical, Biochemical, Genotype, and Prognosis of Propionic Acidemia in 133 Patients from China

Evaluation of the Clinical, Biochemical, Genotype, and Prognosis of Propionic Acidemia in 133 Patients from China | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Evaluation of the Clinical, Biochemical, Genotype, and Prognosis of Propionic Acidemia in 133 Patients from China Lili Liang, Yuhui Hu, Yue Yu, Shiying Ling, Wenjuan Qiu, Jun Ye, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3819961/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Propionic acidemia (PA) is an inherited organic acid metabolic disease involving multiple physiological systems with variable manifestations. The causative genes, PCCA and PCCB , carry a wide range of mutations. The present study aimed to investigate the phenotype and genotype features of PA in Chinese patients. Methods We enrolled 133 PA patients who were treated during the past 17 years. We investigated their clinical data in detail, including national newborn screening (NBS) status and disease onset, biochemical metabolites, gene variations, and recent prognosis, to investigate the phenotype and genotype features. Results Among the 133 PA patients, 36 patients were diagnosed thanks to NBS expanded by tandem mass spectrometry (MS/MS). The median onset time was four months old, with symptoms involving multiple systems without specificity. The blood propionylcarnitine/ acetylcarnitine (C3/C2) ratio and urine 3-hydroxypropionic acid (3-OHPA) levels decreased after treatment. The overall prognosis of was poor, with 25.5% being healthy (34/133), 36.1% having developmental delays (48/133), 24.1% dying (32/133) and 14.3% being lost to follow-up (19/133). In the PCCA gene of 49 patients, 60 variants were detected, including 43 new variations. The variations c.2002G > A, c.229C > T, and c.1118T > A were the three most frequent variations. In the PCCB gene of 80 patients, 64 variants were detected, including 40 new variations. The variations c.1087T > C, c.838dup, and c.1228C > T were the three most frequent variations. Conclusion PA is a serious organic acidemia with early onset and nonspecific symptoms. The overall prognosis is poor. There are wide and relative common variations in Chinese patients in causative genes. propionic acidemia mutation newborn screening tandem mass spectrometry Figures Figure 1 Figure 2 Introduction Propionic acidemia (PA) is a rare autosomal recessive inherited organic acid metabolic disorder (OMIM 606054). The primary defect occurs in propionyl-CoA carboxylase (EC 6.4.1.3), which catalyzes the carboxylation of propionyl-CoA with bicarbonate, producing methylmalonyl-CoA, which is then converted to succinyl-CoA [ 1 ]. The reduction or absence of propionyl-CoA carboxylase activity results in the accumulation of propionyl-CoA, which is spontaneously converted to propionylcarnitine (C3), propionic acid, and other organic acids, including 3-hydroxypropionic acid (3-OHPA) and methylcitric acid (MCA), which also accumulate and are excreted in the urine of affected patients [ 1 – 3 ]. The accumulation of these abnormal acidic metabolites causes various clinical symptoms, ranging from severe early onset (onset before three months old) with high mortality to milder late onset (onset after three months old) with elevated morbidity. Patients with the early-onset form may present with progressive encephalopathy in the first days of life manifested as lethargy, seizures, and coma that may progress to death if it is not diagnosed and treated promptly. Late-onset patients may also present with acute encephalopathy following metabolic decompensation but usually experience a more insidious onset with the development of multiorgan complications, such as failure to thrive, vomiting, developmental delay, neurological regression and cardiomyopathy [ 2 , 4 – 5 ]. Long-term management is mainly based on dietary restriction of specific amino acids (isoleucine, valine, threonine, and methionine) and L-carnitine supplementation, which has been shown to partly reduce mortality but is still inadequate to prevent chronic morbidity [ 3 , 6 – 7 ]. The incidence of this disorder differs greatly in patients with different origins and from different regions [ 3 , 8 ]. The incidence in Western countries is estimated to be 1/50000 to 1/500000 [ 3 ]. However, a much higher incidence is observed in isolated areas or some specific populations, such as certain tribes in Saudi Arabia, with incidences as high as 1/2000 to 1/5000 [ 3 ], and Inuits in Greenland, with a rough first-estimate incidence of 1/1000 [ 9 ]. Implementation of newborn screening in various countries has allowed for the estimation of birth prevalence of PA. The reported incidence of PA is 1/242,741 in the United States, 1/284450 in Southwest Germany (1/202617 in Germany nationwide), 1/59426 in Kuwait [ 10 ], 1/45000 in Japan [ 11 ], and 1/195492 in mainland China [ 12 ]. An expanded screening program for newborns by tandem mass spectrometry (MS/MS) is currently performed in an increasing number of regions of China. The advanced use of MS/MS and gene detection is greatly beneficial for the proper and timely diagnosis of PA. Propionyl-CoA carboxylase consists of two subunits, α and β, encoded by the PCCA gene and PCCB gene, respectively. The native enzyme is believed to have an α6β6 conformation. Deficiency of the enzyme due to mutations in either of the two genes results in PA. The PCCA gene is located on chromosome 13q32 and encodes a polypeptide of 703 amino acids, while the PCCB gene is located on chromosome 3q13.3-q22 and encodes a polypeptide of 539 amino acids. It was reported that mutations in the PCCA gene are highly heterogeneous, without common single mutations predominant in any population. However, there are limited numbers of mutations in the PCCB gene that account for most of the patients in different ethnic groups [ 13 ]. Since the first report of PA by Childs et al. in 1961 [ 14 ], research on its clinical manifestations, biochemical characteristics, diagnosis and treatment strategies has continuously improved. Concern about this disease started late in China. Although related reports have increased gradually in recent years, patients might be misdiagnosed or missed due to the lack of specific clinical manifestations. In the present study, we investigated 133 PA patients from our department at Shanghai Xinhua Hospital during the last 18 years, from 2004 to 2022. We performed a retrospective chart review of their clinical data in detail, including metabolites, molecular diagnosis, treatment, and outcomes, and aimed to investigate the clinical phenotype and the genotype of the disease, providing clinical experience for clinicians. Methods 1. Patients From 2004 to 2022, a total of 133 PA patients were diagnosed and treated at the Department of Pediatric Endocrinology/Genetics, Shanghai Xinhua Hospital. We reviewed the clinical and biochemical phenotypes, genotypes and outcomes of patients in detail. Written informed consent was obtained from the parents of the study participants. This study was approved by the Ethics Committee of Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (approval ID: XHEC-D-2023-029). 2. Detection of metabolites Blood levels of acylcarnitines, including C3 and acetylcarnitine (C2), were detected by MS/MS (API 4000, American Bio-Systems Inc.) using blood filter papers. Urinary organic acids, including 3-OHPA and MCA, were measured by gas chromatography‒mass spectrometry (GC‒MS) (Shimadzu Limited, QP2010) [ 1 ]. 3. Gene mutation detection and evaluation PCCA and PCCB were detected by Sanger sequencing or high-throughput next-generation sequencing. Mutations were identified using the normal human PCCA and PCCB sequences as a reference (NM_000282.4 and NM_000532.5, respectively). We used the ClinVar database, the HGMD database and the previous literature to identify whether the mutations had been reported. The pathogenicity of the missense mutations was predicted by Mutation Taster, PolyPhen-2, Proven and SIFT software. 4. Diagnosis and treatment The diagnosis of PA was based on increases in blood C3, blood C3/C2 ratio, urine 3-OHPA, and urine MCA or the detection of mutations in the gene encoding propionyl-CoA carboxylase. In the stable stage, PA was mainly treated by L-carnitine and a diet low in isoleucine, valine, threonine, and methionine. In the acute stage, maintaining the stability of the internal environment and symptomatic treatment were the focus, including limiting protein intake, supplementing energy with glucose and lipids, and administering an intravenous drip of L-carnitine and sodium bicarbonate to promote abnormal metabolite excretion and correct metabolic acidosis. Children with hyperammonemia were given arginine, sodium benzoate, sodium phenylbutyrate arginine and even extracorporeal detoxification, according to the degree of hyperammonemia [ 1 , 3 , 15 ]. 5. Prognosis evaluation Clinical follow-up parameters were used to assess basic motor function and language development. Based on prognosis, the patients were divided into healthy and developmental delay groups. The healthy patients exhibited no significant disability in daily life, while the developmental delay patients presented with delayed achievement of motor and/or speech milestones, including the need for support when walking and being unable to communicate or pronounce words effectively. 6. Statistical analysis Normally distributed measurement data were evaluated statistically by using Student’s t test, while nonnormally distributed data were analyzed by the Wilcoxon rank-sum test. The comparison of rates was performed by the chi-square test. Statistical analyses were performed using GraphPad Prism 5 software (GraphPad Software Inc., San Diego, CA, USA). A p value of < 0.05 was considered a significant difference between two groups. Results 1. Clinical features This study recruited 133 individuals with a confirmed PA diagnosis. There were 86 boys and 47 girls. The median follow-up age was 4.15 years old, ranging from two months to 18 years and three months old. A total of 36 (27.1%) affected individuals were identified by the MS/MS expanded NBS project. Among them, disease onset occurred in 22 cases, while 13 cases did not, and the remaining one case was lost to follow-up and we were not sure if the patient experienced disease onset. The remaining 97 patients were diagnosed by onset of the disease (96 cases) or sibling MMA diagnosis (one case, without disease onset). In total, 118 patients (22 with NBS, 96 without NBS) showed disease onset, with a median age of disease onset of four months old, ranging from one day after birth to six years and three months old. Except for the nine cases whose specific onset time was unknown, 27 cases showed disease onset within three months after birth, 59 cases showed disease onset between three months and 12 months old, 18 cases showed disease onset between one year and three years old, and five cases showed onset after three years old. Therefore, early-onset type patients (onset within three months old) accounted for 24.8% (27/109), while late-onset type patients (onset after three months old) accounted for 75.2% (82/109). Most of the patients showed acute disease onset, with nonspecific symptoms, including vomiting, diarrhea, difficulty feeding, jaundice, lethargy, convulsion, muscle weakness, mental retardation, and coma, accompanied by metabolic acidosis, hypoglycemia, hyperlactatemia and hyperammonemia. In addition, some patients showed progressive mental retardation instead of acute disease onset. 2 Biochemical features The blood C3 levels, the C3/C2 ratio, and the urinary 3-OHPA and MCA levels before and after treatment in the patients were evaluated statistically as biochemical markers and are presented in Table 1 . In the primary state before treatment, the blood C3 levels, C3/C2 ratio, and urinary 3-OHPA and MCA levels in patients showed obvious increases above the normal range. After treatment, the C3/C2 ratio and the levels of urinary 3-OHPA decreased compared with those before treatment, with a significant difference. However, the level of blood C3 increased after treatment compared with that before treatment, with a significant difference. The MCA level showed no significant difference before and after treatment. Table 1 Biochemical Characteristics in Mass Spectrometry of the PA Patients Before and After Treatment C3 C3/C2 Methylmalonic Acid Methylcitric acid Before After Before After Before After Before After 12.93 (2.58, 56.77) 19.50 (3.76, 83.01) 1.31 (0.15, 6.20) 1.12 (0.13, 4.18) 55.93 (0.00, 715.70) 19.96 (0.00,1118.00) 26.10 (0.40, 240.30) 23.28 (1.40, 283.20) n = 122 n = 114 n = 122 n = 114 n = 104 n = 112 n = 107 n = 112 P < 0.0001 P = 0.0416 P = 0.0049 P = 0.3063 Typical reference range of C3: 0.50-4.00 µmol/L; typical reference range of C3/C2: 0.04–0.25; typical reference range of 3-OHPA: 0–4 mmol/mol creatinine; typical reference range of methylcitric acid: 0-0.8 mmol/mol creatinine. 3 Genetic analysis A total of 128 patients were sequenced for the PCCA gene and PCCB gene. Forty-four patients exhibited two compound heterozygous or homozygous variations in the PCCA gene. One patient with three variations in their two alleles of PCCA gene and three patients exposed only one variant in the PCCA gene. Meanwhile, 73 patients exhibited two compound heterozygous or homozygous variations in the PCCB gene, and six patients exposed only one variant. Unusually, one patient with typical clinical manifestations and a biochemical phenotype carried one variant in the PCCA gene (c.1676G > T) and one variant in the PCCB gene (c.1087T > C). In the PCCA gene, 95 variations, of 60 kinds, were exposed in 94 alleles. The variations and their pathogenicity ratings are described in detail in Table 2 . The 60 specific variations and their respective proportions are described in Fig. 1 a, including 21 missense variants (35.0%), 11 nonsense variants (18.3%), 11 frameshift variants (18.3%), eight splicing variants (13.3%), four exon deletions (6.7%), three synonymous variants (5.0%), and two small deletions (3.3%). The most frequent variant was c.2002G > A (20/95, 21.1%), followed by c.229C > T (7/95, 7.4%), c.1118T > A (5/95, 5.3%), c.1288C > T (4/95, 4.2%), and c.1961T > A (2/95, 2.1%). A total of six patients carried homozygous variants. Three patients carried homozygous c.2002G > A. One patient each was homozygous for c.229C > T, c.1118T > A, and c.1961T > A. Among the 60 variations, 43 novel variants were identified (Table 2 ). Table 2 Summary of Variations Found in the PCCA Gene Variations No. Exon/ intron Nucleotide change Predicted Protein change Numbers of homozygous case Numbers of heterozygous case Variation Frequency Grade of Pathogenicity 1 E1 c.2T > A p.M1K 0 1 1.05% PM2 + PP3 + PP4 2 E1 c.39del p.A14Pfs*12 0 1 1.05% P(PM2 + PVS1 + PP4) 3 E1 c.43G > T p.G15* 0 1 1.05% P(PM2 + PVS1 + PP4) 4 E1 c.59G > A P.W20* 0 1 1.05% P(PM2 + PVS1 + PP4) 5 I1 c.106-2A > G Splicing 0 1 1.05% P(PM2 + PVS1 + PP4) 6 E2 c.117C > G p.Y39* 0 1 1.05% P(PM2 + PVS1 + PP4) 7 E2 c.127C > T p.Q43* 0 1 1.05% P(PM2 + PVS1 + PP4) 8 E2 c.131delinsATT p.C44Yfs*3 0 1 1.05% P(PM2 + PVS1 + PP4) 9 E2 c.151C > T p.L51F 0 1 1.05% LP(PM2 + PM3 + PP4 + PM1) 10 E3 c.216del E73Kfs*31 0 1 1.05% P(PM2 + PVS1 + PP4) 11 E3 c.229C > T p.R77W 1 5 7.37% P(PM1 + PP3 + PP4 + PM3_STR + PM2) 12 I3 c.231 + 1G > A Splicing 0 1 1.05% P(PM2 + PVS1 + PP4 + PM5) 13 E4 c.289G > C p.D97H 0 1 1.05% LP(PM2 + PP3 + PP4 + PM1) 14 E5 c.305del p.H102Lfs*2 0 1 1.05% P(PM2 + PVS1 + PP4) 15 E5 c.317C > A p.A106E 0 1 1.05% LP(PP3 + PM1 + PM2 + PP4) 16 E5 c.375_386del p.D125_M128del 0 1 1.05% LP(PM4 + PM2 + PM3 + PP4) 17 E7 c.491T > C P.I164T 0 1 1.05% LP(PM2 + PP3 + PP4 + PM1 + PM3) 18 E7 c.497del p.P166Lfs*18 0 2 2.11% P(PVS1 + PM2 + PP4) 19 E7 c.541A > C p.K181Q 0 1 1.05% LP(PM1 + PM2 + PP3 + PP4) 20 E7 c.596T > A p.V199D 0 1 1.05% LP(PM2 + PP3 + PP4 + PM1 + PM3) 21 E9 c.683G > T p.G228V 0 1 1.05% LP(PM2 + PP3 + PP4 + PM1) 22 E9 c.734C > A p.S245* 0 1 1.05% P(PM2 + PVS1 + PP4) 23 E10 c.734C > G p.S245* 0 2 2.11% P(PVS1 + PP4 + PM2) 24 E10 c.803G > T R268L 0 1 1.05% LP(PM5 + PM2 + PP3 + PP4 + PM1) 25 I10 c.819 + 1G > A Splicing 0 1 1.05% P(PM2 + PVS1 + PP4) 26 I10 c.819 + 2T > A Splicing 0 1 1.05% P(PM2 + PVS1 + PP4) 27 E11 c.863G > A R288K 0 1 1.05% LP(PP3 + PM1 + PM2 + PM5 + PM3 + PP4) 28 E11 C.872C > T p.S291L 0 1 1.05% LP(PM5 + PM2 + PP3 + PM1 + PP4) 29 E12 c.937 C > T p.R313* 0 1 1.05% P(PVS1 + PM3_STR + PP4 + PM5) 30 E12 c.978del p.V327* 0 1 1.05% P(PVS1 + PM2 + PP4) 31 E12 c.984del p.K328Nfs*23 0 1 1.05% P(PVS1 + PM2 + PP4) 32 E12 c.1004T > G p.V335G 0 1 1.05% LP(PP3 + PM1 + PM2 + PP4) 33 E13 c.1079T > G p.V360G 0 1 1.05% LP(PM1 + PM2 + PP3 + PP4) 34 E13 c.1085A > T p.E362V 0 1 1.05% LP(PM1 + PM2 + PP3 + PP4) 35 E13 c.1118T > A p.M373K 1 3 5.26% P(PM2 + PP3 + PP4 + PM1 + PM3_STR) 36 E13 c.1147dup p.R383Kfs*6 0 1 1.05% P(PVS1 + PM2 + PP4) 37 E13 c.1185A > C p.(=) 0 1 1.05% VUS(PM2 + PP4) 38 E13 c.1187T > A p.V396D 0 1 1.05% LP(PP3 + PM1 + PM2 + PP4 + PM5) 39 E13 c.1196G > T p.R399L 0 1 1.05% P(PM5_STR + PM2 + PP4 + PP3 + PM3) 40 I13 c.1210-7C > G Splicing 0 1 1.05% VUS(PM2 + PP4) 41 E14 c.1275T > C p.(=) 0 1 1.05% VUS(PM2 + PP4) 42 I14 c.1284 + 1G > A Splicing 0 1 1.05% P(PM2 + PVS1 + PP4 + PM3_STR) 43 E15 c.1288C > T p.R430* 0 4 4.21% P(PVS1 + PP4 + PM2) 44 E15 c.1330dup p.Y444Lfs*3 0 1 1.05% P(PVS1 + PP4 + PM2) 45 E16 c.1415dup p.N472Kfs*10 0 1 1.05% P(PVS1 + PP4 + PM2) 46 E16 c.1426C > T p.R476* 0 1 1.05% P(PVS1 + PP4 + PM2) 47 I16 c.1429 + 2T > C Splicing 0 1 1.05% P(PVS1 + PP4 + PM2) 48 I17 c.1540 + 2T > C Splicing 0 1 1.05% P(PM2 + PVS1 + PP4) 49 E18 c.1593_1595del p.L532del 0 1 1.05% LP(PM2 + PM3 + PP4 + PM4_SUP) 50 E19 c.1676G > T p.W559L 0 1 1.05% VUS(BS1 + PM1) 51 E19 c.1746G > C p.(=) 0 1 1.05% VUS(BP4 + PM2) 52 E20 c.1831C > T p.Q611* 0 1 1.05% P(PVS1 + PM2 + PP4) 53 E21 c.1863del p.G622Vfs*4 0 1 1.05% P(PVS1 + PM2 + PP4) 54 E22 c.2002G > A p.G668R 3 14 21.05% LP(PM2_SUP + PM3_STR + PP3 + PP4 + PM1) 55 E22 c.1961T > A p.V654E 1 0 2.11% VUS(PM2 + BP4) 56 E24 c.2149_2157dup p.T717_G719dup 0 1 1.05% LP(PM2 + PM4 + PM3 + PP4) 57 E3-E4 deletion / 0 1 1.05% P(PM2 + PVS1 + PP4) 58 E6 deletion / 0 1 1.05% P(PM2 + PVS1 + PP4) 59 E9-E22 deletion / 0 1 1.05% P(PM2 + PVS1 + PP4) 60 E19 deletion / 0 1 1.05% P(PM2 + PVS1 + PP4) Total / 60 / 6 83 100.00% / New variants are indicated in bold. P: pathogenic; LP: likely pathogenic; VUS: variant of unknown significance. In the PCCB gene, 153 variations, of 64 different kinds, were exposed in 153 alleles. The variations and their pathogenicity ratings are described in detail in Table 3 . The specific variations and respective proportions of the 64 variations are described in Fig. 1 b, including 36 missense variants (55.4%), 10 frameshift variants (15.4%), seven splicing variants (10.8%), 6 nonsense variants (9.2%), two exon deletions (3.1%), two small deletion-insertions (3.1%), one synonymous variant (1.5%) and one small deletion (1.5%). The most frequent variant was c.1087T > C (27/153, 17.6%), followed by c.838dup (13/153, 8.5%), c.1228C > T (7/153, 4.6%), c.1316A > G (6/153, 3.9%), c.331C > T (6/153, 3.9%) and c.167_179delinsC (6/153, 3.9%). A total of eight patients carried homozygous variants. Four patients carried homozygous c.1087T > C. One patient each was homozygous for c.1316A > G, c.167_179delinsC, c.1535G > A, and c.1599A > C. Among the 64 variations, 40 novel variants were identified (Table 3 ). Table 3 Summary of Variations Found in the PCCB Gene Variations No. Exon/ intron Nucleotide change Predicted Protein change Numbers of homozygous case Numbers of heterozygous case Variation Frequency Grade of Pathogenicity 1 UTR c.-2A > G Splicing 0 2 1.31% VUS(PM2 + PM3 + PP4) 2 E1 c.2T > C p.M1T 0 1 0.65% LP(PM2 + PM3 + PP3 + PP4) 3 E1 c.31-40del p.G11Sfs*51 0 2 1.31% P(PVS1 + PM2 + PP4) 4 E1 c.146del p.G49Efs*16 0 1 0.65% P(PVS1 + PM2 + PP4) 5 E1 c.167_179delinsC p.D56_K60delinsA 1 4 3.92% LP(PM4 + PM2 + PP4 + PM3_SUP) 6 E1 c.168_179del p.D56_K60delinsE 0 2 1.31% LP(PM4 + PM2 + PP4 + PM3_SUP) 7 I1 c.184-2A > G Splicing 0 3 1.96% P(PVS1 + PM2 + PP4) 8 E2 c.223G > C p.D75H 0 2 1.31% LP(PM2 + PP3 + PP4 + PM2) 9 E2 c.224 A > C p.D75A 0 1 0.65% LP(PP3 + PP4 + PM2 + PM1) 10 E3 c.331C > T p.R111* 0 6 3.92% P(PVS1 + PM2 + PP4) 11 E3 c.337C > T p.R113* 0 4 2.61% P(PM2_SUP + PP4 + PVS1 + PM3) 12 E3 c.369_372del p.S123Rfs*26 0 3 1.96% P(PVS1 + PM2 + PP4) 13 E3 c.370C > T p.Q124* 0 1 0.65% P(PVS1 + PM2 + PP4) 14 E3_I3 c.366_372 + 7del F122Lfs*26 0 1 0.65% P(PVS1 + PM2 + PP4) 15 E4 c.391G > C p.G131R 0 1 0.65% LP(PP3 + PM2 + PM1 + PP4) 16 E4 c.428A > T p.K143I 0 1 0.65% LP(PM1 + PP3 + PP4 + PM2) 17 I4 c.429 + 5G > A Splicing 0 1 0.65% VUS(PM2 + PM3) 18 E6 c.553dup p.T185Nfs*45 0 1 0.65% P(PVS1 + PM2 + PP4) 19 E6 c.562G > A p.G188R 0 1 0.65% P(PM2 + PM3_STR + PP3 + PP4 + PM1) 20 E6 c.605G > A p.G202D 0 1 0.65% LP(PP3 + PP4 + PM1 + PM2) 21 E6 c.634G > T p.D212Y 0 1 0.65% LP(PM2 + PP3 + PP4 + PM1) 22 E6 c.647T > C p.M216T 0 2 1.31% LP(PP3 + PP4 + PM1 + PM2) 23 E7 c.733G > A p.G245S 0 3 1.96% LP(PP3 + PM1 + PP4 + PM2) 24 I7 c.763 + 1G > A Splicing 0 1 0.65% P(PVS1 + PM2 + PP4) 25 E8 c.838dup p.L280Pfs*11 0 13 8.49% P(PVS1 + PM2 + PP4) 26 E8 c.839dup p.S281Efs*10 0 2 1.31% P(PVS1 + PM2 + PP4) 27 E8 c.839del p.L280Rfs*68 0 1 0.65% P(PVS1 + PM2 + PP4) 28 E8 c.866G > C p.R289P 0 2 1.31% LP(PM2 + PP4 + PM1 + PM3) 29 I9 c.967-2A > T Splicing 0 1 0.65% P(PVS1 + PM2 + PP4) 30 E10 c.967_969del p.V324del 0 1 0.65% LP(PM4_SUP + PP4 + PM2 + PM3) 31 E10 c.1028G > A p.G343D 0 1 0.65% LP(PM2 + PP3 + PP4 + PM1) 32 E10 c.1076C > T p.P359L 0 1 0.65% LP(PM2 + PP3 + PP4 + PM1) 33 E10 c.1087T > C p.S363P 4 19 17.65% P(PM2_SUP + PP3 + PP4 + PM3 + PM1 + PS4_OR) 34 I10 c.1091-2A > G Splicing 0 1 0.65% P(PM2 + PVS1 + PP3 + PP4) 35 E11 c.1108T > C p.S370P 0 1 0.65% LP(PM2 + PP3 + PP4 + PM1) 36 E11 c.1112C > T P.S371F 0 1 0.65% LP(PM2 + PP3 + PP4 + PM1) 37 E11 c.1150T > G p.F384V 0 1 0.65% LP(PM2 + PP3 + PP4 + PM1) 38 E11 c.1174G > A p.V392I 0 1 0.65% VUS(PM2 + PP4 + PM1) 39 E11 c.1196C > G p.P399R 0 2 1.31% LP(PM2_SUP + PM3 + PM1 + PP3 + PP4) 40 E12 c.1220del p.G407Afs*36 0 3 1.96% P(PVS1 + PP4 + PM2) 41 E12 c.1228C > T p.R410W 0 7 4.58% P(PM1 + PP3 + PP4 + PM3_STR + PM2) 42 E12 c.1229G > A p.R410Q 0 1 0.65% LP(PM5 + PM2_SUP + PM3 + PP3 + PP4) 43 E12 c.1234G > C p.G412R 0 1 0.65% LP(PM1 + PM2 + PP3 + PP4) 44 E12 c.1244T > C p.L415P 0 1 0.65% LP(PP3 + PP4 + PM1 + PM2) 45 E12 c.1253C > T p.A418V 0 3 1.96% LP(PP3 + PM1 + PM2 + PP4) 46 E12 c.1267A > C p.T423P 0 1 0.65% LP(PP3 + PP4 + PM2 + PM1) 47 E12 c.1274 C > G p.P425R 0 1 0.65% LP(PP3 + PM1 + PM2 + PP4) 48 E12 c.1283C > T p.T428I 0 1 0.65% P(PM3_STR + PP3 + PP4 + PM1 + PM2) 49 E13 c.1301C > T p.A434V 0 2 1.31% LP(PP3 + PM1 + PM2_SUP + PP4 + PM3) 50 E13 c.1313C > T p.A438V 0 1 0.65% LP(PP3 + PM2 + PP4 + PM1) 51 E13 c.1316A > G p.Y439C 1 4 3.92% P(PS3 + PP3 + PM2_SUP + PM1 + PP4 + PM3) 52 E13 c.1329C > G p.S443R 0 1 0.65% LP(PM2 + PP3 + PM1 + PP4) 53 E13 c.1339C > T p.L447F 0 2 1.31% LP(PP3 + PM1 + PM2 + PP4) 54 E13 c.1373C > T p.A458V 0 1 0.65% LP(PP3 + PM2 + PP4 + PM3 + PM1) 55 E14 c.1495C > T p.R499* 0 3 1.96% LP(PVS1_M + PM2 + PP4 + PM3) 56 E14 c.1497A > G p.(=) 0 1 0.65% VUS(PM2 + PM5 + PP4) 57 I14 c.1499-2A > G Splicing 0 2 1.31% LP(PVS1_M + PM2 + PP4 + PM3) 58 E15 c.1535G > A p.R512H 1 0 1.31% LP(PP3 + PM5 + PM3 + PM2 + PM1 + PP4) 59 E15 c.1540C > T p.R514* 0 3 1.96% LP(PM2 + PVS1_M + PM3_STR + PP4) 60 E15 c.1541G > C P.R514P 0 1 0.65% LP(PM1 + PP3 + PM5 + PP4 + PM2) 61 E15 c.1582C > T Q528* 0 1 0.65% LP(PVS1_M + PM2 + PP4 + PM3) 62 E15 c.1599A > C p.K533N 1 0 1.31% LP(PP3 + PP4 + PM2 + PM1) 63 E1 deletion / 0 1 0.65% P(PM2 + PVS1 + PP4) 64 E1-E8 deletion / 0 1 0.65% P(PM2 + PVS1 + PP4) Total / 64 / 8 137 100.00% / New variants are indicated in bold. P: pathogenic; LP: likely pathogenic; VUS: variant of unknown significance. We selected the most common mutations in the PCCA gene (c.2002G > A) and PCCB gene (c.1087T > C) to track their corresponding phenotypes. For c.2002G > A in the PCCA gene, there were three homozygous patients and 14 heterozygous patients. The three homozygous patients had a median disease onset age of 3 days after birth, ranging from 0 days to 16 days. In terms of prognosis, two patients died (2/3), and one patient had developmental delays (1/3). The 14 heterozygous patients had a better overall prognosis: three patients died (3/14), five patients had developmental delays (5/14), four patients remained healthy (4/14) and two patients were lost to follow-up (2/14). For c.1087T > C in the PCCB gene, there were four homozygous patients and 18 heterozygous patients. The four homozygous patients had disease onset ages of three days, six months and 75 months after birth, and one patient did not have disease onset. In terms of prognosis, three patients remained healthy (3/4), and one patient had developmental delays (1/4). For the 18 heterozygous patients, eight patients remained healthy (8/18), five patients had developmental delays (5/18), two patients died (2/18), and three patients were lost to follow-up (3/18). To explore the geographical distribution of the variations in the PCCA and PCCB genes, we analyzed the origin of the patients and evaluated the common variations in different regions. The patients were from 23 provinces across China. The three provinces with the highest incidence were Shandong (31 cases), Jiangsu (21 cases) and Zhejiang provinces (14 cases), which accounted for 49.6% of all 133 patients, followed by Shanghai (13 cases), Henan (nine cases) and Anhui provinces (eight cases). Among the 31 patients from Shandong Province, there were 21 patients with two variations in the PCCB gene, eight patients with two variations in the PCCA gene and two patients without variations. The three most frequent mutations in Shandong Province were c.838dup (8/42, 19.1%), c.1087T > C (6/42, 14.3%), and c.167_179delinsC (3/42, 7.1%) in the PCCB gene, without common variations in the PCCA gene. Among the 21 patients from Jiangsu Province, 13 patients had two variations in the PCCB gene, and eight patients had two variations in the PCCA gene. The three most frequent mutations in Jiangsu Province were c.1087T > C (5/26, 19.2%) and c.1228C > T (3/26, 11.5%) in the PCCB gene and c.229C > T (3/16, 18.6%) in the PCCA gene. 4. Treatment effect and prognosis In our cohort, most patients were treated with L-carnitine and a diet low in isoleucine, valine, threonine, and methionine 6 . We evaluated the health conditions of the patients to 2022. The prognosis is shown in detail in Fig. 2 . Among the 36 positive NBS patients, disease onset occurred in 22 patients; 13 patients did not have disease onset, and the remaining patient was lost to follow-up. For the prognosis of the 22 positive NBS patients who exhibited disease onset, 12 patients showed developmental delays, four patients were healthy, four patients died, and two patients were lost to follow-up. The 13 patients who did not encounter disease onset lived healthy lives without symptoms. Regarding the prognosis of the 96 patients diagnosed by clinical onset of the disease without NBS, 36 patients showed developmental delays, 16 patients were healthy, 28 patients died, and 16 patients were lost to follow-up. One patient diagnosed because of a sibling diagnosis was healthy, without NBS and without disease onset. Therefore, 118 patients (22 with NBS, 96 without NBS) showed disease onset. The overall prognosis of the entire cohort was as follows: 48 (48/133, 36.1%) patients showed progressive developmental delays or intelligence impairment, 34 patients (34/133, 25.5%) were healthy and lived normal lives asymptomatically, 32 patients died (32/133, 24.1%), and 19 patients could not be followed up (19/133, 14.3%). Discussion In the present study, we recruited a large cohort of 133 PA patients; collected their disease onset and NBS status, biochemical metabolite levels, gene variations and prognosis; and achieved the results described above. With a median age at disease onset of 4 months old, 78.9% (86/109) of the patients exhibited disease onset before 12 months old. In addition, no specificity in the clinical manifestations of these patients existed at disease onset. Symptoms in multiple systems and multiple biochemical abnormalities were present, such as vomiting, difficulty feeding, jaundice, lethargy, convulsion, and mental retardation, accompanied by metabolic acidosis, hypoglycemia, and hyperammonemia. Early diagnosis and timely treatment are of great importance for these patients. The diagnosis of PA depends on specific technology, such as MS/MS, GC-MS, and gene analysis. In recent years, MS/MS expanded NBS has played an increasingly critical role in the early diagnosis and timely treatment of PA. NBS has been shown to increase the chance of early diagnosis of PA patients, especially in late-onset cases, and might decrease neonatal mortality [ 16 , 17 ]. MS/MS expanded NBS, which detects blood acylcarnitine and amino acids in newborns by MS/MS, can diagnose dozens of inherited metabolic diseases, including PA. After the first attempt in our NBS center of Shanghai Xinhua Hospital in 2003, MS/MS expanded NBS was promoted to an increasing number of regions in China gradually. To date, it is available in about 60% of the 246 NBS centers in China (147/246), with the detection report available in two weeks after the newborn birth. PA patients could benefit greatly from the MS/MS expanded NBS. Because the manifestations of PA had no specificity at disease onset, patients could only be treated symptomatically before diagnosis. Once the NBS results arrived, the diagnosis was clear, and targeted etiological treatment for PA could begin immediately. Therefore, NBS can significantly improve patient prognosis. This can be confirmed by the difference in prognosis between patients with NBS and patients without NBS shown in Fig. 2 . A total of 36 patients were diagnosed by the MS/MS expanded NBS; 13 patients remained asymptomatic without disease onset, and four patients returned to a healthy status after disease onset, with a healthy rate of 47.2% (17/36). However, of the 96 patients diagnosed by clinical disease onset, only 16 patients remained healthy, with a healthy rate of 16.7% (16/96). Among the 97 patients who were not diagnosed by NBS but from clinical disease onset or sibling diagnosis, some missed the MS/MS expanded NBS because they were born before the project was introduced locally. Therefore, MS/MS expanded NBS should be promoted urgently to a much broader range of newborns in China to diagnose this disease. For the biochemical markers, compared with the levels before treatment, the C3 blood levels increased after treatment. This does not represent a worsening of the disease. We considered that the low C3 blood level before treatment was due to the consumption of carnitine by excessive abnormal acidic metabolites in the body. After treatment with free carnitine (C0) supplementation, the levels of acylcarnitines, including C3 and C2, increased. Thus, the increase in the C3 blood level after treatment did not suggest the deterioration of biochemical indicators but the interference of treatment. This deduction was also confirmed because the C3/C2 ratio did not increase but decreased after treatment (before 1.31 vs. after 1.12). In the case of urine organic acids, improvement was embodied in the decrease in 3-OHPA after treatment. The mutations in the PCCA gene were highly heterogeneous. None of the mutations detected are predominant in Caucasians, with an exception in Japanese individuals; three mutations, c.922_923insT, c.1644-6C > G, and c.1196G > A, account for 56% of the total mutant alleles 13 . In our cohort, as many as 60 variants were detected in the PCCA gene. Although there were no predominant single mutations in the gene, we found that the relatively frequent mutations in the Chinese population were c.2002G > A, c.229C > T, and c.1118T > A. In the PCCB gene, there are usually limited numbers of mutations that account for most of the patients in different ethnic groups. For example, 1218del14ins12 appears to be the most common PCCB mutation in Caucasians [ 13 ], 1540insCCC seems to be a prevalent PCCB mutation in Greenland [ 9 ], and c.1172_1173insT and c.502G > A are common specifically in the Spanish and Latin American populations [ 13 ]. In Korea, the allele frequency of c.1283C > T in patients with PA was 56.3% in one study [ 18 ]. In Japan, c.1304T > C and c.1283C > T have been reported to be the most common mutations [ 11 , 19 ]. Furthermore, c.1283C > T is related to a severe phenotype, while patients with the c.1304T > C mutation are expected to be free from the symptoms of PA [ 11 ]. In the present study, we determined that the common mutations in the PCCB gene were c.1087T > C, c.838dup, c.1228C > T, and c.1316A > G in the Chinese population, which are different from those in previous countries. Specific variations belonged to specific phenotypes. It is well known that homozygotes can best embody the function of variations. We investigated the disease onset and prognosis of the most frequent variations, c.2002G > A in the PCCA gene and c.1087T > C in the PCCB gene. The c.2002G > A variant was associated with a relatively serious phenotype, while the c.1087T > C variant was associated with a relatively mild phenotype. In China, more patients have mutations in the PCCB gene than in the PCCA gene. In our cohort, 45 patients had variations in the PCCA gene, while 73 patients had variations in the PCCB gene. In another large cohort study in China that included 60 PA patients reported by Liu Y et al., 24 (41.4%) patients had mutations in the PCCA gene, and 34 (58.6%) patients had mutations in the PCCB gene [ 20 ]. In that cohort, c.2002G > A in PCCA and c.838dup in PCCB were the most common variants, with frequencies of 13.9% (6/44 alleles) and 12.5% (8/64 alleles), respectively. The conclusion is similar to our study, with the difference that the most common variation in the PCCB gene was c.1087T > C, and c.838dup was the second most frequent variant in our study. In addition, we identified 43 novel variations in the PCCA gene and 40 novel variations in the PCCB gene. This study expanded the variation spectrum in Chinese patients and could be of importance regarding genetic counseling of PA patients. Functional studies, such as enzymatic activity determination, should be conducted further to evaluate the effects of the novel variations. Specifically, in the 48 patients with mutations in the PCCA gene, three patients exhibited one mutation. In the 79 patients with mutations in the PCCB gene, six patients exhibited one mutation. Furthermore, one patient had one mutation in the PCCA gene and one mutation in the PCCB gene, without a third mutation in either the PCCA gene or PCCB gene. All the ten cases had classical clinical or biochemical manifestations of PA. In our study, the PCCA and PCCB gene tests were performed mainly by high-throughput next-generation sequencing or Sanger sequencing, which can discover variations of a single base or a few bases. Multiplex ligation-dependent probe amplification (MLPA) was performed in only a few of the patients in our cohort, through which we detected only four exon deletions in the PCCA gene and two exon deletions in the PCCB gene. We speculate that exon deletion or intron variations might exist on another allele in the ten patients, which we plan to identify in the future. This study had limitations. First, the treatment records of some patients were not detailed enough. Many parents could not remember all the drugs the patients had used when they came to our clinic. In the future, we will collect the clinical information in as detailed a manner as possible. Furthermore, some mutations were found in only a few patients. The limited number of homozygous patients and the high frequency of compound heterozygous patients made it difficult to assess the precise relationship between these variations and their clinical phenotypes. Conclusion The present study enrolled a large cohort of 133 PA patients with different phenotypes and genotypes. Disease onset was usually early with various nonspecific symptoms. A total of 248 variations (95 in the PCCA gene and 153 in the PCCB gene) were detected in these patients, including 84 novel variations (43 in the PCCA gene and 40 in the PCCB gene), with common mutations and an expanded variation spectrum in the PCCA and PCCB genes. The c.2002G > A variant in the PCCA gene was associated with a relatively serious phenotype, while the c.1087T > C variant in the PCCB gene was associated with a relatively mild phenotype. The overall prognosis of these patients was poor, with more than one-third of the patients exhibiting developmental delays, nearly one-quarter of the patients dying and only one-quarter of the patients remaining healthy. Among the patients, the group that underwent NBS had a better prognosis than the group that did not undergo NBS. These results provide clinical experience for clinicians. This study helps to improve the understanding of the clinical manifestation and genetic background of PA in Chinese patients. MS/MS expanded NBS and gene sequencing facilitate early diagnosis and treatment for PA and should be promoted further. Abbreviations C2 acetylcarnitine C3 propionylcarnitine GC‒MS gas chromatography‒mass spectrometry MCA methylcitric acid MS/MS tandem mass spectrometry 3-OHPA 3-hydroxypropionic acid PA Propionic Acidemia Declarations Ethics approval and consent to participate This study was approved by the Ethics Committee of Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (Approval number: XHEC-D-2023-029). Informed consent was obtained from all individual participants included in the study. Consent for publication The manuscript does not contain personal identification information that can be match to individuals, such as name, sex and images. The authors affirm that the participants provided informed consent for publication of the research. Availability of data and materials All data generated or analyzed during this study are included in the published article and also be available from the corresponding author on reasonable request. Competing interests The authors declare that there is no conflict of interest about this article. Funding This work was supported by the Scientific Research Project Plan of Shanghai Municipal Health Commission (No.202040448, No.202140346) and the National Natural Science Foundation of China (No.81600701). Authors' contributions LLL, as the doctor of many of these patients, contributed to reorganizing and analyzing the clinical data of the patients and drafting the manuscript. YHH contributed to collecting and reorganizing the clinical data of the patients and revising the manuscript. YY and SYL contributed to collecting the clinical data of the patients. WJQ, JY, HWZ, DYL, YGY, and XFG contributed to collecting and treating the patients and providing the clinical data. WJJ and FX contributed to the detection of the blood acylcarnitines of the patients by MS/MS. XZ and YCL contributed to the detection of the urinary organic acids of the patients by GC‒MS. ZWG contributed to gene variation analysis. LSH, as the doctor of most of the patients, contributed to the research design, treating the patients, providing the clinical data and revising the manuscript. Acknowledgements We acknowledge all patients and families for their participation in this study. References Ramsay J, Morton J, Norris M, Kanungo S. Organic acid disorders. Ann Transl Med. 2018;6:472. Wongkittichote P, Ah Mew N, Chapman KA. Propionyl-CoA carboxylase - A review. Mol Genet Metab. 2017;122:145–52. Baumgartner MR, Horster F, Dionisi-Vici C, Haliloglu G, Karall D, Chapman KA, et al. Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia. Orphanet J Rare Dis. 2014;9:130. Grunert SC, Mullerleile S, De Silva L, Barth M, Walter M, Walter K, et al. Propionic acidemia: clinical course and outcome in 55 pediatric and adolescent patients. Orphanet J Rare Dis. 2013;8:6. Riemersma M, Hazebroek MR, Helderman-van den Enden A, Salomons GS, Ferdinandusse S, Brouwers M, et al. Propionic acidemia as a cause of adult-onset dilated cardiomyopathy. Eur J Hum Genet. 2017;25:1195–201. Fraser JL, Venditti CP. Methylmalonic and propionic acidemias: clinical management update. Curr Opin Pediatr. 2016;28:682–93. Pena L, Franks J, Chapman KA, Gropman A, Ah Mew N, Chakrapani A, et al. Natural history of propionic acidemia. Mol Genet Metab. 2012;105:5–9. Cappuccio G, Atwal PS, Donti TR, Ugarte K, Merchant N, Craigen WJ, et al. Expansion of the Phenotypic Spectrum of Propionic Acidemia with Isolated Elevated Propionylcarnitine. JIMD Rep. 2017;35:33–7. Ravn K, Chloupkova M, Christensen E, Brandt NJ, Simonsen H, Kraus JP, et al. 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Unexpectedly high prevalence of the mild form of propionic acidemia in Japan: presence of a common mutation and possible clinical implications. Hum Genet. 2002;111:161–5. Liu Y, Chen Z, Dong H, Ding Y, He R, Kang L, et al. Analysis of the relationship between phenotypes and genotypes in 60 Chinese patients with propionic acidemia: a fourteen-year experience at a tertiary hospital. Orphanet J Rare Dis. 2022;17:135. Supplementary Files HGVSPCCA.xlsx HGVSPCCB.xlsx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3819961","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":267008162,"identity":"821552a3-fbdb-47a1-8260-5dd3a131571f","order_by":0,"name":"Lili 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Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yuhui","middleName":"","lastName":"Hu","suffix":""},{"id":267008164,"identity":"b13b3b8e-671f-44fb-a41a-c8b47408fa87","order_by":2,"name":"Yue Yu","email":"","orcid":"","institution":"Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine: Shanghai Jiaotong University School of Medicine Xinhua Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yue","middleName":"","lastName":"Yu","suffix":""},{"id":267008165,"identity":"4ce33c30-0a51-44d6-b425-b58e4a9625ee","order_by":3,"name":"Shiying Ling","email":"","orcid":"","institution":"Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine: Shanghai Jiaotong University School of Medicine Xinhua Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shiying","middleName":"","lastName":"Ling","suffix":""},{"id":267008166,"identity":"a1e2f278-1974-47e4-954b-016c3f67ff46","order_by":4,"name":"Wenjuan Qiu","email":"","orcid":"","institution":"Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine: Shanghai Jiaotong University School of Medicine Xinhua Hospital","correspondingAuthor":false,"prefix":"","firstName":"Wenjuan","middleName":"","lastName":"Qiu","suffix":""},{"id":267008167,"identity":"e3fcb744-c0f6-48d4-86af-c9300d85f387","order_by":5,"name":"Jun Ye","email":"","orcid":"","institution":"Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine: Shanghai Jiaotong University School of Medicine Xinhua Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jun","middleName":"","lastName":"Ye","suffix":""},{"id":267008168,"identity":"5b0852ba-32f4-4a41-9126-30e4027efb9b","order_by":6,"name":"Huiwen Zhang","email":"","orcid":"","institution":"Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine: Shanghai Jiaotong University School of Medicine Xinhua Hospital","correspondingAuthor":false,"prefix":"","firstName":"Huiwen","middleName":"","lastName":"Zhang","suffix":""},{"id":267008169,"identity":"a9a0ead2-84d4-4788-8c88-e3f4ffdd5982","order_by":7,"name":"Deyun Lu","email":"","orcid":"","institution":"Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine: Shanghai Jiaotong University School of Medicine Xinhua Hospital","correspondingAuthor":false,"prefix":"","firstName":"Deyun","middleName":"","lastName":"Lu","suffix":""},{"id":267008170,"identity":"369395fe-e218-4315-9c18-8455f4d699b6","order_by":8,"name":"Zhuwen Gong","email":"","orcid":"","institution":"Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine: Shanghai Jiaotong University School of Medicine Xinhua Hospital","correspondingAuthor":false,"prefix":"","firstName":"Zhuwen","middleName":"","lastName":"Gong","suffix":""},{"id":267008171,"identity":"08027cd9-5bf5-480f-8033-1d36cd009ba1","order_by":9,"name":"Xia Zhan","email":"","orcid":"","institution":"Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine: Shanghai Jiaotong University School of Medicine Xinhua Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xia","middleName":"","lastName":"Zhan","suffix":""},{"id":267008172,"identity":"9d5133be-733d-4b29-9038-ab5c572fdb99","order_by":10,"name":"Wenjun Ji","email":"","orcid":"","institution":"Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine: Shanghai Jiaotong University School of Medicine Xinhua Hospital","correspondingAuthor":false,"prefix":"","firstName":"Wenjun","middleName":"","lastName":"Ji","suffix":""},{"id":267008173,"identity":"3ed3391a-f289-4311-a97b-0dc283a43deb","order_by":11,"name":"Feng Xu","email":"","orcid":"","institution":"Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine: Shanghai Jiaotong University School of Medicine Xinhua Hospital","correspondingAuthor":false,"prefix":"","firstName":"Feng","middleName":"","lastName":"Xu","suffix":""},{"id":267008174,"identity":"b43ab657-cd6e-4e27-ae4d-e78e8d5df667","order_by":12,"name":"Yuchao Liu","email":"","orcid":"","institution":"Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine: Shanghai Jiaotong University School of Medicine Xinhua Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yuchao","middleName":"","lastName":"Liu","suffix":""},{"id":267008175,"identity":"02954108-abf3-4226-957f-fae36d0594ae","order_by":13,"name":"Yongguo Yu","email":"","orcid":"","institution":"Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine: Shanghai Jiaotong University School of Medicine Xinhua Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yongguo","middleName":"","lastName":"Yu","suffix":""},{"id":267008176,"identity":"aa4c90bf-4f26-4cae-8459-fd3ecb6708a4","order_by":14,"name":"Xuefan Gu","email":"","orcid":"","institution":"Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine: Shanghai Jiaotong University School of Medicine Xinhua Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xuefan","middleName":"","lastName":"Gu","suffix":""},{"id":267008177,"identity":"2b7c2ba1-9e35-4bdf-beb2-c06d9373977d","order_by":15,"name":"Lianshu Han","email":"","orcid":"https://orcid.org/0000-0003-4209-5119","institution":"Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine: Shanghai Jiaotong University School of Medicine Xinhua Hospital","correspondingAuthor":false,"prefix":"","firstName":"Lianshu","middleName":"","lastName":"Han","suffix":""}],"badges":[],"createdAt":"2023-12-29 07:11:57","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3819961/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3819961/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":49710511,"identity":"820f6766-a7c8-48df-a83c-8c6783e77050","added_by":"auto","created_at":"2024-01-16 19:43:13","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":292499,"visible":true,"origin":"","legend":"\u003cp\u003eThe variation spectrum in the \u003cem\u003ePCCA\u003c/em\u003egene (a) and \u003cem\u003ePCCB\u003c/em\u003e gene (b).\u003c/p\u003e","description":"","filename":"OnlineFigure1.png","url":"https://assets-eu.researchsquare.com/files/rs-3819961/v1/3e806bbba2234b124ed657a5.png"},{"id":49710510,"identity":"d7a6a96b-4568-4e72-b451-919fa2679cc9","added_by":"auto","created_at":"2024-01-16 19:43:13","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":22269,"visible":true,"origin":"","legend":"\u003cp\u003eSummary of the newborn screening status, disease onset, and clinical outcome data for the participants in this study.\u003c/p\u003e\n\u003cp\u003eDD: developmental delay.\u003c/p\u003e","description":"","filename":"OnlineFigure2.png","url":"https://assets-eu.researchsquare.com/files/rs-3819961/v1/d540d5bd212d04791b5ffa0b.png"},{"id":55870422,"identity":"88eba703-5d80-4700-bc96-737bd37aa5b6","added_by":"auto","created_at":"2024-05-05 11:44:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1894414,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3819961/v1/6c204d7f-5457-41e4-a94b-37216601cc37.pdf"},{"id":49711093,"identity":"ad5087da-a8c0-4e9a-9280-72391a0971db","added_by":"auto","created_at":"2024-01-16 19:51:13","extension":"xlsx","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":17369,"visible":true,"origin":"","legend":"","description":"","filename":"HGVSPCCA.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-3819961/v1/bf306d7df9e380f6f4d53fa4.xlsx"},{"id":49710513,"identity":"6392cd74-61f5-41e4-9769-e0bfd73ce7b6","added_by":"auto","created_at":"2024-01-16 19:43:13","extension":"xlsx","order_by":9,"title":"","display":"","copyAsset":false,"role":"supplement","size":17814,"visible":true,"origin":"","legend":"","description":"","filename":"HGVSPCCB.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-3819961/v1/25c0c5df72b56ebb4defe108.xlsx"}],"financialInterests":"","formattedTitle":"Evaluation of the Clinical, Biochemical, Genotype, and Prognosis of Propionic Acidemia in 133 Patients from China","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePropionic acidemia (PA) is a rare autosomal recessive inherited organic acid metabolic disorder (OMIM 606054). The primary defect occurs in propionyl-CoA carboxylase (EC 6.4.1.3), which catalyzes the carboxylation of propionyl-CoA with bicarbonate, producing methylmalonyl-CoA, which is then converted to succinyl-CoA [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The reduction or absence of propionyl-CoA carboxylase activity results in the accumulation of propionyl-CoA, which is spontaneously converted to propionylcarnitine (C3), propionic acid, and other organic acids, including 3-hydroxypropionic acid (3-OHPA) and methylcitric acid (MCA), which also accumulate and are excreted in the urine of affected patients [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e–\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe accumulation of these abnormal acidic metabolites causes various clinical symptoms, ranging from severe early onset (onset before three months old) with high mortality to milder late onset (onset after three months old) with elevated morbidity. Patients with the early-onset form may present with progressive encephalopathy in the first days of life manifested as lethargy, seizures, and coma that may progress to death if it is not diagnosed and treated promptly. Late-onset patients may also present with acute encephalopathy following metabolic decompensation but usually experience a more insidious onset with the development of multiorgan complications, such as failure to thrive, vomiting, developmental delay, neurological regression and cardiomyopathy [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e–\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Long-term management is mainly based on dietary restriction of specific amino acids (isoleucine, valine, threonine, and methionine) and L-carnitine supplementation, which has been shown to partly reduce mortality but is still inadequate to prevent chronic morbidity [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e–\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe incidence of this disorder differs greatly in patients with different origins and from different regions [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The incidence in Western countries is estimated to be 1/50000 to 1/500000 [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. However, a much higher incidence is observed in isolated areas or some specific populations, such as certain tribes in Saudi Arabia, with incidences as high as 1/2000 to 1/5000 [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], and Inuits in Greenland, with a rough first-estimate incidence of 1/1000 [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Implementation of newborn screening in various countries has allowed for the estimation of birth prevalence of PA. The reported incidence of PA is 1/242,741 in the United States, 1/284450 in Southwest Germany (1/202617 in Germany nationwide), 1/59426 in Kuwait [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], 1/45000 in Japan [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], and 1/195492 in mainland China [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. An expanded screening program for newborns by tandem mass spectrometry (MS/MS) is currently performed in an increasing number of regions of China. The advanced use of MS/MS and gene detection is greatly beneficial for the proper and timely diagnosis of PA.\u003c/p\u003e \u003cp\u003ePropionyl-CoA carboxylase consists of two subunits, α and β, encoded by the \u003cem\u003ePCCA\u003c/em\u003e gene and \u003cem\u003ePCCB\u003c/em\u003e gene, respectively. The native enzyme is believed to have an α6β6 conformation. Deficiency of the enzyme due to mutations in either of the two genes results in PA. The \u003cem\u003ePCCA\u003c/em\u003e gene is located on chromosome 13q32 and encodes a polypeptide of 703 amino acids, while the \u003cem\u003ePCCB\u003c/em\u003e gene is located on chromosome 3q13.3-q22 and encodes a polypeptide of 539 amino acids. It was reported that mutations in the \u003cem\u003ePCCA\u003c/em\u003e gene are highly heterogeneous, without common single mutations predominant in any population. However, there are limited numbers of mutations in the \u003cem\u003ePCCB\u003c/em\u003e gene that account for most of the patients in different ethnic groups [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSince the first report of PA by Childs et al. in 1961 [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], research on its clinical manifestations, biochemical characteristics, diagnosis and treatment strategies has continuously improved. Concern about this disease started late in China. Although related reports have increased gradually in recent years, patients might be misdiagnosed or missed due to the lack of specific clinical manifestations. In the present study, we investigated 133 PA patients from our department at Shanghai Xinhua Hospital during the last 18 years, from 2004 to 2022. We performed a retrospective chart review of their clinical data in detail, including metabolites, molecular diagnosis, treatment, and outcomes, and aimed to investigate the clinical phenotype and the genotype of the disease, providing clinical experience for clinicians.\u003c/p\u003e "},{"header":"Methods","content":"\u003ch2\u003e1. Patients\u003c/h2\u003e\u003cp\u003eFrom 2004 to 2022, a total of 133 PA patients were diagnosed and treated at the Department of Pediatric Endocrinology/Genetics, Shanghai Xinhua Hospital. We reviewed the clinical and biochemical phenotypes, genotypes and outcomes of patients in detail. Written informed consent was obtained from the parents of the study participants. This study was approved by the Ethics Committee of Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (approval ID: XHEC-D-2023-029).\u003c/p\u003e\u003ch3\u003e2. Detection of metabolites\u003c/h3\u003e\u003cp\u003eBlood levels of acylcarnitines, including C3 and acetylcarnitine (C2), were detected by MS/MS (API 4000, American Bio-Systems Inc.) using blood filter papers. Urinary organic acids, including 3-OHPA and MCA, were measured by gas chromatography‒mass spectrometry (GC‒MS) (Shimadzu Limited, QP2010) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e\u003ch2\u003e3. Gene mutation detection and evaluation\u003c/h2\u003e\u003cp\u003e \u003cem\u003ePCCA\u003c/em\u003e and \u003cem\u003ePCCB\u003c/em\u003e were detected by Sanger sequencing or high-throughput next-generation sequencing. Mutations were identified using the normal human \u003cem\u003ePCCA\u003c/em\u003e and \u003cem\u003ePCCB\u003c/em\u003e sequences as a reference (NM_000282.4 and NM_000532.5, respectively). We used the ClinVar database, the HGMD database and the previous literature to identify whether the mutations had been reported. The pathogenicity of the missense mutations was predicted by Mutation Taster, PolyPhen-2, Proven and SIFT software.\u003c/p\u003e\u003ch3\u003e4. Diagnosis and treatment\u003c/h3\u003e\u003cp\u003eThe diagnosis of PA was based on increases in blood C3, blood C3/C2 ratio, urine 3-OHPA, and urine MCA or the detection of mutations in the gene encoding propionyl-CoA carboxylase. In the stable stage, PA was mainly treated by L-carnitine and a diet low in isoleucine, valine, threonine, and methionine. In the acute stage, maintaining the stability of the internal environment and symptomatic treatment were the focus, including limiting protein intake, supplementing energy with glucose and lipids, and administering an intravenous drip of L-carnitine and sodium bicarbonate to promote abnormal metabolite excretion and correct metabolic acidosis. Children with hyperammonemia were given arginine, sodium benzoate, sodium phenylbutyrate arginine and even extracorporeal detoxification, according to the degree of hyperammonemia [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e\u003ch3\u003e5. Prognosis evaluation\u003c/h3\u003e\u003cp\u003eClinical follow-up parameters were used to assess basic motor function and language development. Based on prognosis, the patients were divided into healthy and developmental delay groups. The healthy patients exhibited no significant disability in daily life, while the developmental delay patients presented with delayed achievement of motor and/or speech milestones, including the need for support when walking and being unable to communicate or pronounce words effectively.\u003c/p\u003e\u003ch2\u003e6. Statistical analysis\u003c/h2\u003e\u003cp\u003eNormally distributed measurement data were evaluated statistically by using Student’s t test, while nonnormally distributed data were analyzed by the Wilcoxon rank-sum test. The comparison of rates was performed by the chi-square test. Statistical analyses were performed using GraphPad Prism 5 software (GraphPad Software Inc., San Diego, CA, USA). A \u003cem\u003ep\u003c/em\u003e value of \u0026lt; 0.05 was considered a significant difference between two groups.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e1. Clinical features\u003c/h2\u003e \u003cp\u003eThis study recruited 133 individuals with a confirmed PA diagnosis. There were 86 boys and 47 girls. The median follow-up age was 4.15 years old, ranging from two months to 18 years and three months old.\u003c/p\u003e \u003cp\u003eA total of 36 (27.1%) affected individuals were identified by the MS/MS expanded NBS project. Among them, disease onset occurred in 22 cases, while 13 cases did not, and the remaining one case was lost to follow-up and we were not sure if the patient experienced disease onset. The remaining 97 patients were diagnosed by onset of the disease (96 cases) or sibling MMA diagnosis (one case, without disease onset). In total, 118 patients (22 with NBS, 96 without NBS) showed disease onset, with a median age of disease onset of four months old, ranging from one day after birth to six years and three months old. Except for the nine cases whose specific onset time was unknown, 27 cases showed disease onset within three months after birth, 59 cases showed disease onset between three months and 12 months old, 18 cases showed disease onset between one year and three years old, and five cases showed onset after three years old. Therefore, early-onset type patients (onset within three months old) accounted for 24.8% (27/109), while late-onset type patients (onset after three months old) accounted for 75.2% (82/109). Most of the patients showed acute disease onset, with nonspecific symptoms, including vomiting, diarrhea, difficulty feeding, jaundice, lethargy, convulsion, muscle weakness, mental retardation, and coma, accompanied by metabolic acidosis, hypoglycemia, hyperlactatemia and hyperammonemia. In addition, some patients showed progressive mental retardation instead of acute disease onset.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003e2 Biochemical features\u003c/h3\u003e\n\u003cp\u003eThe blood C3 levels, the C3/C2 ratio, and the urinary 3-OHPA and MCA levels before and after treatment in the patients were evaluated statistically as biochemical markers and are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. In the primary state before treatment, the blood C3 levels, C3/C2 ratio, and urinary 3-OHPA and MCA levels in patients showed obvious increases above the normal range. After treatment, the C3/C2 ratio and the levels of urinary 3-OHPA decreased compared with those before treatment, with a significant difference. However, the level of blood C3 increased after treatment compared with that before treatment, with a significant difference. The MCA level showed no significant difference before and after treatment.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBiochemical Characteristics in Mass Spectrometry of the PA Patients Before and After Treatment\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eC3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003eC3/C2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eMethylmalonic Acid\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003eMethylcitric acid\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBefore\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAfter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBefore\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAfter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBefore\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAfter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eBefore\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eAfter\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12.93\u003c/p\u003e \u003cp\u003e(2.58, 56.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19.50\u003c/p\u003e \u003cp\u003e(3.76, 83.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.31\u003c/p\u003e \u003cp\u003e(0.15, 6.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.12\u003c/p\u003e \u003cp\u003e(0.13, 4.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e55.93\u003c/p\u003e \u003cp\u003e(0.00, 715.70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e19.96\u003c/p\u003e \u003cp\u003e(0.00,1118.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e26.10\u003c/p\u003e \u003cp\u003e(0.40, 240.30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e23.28\u003c/p\u003e \u003cp\u003e(1.40, 283.20)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;122\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;114\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;122\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;114\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;104\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;112\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;107\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;112\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0416\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0049\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.3063\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003eTypical reference range of C3: 0.50-4.00 \u0026micro;mol/L; typical reference range of C3/C2: 0.04\u0026ndash;0.25; typical reference range of 3-OHPA: 0\u0026ndash;4 mmol/mol creatinine; typical reference range of methylcitric acid: 0-0.8 mmol/mol creatinine.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3 Genetic analysis\u003c/h2\u003e \u003cp\u003eA total of 128 patients were sequenced for the \u003cem\u003ePCCA\u003c/em\u003e gene and \u003cem\u003ePCCB\u003c/em\u003e gene. Forty-four patients exhibited two compound heterozygous or homozygous variations in the \u003cem\u003ePCCA\u003c/em\u003e gene. One patient with three variations in their two alleles of \u003cem\u003ePCCA\u003c/em\u003e gene and three patients exposed only one variant in the \u003cem\u003ePCCA\u003c/em\u003e gene. Meanwhile, 73 patients exhibited two compound heterozygous or homozygous variations in the \u003cem\u003ePCCB\u003c/em\u003e gene, and six patients exposed only one variant. Unusually, one patient with typical clinical manifestations and a biochemical phenotype carried one variant in the \u003cem\u003ePCCA\u003c/em\u003e gene (c.1676G\u0026thinsp;\u0026gt;\u0026thinsp;T) and one variant in the \u003cem\u003ePCCB\u003c/em\u003e gene (c.1087T\u0026thinsp;\u0026gt;\u0026thinsp;C).\u003c/p\u003e \u003cp\u003eIn the \u003cem\u003ePCCA\u003c/em\u003e gene, 95 variations, of 60 kinds, were exposed in 94 alleles. The variations and their pathogenicity ratings are described in detail in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The 60 specific variations and their respective proportions are described in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea, including 21 missense variants (35.0%), 11 nonsense variants (18.3%), 11 frameshift variants (18.3%), eight splicing variants (13.3%), four exon deletions (6.7%), three synonymous variants (5.0%), and two small deletions (3.3%). The most frequent variant was c.2002G\u0026thinsp;\u0026gt;\u0026thinsp;A (20/95, 21.1%), followed by c.229C\u0026thinsp;\u0026gt;\u0026thinsp;T (7/95, 7.4%), c.1118T\u0026thinsp;\u0026gt;\u0026thinsp;A (5/95, 5.3%), c.1288C\u0026thinsp;\u0026gt;\u0026thinsp;T (4/95, 4.2%), and c.1961T\u0026thinsp;\u0026gt;\u0026thinsp;A (2/95, 2.1%). A total of six patients carried homozygous variants. Three patients carried homozygous c.2002G\u0026thinsp;\u0026gt;\u0026thinsp;A. One patient each was homozygous for c.229C\u0026thinsp;\u0026gt;\u0026thinsp;T, c.1118T\u0026thinsp;\u0026gt;\u0026thinsp;A, and c.1961T\u0026thinsp;\u0026gt;\u0026thinsp;A. Among the 60 variations, 43 novel variants were identified (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSummary of Variations Found in the \u003cem\u003ePCCA\u003c/em\u003e Gene\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariations\u003c/p\u003e \u003cp\u003eNo.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eExon/\u003c/p\u003e \u003cp\u003eintron\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNucleotide\u003c/p\u003e \u003cp\u003echange\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePredicted\u003c/p\u003e \u003cp\u003eProtein change\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNumbers of homozygous case\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNumbers of heterozygous case\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eVariation Frequency\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eGrade of\u003c/p\u003e \u003cp\u003ePathogenicity\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003ec.2T\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.M1K\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.05%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ePM2\u0026thinsp;+\u0026thinsp;PP3\u0026thinsp;+\u0026thinsp;PP4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003ec.39del\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.A14Pfs*12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.05%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eP(PM2\u0026thinsp;+\u0026thinsp;PVS1\u0026thinsp;+\u0026thinsp;PP4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003ec.43G\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.G15*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.05%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eP(PM2\u0026thinsp;+\u0026thinsp;PVS1\u0026thinsp;+\u0026thinsp;PP4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003ec.59G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP.W20*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.05%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eP(PM2\u0026thinsp;+\u0026thinsp;PVS1\u0026thinsp;+\u0026thinsp;PP4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eI1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003ec.106-2A\u0026thinsp;\u0026gt;\u0026thinsp;G\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSplicing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.05%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eP(PM2\u0026thinsp;+\u0026thinsp;PVS1\u0026thinsp;+\u0026thinsp;PP4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003ec.117C\u0026thinsp;\u0026gt;\u0026thinsp;G\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.Y39*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.05%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eP(PM2\u0026thinsp;+\u0026thinsp;PVS1\u0026thinsp;+\u0026thinsp;PP4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e 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align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.L51F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.05%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLP(PM2\u0026thinsp;+\u0026thinsp;PM3\u0026thinsp;+\u0026thinsp;PP4\u0026thinsp;+\u0026thinsp;PM1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003ec.216del\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eE73Kfs*31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.05%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eP(PM2\u0026thinsp;+\u0026thinsp;PVS1\u0026thinsp;+\u0026thinsp;PP4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.229C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.R77W\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e 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\u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.05%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eP(PM2\u0026thinsp;+\u0026thinsp;PVS1\u0026thinsp;+\u0026thinsp;PP4\u0026thinsp;+\u0026thinsp;PM5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003ec.289G\u0026thinsp;\u0026gt;\u0026thinsp;C\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.D97H\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.05%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLP(PM2\u0026thinsp;+\u0026thinsp;PP3\u0026thinsp;+\u0026thinsp;PP4\u0026thinsp;+\u0026thinsp;PM1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003ec.305del\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.H102Lfs*2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.05%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eP(PM2\u0026thinsp;+\u0026thinsp;PVS1\u0026thinsp;+\u0026thinsp;PP4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.317C\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.A106E\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.05%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e 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colname=\"c1\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eI10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003ec.819\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSplicing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.05%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eP(PM2\u0026thinsp;+\u0026thinsp;PVS1\u0026thinsp;+\u0026thinsp;PP4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e 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colname=\"c7\"\u003e \u003cp\u003e1.05%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLP(PM1\u0026thinsp;+\u0026thinsp;PM2\u0026thinsp;+\u0026thinsp;PP3\u0026thinsp;+\u0026thinsp;PP4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.1118T\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.M373K\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5.26%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eP(PM2\u0026thinsp;+\u0026thinsp;PP3\u0026thinsp;+\u0026thinsp;PP4\u0026thinsp;+\u0026thinsp;PM1\u0026thinsp;+\u0026thinsp;PM3_STR)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003ec.1147dup\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.R383Kfs*6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.05%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e 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colname=\"c1\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003ec.1196G\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.R399L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.05%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eP(PM5_STR\u0026thinsp;+\u0026thinsp;PM2\u0026thinsp;+\u0026thinsp;PP4\u0026thinsp;+\u0026thinsp;PP3\u0026thinsp;+\u0026thinsp;PM3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e 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\u003cp\u003ec.1284\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSplicing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.05%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eP(PM2\u0026thinsp;+\u0026thinsp;PVS1\u0026thinsp;+\u0026thinsp;PP4\u0026thinsp;+\u0026thinsp;PM3_STR)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e 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\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.05%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eP(PVS1\u0026thinsp;+\u0026thinsp;PP4\u0026thinsp;+\u0026thinsp;PM2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eI16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.1429\u0026thinsp;+\u0026thinsp;2T\u0026thinsp;\u0026gt;\u0026thinsp;C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSplicing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.05%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eP(PVS1\u0026thinsp;+\u0026thinsp;PP4\u0026thinsp;+\u0026thinsp;PM2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eI17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003ec.1540\u0026thinsp;+\u0026thinsp;2T\u0026thinsp;\u0026gt;\u0026thinsp;C\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSplicing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.05%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eP(PM2\u0026thinsp;+\u0026thinsp;PVS1\u0026thinsp;+\u0026thinsp;PP4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.1593_1595del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.L532del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.05%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLP(PM2\u0026thinsp;+\u0026thinsp;PM3\u0026thinsp;+\u0026thinsp;PP4\u0026thinsp;+\u0026thinsp;PM4_SUP)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.1676G\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.W559L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.05%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eVUS(BS1\u0026thinsp;+\u0026thinsp;PM1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.1746G\u0026thinsp;\u0026gt;\u0026thinsp;C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.(=)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.05%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eVUS(BP4\u0026thinsp;+\u0026thinsp;PM2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.1831C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.Q611*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.05%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eP(PVS1\u0026thinsp;+\u0026thinsp;PM2\u0026thinsp;+\u0026thinsp;PP4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.1863del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.G622Vfs*4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.05%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eP(PVS1\u0026thinsp;+\u0026thinsp;PM2\u0026thinsp;+\u0026thinsp;PP4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.2002G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.G668R\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e21.05%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLP(PM2_SUP\u0026thinsp;+\u0026thinsp;PM3_STR\u0026thinsp;+\u0026thinsp;PP3\u0026thinsp;+\u0026thinsp;PP4\u0026thinsp;+\u0026thinsp;PM1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003ec.1961T\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.V654E\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.11%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eVUS(PM2\u0026thinsp;+\u0026thinsp;BP4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003ec.2149_2157dup\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.T717_G719dup\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.05%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLP(PM2\u0026thinsp;+\u0026thinsp;PM4\u0026thinsp;+\u0026thinsp;PM3\u0026thinsp;+\u0026thinsp;PP4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE3-E4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003edeletion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.05%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eP(PM2\u0026thinsp;+\u0026thinsp;PVS1\u0026thinsp;+\u0026thinsp;PP4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003edeletion\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.05%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eP(PM2\u0026thinsp;+\u0026thinsp;PVS1\u0026thinsp;+\u0026thinsp;PP4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE9-E22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003edeletion\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.05%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eP(PM2\u0026thinsp;+\u0026thinsp;PVS1\u0026thinsp;+\u0026thinsp;PP4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003edeletion\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.05%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eP(PM2\u0026thinsp;+\u0026thinsp;PVS1\u0026thinsp;+\u0026thinsp;PP4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e100.00%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003eNew variants are indicated in bold. P: pathogenic; LP: likely pathogenic; VUS: variant of unknown significance.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn the \u003cem\u003ePCCB\u003c/em\u003e gene, 153 variations, of 64 different kinds, were exposed in 153 alleles. The variations and their pathogenicity ratings are described in detail in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. The specific variations and respective proportions of the 64 variations are described in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb, including 36 missense variants (55.4%), 10 frameshift variants (15.4%), seven splicing variants (10.8%), 6 nonsense variants (9.2%), two exon deletions (3.1%), two small deletion-insertions (3.1%), one synonymous variant (1.5%) and one small deletion (1.5%). The most frequent variant was c.1087T\u0026thinsp;\u0026gt;\u0026thinsp;C (27/153, 17.6%), followed by c.838dup (13/153, 8.5%), c.1228C\u0026thinsp;\u0026gt;\u0026thinsp;T (7/153, 4.6%), c.1316A\u0026thinsp;\u0026gt;\u0026thinsp;G (6/153, 3.9%), c.331C\u0026thinsp;\u0026gt;\u0026thinsp;T (6/153, 3.9%) and c.167_179delinsC (6/153, 3.9%). A total of eight patients carried homozygous variants. Four patients carried homozygous c.1087T\u0026thinsp;\u0026gt;\u0026thinsp;C. One patient each was homozygous for c.1316A\u0026thinsp;\u0026gt;\u0026thinsp;G, c.167_179delinsC, c.1535G\u0026thinsp;\u0026gt;\u0026thinsp;A, and c.1599A\u0026thinsp;\u0026gt;\u0026thinsp;C. Among the 64 variations, 40 novel variants were identified (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSummary of Variations Found in the \u003cem\u003ePCCB\u003c/em\u003e Gene\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariations\u003c/p\u003e \u003cp\u003eNo.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eExon/\u003c/p\u003e \u003cp\u003eintron\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNucleotide\u003c/p\u003e \u003cp\u003echange\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePredicted\u003c/p\u003e \u003cp\u003eProtein change\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNumbers of homozygous case\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNumbers of heterozygous case\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eVariation Frequency\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eGrade of\u003c/p\u003e \u003cp\u003ePathogenicity\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUTR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003ec.-2A\u0026thinsp;\u0026gt;\u0026thinsp;G\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSplicing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.31%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eVUS(PM2\u0026thinsp;+\u0026thinsp;PM3\u0026thinsp;+\u0026thinsp;PP4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.2T\u0026thinsp;\u0026gt;\u0026thinsp;C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.M1T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.65%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLP(PM2\u0026thinsp;+\u0026thinsp;PM3\u0026thinsp;+\u0026thinsp;PP3\u0026thinsp;+\u0026thinsp;PP4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.31-40del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.G11Sfs*51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.31%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eP(PVS1\u0026thinsp;+\u0026thinsp;PM2\u0026thinsp;+\u0026thinsp;PP4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.146del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.G49Efs*16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.65%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eP(PVS1\u0026thinsp;+\u0026thinsp;PM2\u0026thinsp;+\u0026thinsp;PP4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.167_179delinsC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.D56_K60delinsA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.92%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLP(PM4\u0026thinsp;+\u0026thinsp;PM2\u0026thinsp;+\u0026thinsp;PP4\u0026thinsp;+\u0026thinsp;PM3_SUP)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003ec.168_179del\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.D56_K60delinsE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.31%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLP(PM4\u0026thinsp;+\u0026thinsp;PM2\u0026thinsp;+\u0026thinsp;PP4\u0026thinsp;+\u0026thinsp;PM3_SUP)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eI1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003ec.184-2A\u0026thinsp;\u0026gt;\u0026thinsp;G\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSplicing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.96%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eP(PVS1\u0026thinsp;+\u0026thinsp;PM2\u0026thinsp;+\u0026thinsp;PP4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003ec.223G\u0026thinsp;\u0026gt;\u0026thinsp;C\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.D75H\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.31%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLP(PM2\u0026thinsp;+\u0026thinsp;PP3\u0026thinsp;+\u0026thinsp;PP4\u0026thinsp;+\u0026thinsp;PM2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003ec.224 A\u0026thinsp;\u0026gt;\u0026thinsp;C\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.D75A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.65%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLP(PP3\u0026thinsp;+\u0026thinsp;PP4\u0026thinsp;+\u0026thinsp;PM2\u0026thinsp;+\u0026thinsp;PM1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.331C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.R111*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.92%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eP(PVS1\u0026thinsp;+\u0026thinsp;PM2\u0026thinsp;+\u0026thinsp;PP4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.337C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.R113*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.61%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eP(PM2_SUP\u0026thinsp;+\u0026thinsp;PP4\u0026thinsp;+\u0026thinsp;PVS1\u0026thinsp;+\u0026thinsp;PM3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003ec.369_372del\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.S123Rfs*26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.96%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eP(PVS1\u0026thinsp;+\u0026thinsp;PM2\u0026thinsp;+\u0026thinsp;PP4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003ec.370C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.Q124*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" 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colname=\"c8\"\u003e \u003cp\u003eP(PVS1\u0026thinsp;+\u0026thinsp;PM2\u0026thinsp;+\u0026thinsp;PP4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.391G\u0026thinsp;\u0026gt;\u0026thinsp;C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.G131R\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.65%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e 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align=\"left\" colname=\"c1\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.562G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.G188R\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.65%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eP(PM2\u0026thinsp;+\u0026thinsp;PM3_STR\u0026thinsp;+\u0026thinsp;PP3\u0026thinsp;+\u0026thinsp;PP4\u0026thinsp;+\u0026thinsp;PM1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e20\u003c/p\u003e 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align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.L280Pfs*11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e8.49%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eP(PVS1\u0026thinsp;+\u0026thinsp;PM2\u0026thinsp;+\u0026thinsp;PP4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003ec.839dup\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.S281Efs*10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.31%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eP(PVS1\u0026thinsp;+\u0026thinsp;PM2\u0026thinsp;+\u0026thinsp;PP4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003ec.839del\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.L280Rfs*68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e 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colname=\"c1\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003ec.1076C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.P359L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.65%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLP(PM2\u0026thinsp;+\u0026thinsp;PP3\u0026thinsp;+\u0026thinsp;PP4\u0026thinsp;+\u0026thinsp;PM1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e 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colname=\"c2\"\u003e \u003cp\u003eI10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003ec.1091-2A\u0026thinsp;\u0026gt;\u0026thinsp;G\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSplicing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.65%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eP(PM2\u0026thinsp;+\u0026thinsp;PVS1\u0026thinsp;+\u0026thinsp;PP3\u0026thinsp;+\u0026thinsp;PP4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE11\u003c/p\u003e \u003c/td\u003e 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\u003cp\u003e\u003cb\u003ec.1112C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP.S371F\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.65%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLP(PM2\u0026thinsp;+\u0026thinsp;PP3\u0026thinsp;+\u0026thinsp;PP4\u0026thinsp;+\u0026thinsp;PM1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003ec.1150T\u0026thinsp;\u0026gt;\u0026thinsp;G\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.F384V\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.65%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLP(PM2\u0026thinsp;+\u0026thinsp;PP3\u0026thinsp;+\u0026thinsp;PP4\u0026thinsp;+\u0026thinsp;PM1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e 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align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.P399R\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.31%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLP(PM2_SUP\u0026thinsp;+\u0026thinsp;PM3\u0026thinsp;+\u0026thinsp;PM1\u0026thinsp;+\u0026thinsp;PP3\u0026thinsp;+\u0026thinsp;PP4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.1220del\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.G407Afs*36\u003c/p\u003e \u003c/td\u003e 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colname=\"c6\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4.58%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eP(PM1\u0026thinsp;+\u0026thinsp;PP3\u0026thinsp;+\u0026thinsp;PP4\u0026thinsp;+\u0026thinsp;PM3_STR\u0026thinsp;+\u0026thinsp;PM2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.1229G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.R410Q\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e 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colname=\"c7\"\u003e \u003cp\u003e0.65%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLP(PM1\u0026thinsp;+\u0026thinsp;PM2\u0026thinsp;+\u0026thinsp;PP3\u0026thinsp;+\u0026thinsp;PP4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003ec.1244T\u0026thinsp;\u0026gt;\u0026thinsp;C\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.L415P\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.65%\u003c/p\u003e \u003c/td\u003e 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\u003cp\u003eLP(PP3\u0026thinsp;+\u0026thinsp;PM1\u0026thinsp;+\u0026thinsp;PM2\u0026thinsp;+\u0026thinsp;PP4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003ec.1373C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.A458V\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.65%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLP(PP3\u0026thinsp;+\u0026thinsp;PM2\u0026thinsp;+\u0026thinsp;PP4\u0026thinsp;+\u0026thinsp;PM3\u0026thinsp;+\u0026thinsp;PM1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.1495C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.R499*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.96%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLP(PVS1_M\u0026thinsp;+\u0026thinsp;PM2\u0026thinsp;+\u0026thinsp;PP4\u0026thinsp;+\u0026thinsp;PM3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003ec.1497A\u0026thinsp;\u0026gt;\u0026thinsp;G\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.(=)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.65%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eVUS(PM2\u0026thinsp;+\u0026thinsp;PM5\u0026thinsp;+\u0026thinsp;PP4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eI14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003ec.1499-2A\u0026thinsp;\u0026gt;\u0026thinsp;G\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSplicing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.31%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLP(PVS1_M\u0026thinsp;+\u0026thinsp;PM2\u0026thinsp;+\u0026thinsp;PP4\u0026thinsp;+\u0026thinsp;PM3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.1535G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.R512H\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.31%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLP(PP3\u0026thinsp;+\u0026thinsp;PM5\u0026thinsp;+\u0026thinsp;PM3\u0026thinsp;+\u0026thinsp;PM2\u0026thinsp;+\u0026thinsp;PM1\u0026thinsp;+\u0026thinsp;PP4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ec.1540C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.R514*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.96%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLP(PM2\u0026thinsp;+\u0026thinsp;PVS1_M\u0026thinsp;+\u0026thinsp;PM3_STR\u0026thinsp;+\u0026thinsp;PP4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003ec.1541G\u0026thinsp;\u0026gt;\u0026thinsp;C\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP.R514P\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.65%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLP(PM1\u0026thinsp;+\u0026thinsp;PP3\u0026thinsp;+\u0026thinsp;PM5\u0026thinsp;+\u0026thinsp;PP4\u0026thinsp;+\u0026thinsp;PM2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003ec.1582C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eQ528*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.65%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLP(PVS1_M\u0026thinsp;+\u0026thinsp;PM2\u0026thinsp;+\u0026thinsp;PP4\u0026thinsp;+\u0026thinsp;PM3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003ec.1599A\u0026thinsp;\u0026gt;\u0026thinsp;C\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep.K533N\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.31%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLP(PP3\u0026thinsp;+\u0026thinsp;PP4\u0026thinsp;+\u0026thinsp;PM2\u0026thinsp;+\u0026thinsp;PM1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003edeletion\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.65%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eP(PM2\u0026thinsp;+\u0026thinsp;PVS1\u0026thinsp;+\u0026thinsp;PP4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eE1-E8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003edeletion\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.65%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eP(PM2\u0026thinsp;+\u0026thinsp;PVS1\u0026thinsp;+\u0026thinsp;PP4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e137\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e100.00%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003eNew variants are indicated in bold. P: pathogenic; LP: likely pathogenic; VUS: variant of unknown significance.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eWe selected the most common mutations in the \u003cem\u003ePCCA\u003c/em\u003e gene (c.2002G\u0026thinsp;\u0026gt;\u0026thinsp;A) and \u003cem\u003ePCCB\u003c/em\u003e gene (c.1087T\u0026thinsp;\u0026gt;\u0026thinsp;C) to track their corresponding phenotypes. For c.2002G\u0026thinsp;\u0026gt;\u0026thinsp;A in the \u003cem\u003ePCCA\u003c/em\u003e gene, there were three homozygous patients and 14 heterozygous patients. The three homozygous patients had a median disease onset age of 3 days after birth, ranging from 0 days to 16 days. In terms of prognosis, two patients died (2/3), and one patient had developmental delays (1/3). The 14 heterozygous patients had a better overall prognosis: three patients died (3/14), five patients had developmental delays (5/14), four patients remained healthy (4/14) and two patients were lost to follow-up (2/14). For c.1087T\u0026thinsp;\u0026gt;\u0026thinsp;C in the \u003cem\u003ePCCB\u003c/em\u003e gene, there were four homozygous patients and 18 heterozygous patients. The four homozygous patients had disease onset ages of three days, six months and 75 months after birth, and one patient did not have disease onset. In terms of prognosis, three patients remained healthy (3/4), and one patient had developmental delays (1/4). For the 18 heterozygous patients, eight patients remained healthy (8/18), five patients had developmental delays (5/18), two patients died (2/18), and three patients were lost to follow-up (3/18).\u003c/p\u003e \u003cp\u003eTo explore the geographical distribution of the variations in the \u003cem\u003ePCCA\u003c/em\u003e and \u003cem\u003ePCCB\u003c/em\u003e genes, we analyzed the origin of the patients and evaluated the common variations in different regions. The patients were from 23 provinces across China. The three provinces with the highest incidence were Shandong (31 cases), Jiangsu (21 cases) and Zhejiang provinces (14 cases), which accounted for 49.6% of all 133 patients, followed by Shanghai (13 cases), Henan (nine cases) and Anhui provinces (eight cases). Among the 31 patients from Shandong Province, there were 21 patients with two variations in the \u003cem\u003ePCCB\u003c/em\u003e gene, eight patients with two variations in the \u003cem\u003ePCCA\u003c/em\u003e gene and two patients without variations. The three most frequent mutations in Shandong Province were c.838dup (8/42, 19.1%), c.1087T\u0026thinsp;\u0026gt;\u0026thinsp;C (6/42, 14.3%), and c.167_179delinsC (3/42, 7.1%) in the \u003cem\u003ePCCB\u003c/em\u003e gene, without common variations in the \u003cem\u003ePCCA\u003c/em\u003e gene. Among the 21 patients from Jiangsu Province, 13 patients had two variations in the \u003cem\u003ePCCB\u003c/em\u003e gene, and eight patients had two variations in the \u003cem\u003ePCCA\u003c/em\u003e gene. The three most frequent mutations in Jiangsu Province were c.1087T\u0026thinsp;\u0026gt;\u0026thinsp;C (5/26, 19.2%) and c.1228C\u0026thinsp;\u0026gt;\u0026thinsp;T (3/26, 11.5%) in the \u003cem\u003ePCCB\u003c/em\u003e gene and c.229C\u0026thinsp;\u0026gt;\u0026thinsp;T (3/16, 18.6%) in the \u003cem\u003ePCCA\u003c/em\u003e gene.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e4. Treatment effect and prognosis\u003c/h2\u003e \u003cp\u003eIn our cohort, most patients were treated with L-carnitine and a diet low in isoleucine, valine, threonine, and methionine\u003csup\u003e6\u003c/sup\u003e. We evaluated the health conditions of the patients to 2022. The prognosis is shown in detail in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Among the 36 positive NBS patients, disease onset occurred in 22 patients; 13 patients did not have disease onset, and the remaining patient was lost to follow-up. For the prognosis of the 22 positive NBS patients who exhibited disease onset, 12 patients showed developmental delays, four patients were healthy, four patients died, and two patients were lost to follow-up. The 13 patients who did not encounter disease onset lived healthy lives without symptoms. Regarding the prognosis of the 96 patients diagnosed by clinical onset of the disease without NBS, 36 patients showed developmental delays, 16 patients were healthy, 28 patients died, and 16 patients were lost to follow-up. One patient diagnosed because of a sibling diagnosis was healthy, without NBS and without disease onset. Therefore, 118 patients (22 with NBS, 96 without NBS) showed disease onset. The overall prognosis of the entire cohort was as follows: 48 (48/133, 36.1%) patients showed progressive developmental delays or intelligence impairment, 34 patients (34/133, 25.5%) were healthy and lived normal lives asymptomatically, 32 patients died (32/133, 24.1%), and 19 patients could not be followed up (19/133, 14.3%).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn the present study, we recruited a large cohort of 133 PA patients; collected their disease onset and NBS status, biochemical metabolite levels, gene variations and prognosis; and achieved the results described above.\u003c/p\u003e \u003cp\u003eWith a median age at disease onset of 4 months old, 78.9% (86/109) of the patients exhibited disease onset before 12 months old. In addition, no specificity in the clinical manifestations of these patients existed at disease onset. Symptoms in multiple systems and multiple biochemical abnormalities were present, such as vomiting, difficulty feeding, jaundice, lethargy, convulsion, and mental retardation, accompanied by metabolic acidosis, hypoglycemia, and hyperammonemia. Early diagnosis and timely treatment are of great importance for these patients. The diagnosis of PA depends on specific technology, such as MS/MS, GC-MS, and gene analysis. In recent years, MS/MS expanded NBS has played an increasingly critical role in the early diagnosis and timely treatment of PA. NBS has been shown to increase the chance of early diagnosis of PA patients, especially in late-onset cases, and might decrease neonatal mortality [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMS/MS expanded NBS, which detects blood acylcarnitine and amino acids in newborns by MS/MS, can diagnose dozens of inherited metabolic diseases, including PA. After the first attempt in our NBS center of Shanghai Xinhua Hospital in 2003, MS/MS expanded NBS was promoted to an increasing number of regions in China gradually. To date, it is available in about 60% of the 246 NBS centers in China (147/246), with the detection report available in two weeks after the newborn birth.\u003c/p\u003e \u003cp\u003ePA patients could benefit greatly from the MS/MS expanded NBS. Because the manifestations of PA had no specificity at disease onset, patients could only be treated symptomatically before diagnosis. Once the NBS results arrived, the diagnosis was clear, and targeted etiological treatment for PA could begin immediately. Therefore, NBS can significantly improve patient prognosis. This can be confirmed by the difference in prognosis between patients with NBS and patients without NBS shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. A total of 36 patients were diagnosed by the MS/MS expanded NBS; 13 patients remained asymptomatic without disease onset, and four patients returned to a healthy status after disease onset, with a healthy rate of 47.2% (17/36). However, of the 96 patients diagnosed by clinical disease onset, only 16 patients remained healthy, with a healthy rate of 16.7% (16/96). Among the 97 patients who were not diagnosed by NBS but from clinical disease onset or sibling diagnosis, some missed the MS/MS expanded NBS because they were born before the project was introduced locally. Therefore, MS/MS expanded NBS should be promoted urgently to a much broader range of newborns in China to diagnose this disease.\u003c/p\u003e \u003cp\u003eFor the biochemical markers, compared with the levels before treatment, the C3 blood levels increased after treatment. This does not represent a worsening of the disease. We considered that the low C3 blood level before treatment was due to the consumption of carnitine by excessive abnormal acidic metabolites in the body. After treatment with free carnitine (C0) supplementation, the levels of acylcarnitines, including C3 and C2, increased. Thus, the increase in the C3 blood level after treatment did not suggest the deterioration of biochemical indicators but the interference of treatment. This deduction was also confirmed because the C3/C2 ratio did not increase but decreased after treatment (before 1.31 vs. after 1.12). In the case of urine organic acids, improvement was embodied in the decrease in 3-OHPA after treatment.\u003c/p\u003e \u003cp\u003eThe mutations in the \u003cem\u003ePCCA\u003c/em\u003e gene were highly heterogeneous. None of the mutations detected are predominant in Caucasians, with an exception in Japanese individuals; three mutations, c.922_923insT, c.1644-6C\u0026thinsp;\u0026gt;\u0026thinsp;G, and c.1196G\u0026thinsp;\u0026gt;\u0026thinsp;A, account for 56% of the total mutant alleles\u003csup\u003e13\u003c/sup\u003e. In our cohort, as many as 60 variants were detected in the \u003cem\u003ePCCA\u003c/em\u003e gene. Although there were no predominant single mutations in the gene, we found that the relatively frequent mutations in the Chinese population were c.2002G\u0026thinsp;\u0026gt;\u0026thinsp;A, c.229C\u0026thinsp;\u0026gt;\u0026thinsp;T, and c.1118T\u0026thinsp;\u0026gt;\u0026thinsp;A.\u003c/p\u003e \u003cp\u003eIn the \u003cem\u003ePCCB\u003c/em\u003e gene, there are usually limited numbers of mutations that account for most of the patients in different ethnic groups. For example, 1218del14ins12 appears to be the most common \u003cem\u003ePCCB\u003c/em\u003e mutation in Caucasians [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], 1540insCCC seems to be a prevalent \u003cem\u003ePCCB\u003c/em\u003e mutation in Greenland [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], and c.1172_1173insT and c.502G\u0026thinsp;\u0026gt;\u0026thinsp;A are common specifically in the Spanish and Latin American populations [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In Korea, the allele frequency of c.1283C\u0026thinsp;\u0026gt;\u0026thinsp;T in patients with PA was 56.3% in one study [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In Japan, c.1304T\u0026thinsp;\u0026gt;\u0026thinsp;C and c.1283C\u0026thinsp;\u0026gt;\u0026thinsp;T have been reported to be the most common mutations [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Furthermore, c.1283C\u0026thinsp;\u0026gt;\u0026thinsp;T is related to a severe phenotype, while patients with the c.1304T\u0026thinsp;\u0026gt;\u0026thinsp;C mutation are expected to be free from the symptoms of PA [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In the present study, we determined that the common mutations in the \u003cem\u003ePCCB\u003c/em\u003e gene were c.1087T\u0026thinsp;\u0026gt;\u0026thinsp;C, c.838dup, c.1228C\u0026thinsp;\u0026gt;\u0026thinsp;T, and c.1316A\u0026thinsp;\u0026gt;\u0026thinsp;G in the Chinese population, which are different from those in previous countries.\u003c/p\u003e \u003cp\u003eSpecific variations belonged to specific phenotypes. It is well known that homozygotes can best embody the function of variations. We investigated the disease onset and prognosis of the most frequent variations, c.2002G\u0026thinsp;\u0026gt;\u0026thinsp;A in the \u003cem\u003ePCCA\u003c/em\u003e gene and c.1087T\u0026thinsp;\u0026gt;\u0026thinsp;C in the \u003cem\u003ePCCB\u003c/em\u003e gene. The c.2002G\u0026thinsp;\u0026gt;\u0026thinsp;A variant was associated with a relatively serious phenotype, while the c.1087T\u0026thinsp;\u0026gt;\u0026thinsp;C variant was associated with a relatively mild phenotype.\u003c/p\u003e \u003cp\u003eIn China, more patients have mutations in the \u003cem\u003ePCCB\u003c/em\u003e gene than in the \u003cem\u003ePCCA\u003c/em\u003e gene. In our cohort, 45 patients had variations in the \u003cem\u003ePCCA\u003c/em\u003e gene, while 73 patients had variations in the \u003cem\u003ePCCB\u003c/em\u003e gene. In another large cohort study in China that included 60 PA patients reported by Liu Y et al., 24 (41.4%) patients had mutations in the \u003cem\u003ePCCA\u003c/em\u003e gene, and 34 (58.6%) patients had mutations in the \u003cem\u003ePCCB\u003c/em\u003e gene [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. In that cohort, c.2002G\u0026thinsp;\u0026gt;\u0026thinsp;A in \u003cem\u003ePCCA\u003c/em\u003e and c.838dup in \u003cem\u003ePCCB\u003c/em\u003e were the most common variants, with frequencies of 13.9% (6/44 alleles) and 12.5% (8/64 alleles), respectively. The conclusion is similar to our study, with the difference that the most common variation in the \u003cem\u003ePCCB\u003c/em\u003e gene was c.1087T\u0026thinsp;\u0026gt;\u0026thinsp;C, and c.838dup was the second most frequent variant in our study.\u003c/p\u003e \u003cp\u003eIn addition, we identified 43 novel variations in the \u003cem\u003ePCCA\u003c/em\u003e gene and 40 novel variations in the \u003cem\u003ePCCB\u003c/em\u003e gene. This study expanded the variation spectrum in Chinese patients and could be of importance regarding genetic counseling of PA patients. Functional studies, such as enzymatic activity determination, should be conducted further to evaluate the effects of the novel variations.\u003c/p\u003e \u003cp\u003eSpecifically, in the 48 patients with mutations in the \u003cem\u003ePCCA\u003c/em\u003e gene, three patients exhibited one mutation. In the 79 patients with mutations in the \u003cem\u003ePCCB\u003c/em\u003e gene, six patients exhibited one mutation. Furthermore, one patient had one mutation in the \u003cem\u003ePCCA\u003c/em\u003e gene and one mutation in the \u003cem\u003ePCCB\u003c/em\u003e gene, without a third mutation in either the \u003cem\u003ePCCA\u003c/em\u003e gene or \u003cem\u003ePCCB\u003c/em\u003e gene. All the ten cases had classical clinical or biochemical manifestations of PA. In our study, the \u003cem\u003ePCCA\u003c/em\u003e and \u003cem\u003ePCCB\u003c/em\u003e gene tests were performed mainly by high-throughput next-generation sequencing or Sanger sequencing, which can discover variations of a single base or a few bases. Multiplex ligation-dependent probe amplification (MLPA) was performed in only a few of the patients in our cohort, through which we detected only four exon deletions in the \u003cem\u003ePCCA\u003c/em\u003e gene and two exon deletions in the \u003cem\u003ePCCB\u003c/em\u003e gene. We speculate that exon deletion or intron variations might exist on another allele in the ten patients, which we plan to identify in the future.\u003c/p\u003e \u003cp\u003eThis study had limitations. First, the treatment records of some patients were not detailed enough. Many parents could not remember all the drugs the patients had used when they came to our clinic. In the future, we will collect the clinical information in as detailed a manner as possible. Furthermore, some mutations were found in only a few patients. The limited number of homozygous patients and the high frequency of compound heterozygous patients made it difficult to assess the precise relationship between these variations and their clinical phenotypes.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe present study enrolled a large cohort of 133 PA patients with different phenotypes and genotypes. Disease onset was usually early with various nonspecific symptoms. A total of 248 variations (95 in the \u003cem\u003ePCCA\u003c/em\u003e gene and 153 in the \u003cem\u003ePCCB\u003c/em\u003e gene) were detected in these patients, including 84 novel variations (43 in the \u003cem\u003ePCCA\u003c/em\u003e gene and 40 in the \u003cem\u003ePCCB\u003c/em\u003e gene), with common mutations and an expanded variation spectrum in the \u003cem\u003ePCCA\u003c/em\u003e and \u003cem\u003ePCCB\u003c/em\u003e genes. The c.2002G\u0026thinsp;\u0026gt;\u0026thinsp;A variant in the \u003cem\u003ePCCA\u003c/em\u003e gene was associated with a relatively serious phenotype, while the c.1087T\u0026thinsp;\u0026gt;\u0026thinsp;C variant in the \u003cem\u003ePCCB\u003c/em\u003e gene was associated with a relatively mild phenotype. The overall prognosis of these patients was poor, with more than one-third of the patients exhibiting developmental delays, nearly one-quarter of the patients dying and only one-quarter of the patients remaining healthy. Among the patients, the group that underwent NBS had a better prognosis than the group that did not undergo NBS. These results provide clinical experience for clinicians. This study helps to improve the understanding of the clinical manifestation and genetic background of PA in Chinese patients. MS/MS expanded NBS and gene sequencing facilitate early diagnosis and treatment for PA and should be promoted further.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eC2\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eacetylcarnitine\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eC3\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epropionylcarnitine\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGC‒MS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003egas chromatography‒mass spectrometry\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMCA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emethylcitric acid\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMS/MS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003etandem mass spectrometry\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e3-OHPA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003e3-hydroxypropionic acid\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePropionic Acidemia\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Ethics Committee of Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (Approval number: XHEC-D-2023-029). Informed consent was obtained from all individual participants included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe manuscript does not contain personal identification information that can be match to individuals, such as name, sex and images. The authors affirm that the participants provided informed consent for publication of the research.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in the published article and also be available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that there is no conflict of interest about this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Scientific Research Project Plan of Shanghai Municipal Health Commission (No.202040448, No.202140346) and the National Natural Science Foundation of China (No.81600701).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLLL, as the doctor of many of these patients,\u0026nbsp;contributed to reorganizing and analyzing\u0026nbsp;the clinical data of the patients and\u0026nbsp;drafting\u0026nbsp;the manuscript.\u003c/p\u003e\n\u003cp\u003eYHH\u0026nbsp;contributed to collecting and reorganizing\u0026nbsp;the clinical data of the patients and\u0026nbsp;revising\u0026nbsp;the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eYY and SYL\u0026nbsp;contributed to collecting\u0026nbsp;the clinical data of the patients.\u003c/p\u003e\n\u003cp\u003eWJQ, JY, HWZ, DYL, YGY, and XFG\u0026nbsp;contributed to collecting and treating\u0026nbsp;the patients and\u0026nbsp;providing\u0026nbsp;the clinical data.\u003c/p\u003e\n\u003cp\u003eWJJ and FX contributed to the detection of the blood acylcarnitines of the patients by MS/MS.\u003c/p\u003e\n\u003cp\u003eXZ and YCL\u0026nbsp;contributed to the\u0026nbsp;detection\u0026nbsp;of\u0026nbsp;the urinary organic acids of the\u0026nbsp;patients\u0026nbsp;by GC‒MS.\u003c/p\u003e\n\u003cp\u003eZWG contributed to gene variation analysis.\u003c/p\u003e\n\u003cp\u003eLSH, as the doctor of most of the patients, contributed to the research design, treating the patients, providing the clinical data and revising the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe acknowledge all patients and families for their participation in this study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRamsay J, Morton J, Norris M, Kanungo S. Organic acid disorders. Ann Transl Med. 2018;6:472.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWongkittichote P, Ah Mew N, Chapman KA. Propionyl-CoA carboxylase - A review. Mol Genet Metab. 2017;122:145\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBaumgartner MR, Horster F, Dionisi-Vici C, Haliloglu G, Karall D, Chapman KA, et al. Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia. Orphanet J Rare Dis. 2014;9:130.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGrunert SC, Mullerleile S, De Silva L, Barth M, Walter M, Walter K, et al. Propionic acidemia: clinical course and outcome in 55 pediatric and adolescent patients. Orphanet J Rare Dis. 2013;8:6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRiemersma M, Hazebroek MR, Helderman-van den Enden A, Salomons GS, Ferdinandusse S, Brouwers M, et al. Propionic acidemia as a cause of adult-onset dilated cardiomyopathy. Eur J Hum Genet. 2017;25:1195\u0026ndash;201.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFraser JL, Venditti CP. Methylmalonic and propionic acidemias: clinical management update. Curr Opin Pediatr. 2016;28:682\u0026ndash;93.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePena L, Franks J, Chapman KA, Gropman A, Ah Mew N, Chakrapani A, et al. Natural history of propionic acidemia. Mol Genet Metab. 2012;105:5\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCappuccio G, Atwal PS, Donti TR, Ugarte K, Merchant N, Craigen WJ, et al. Expansion of the Phenotypic Spectrum of Propionic Acidemia with Isolated Elevated Propionylcarnitine. JIMD Rep. 2017;35:33\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRavn K, Chloupkova M, Christensen E, Brandt NJ, Simonsen H, Kraus JP, et al. High incidence of propionic acidemia in greenland is due to a prevalent mutation, 1540insCCC, in the gene for the beta-subunit of propionyl CoA carboxylase. Am J Hum Genet. 2000;67:203\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChapman KA, Gramer G, Viall S, Summar ML. Incidence of maple syrup urine disease, propionic acidemia, and methylmalonic aciduria from newborn screening data. Mol Genet Metab Rep. 2018;15:106\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTajima G, Kagawa R, Sakura F, Nakamura-Utsunomiya A, Hara K, Yuasa M, et al. Current Perspectives on Neonatal Screening for Propionic Acidemia in Japan: An Unexpectedly High Incidence of Patients with Mild Disease Caused by a Common PCCB Variant. Int J Neonatal Screen. 2021;7:35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGu XHL, Yu Y. Current Status and Prospects of Screening for Newborn Hereditary Metaboolic Disease. J Rare Dis. 2022;1:13\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDesviat LR, Perez B, Perez-Cerda C, Rodriguez-Pombo P, Clavero S, Ugarte M. Propionic acidemia: mutation update and functional and structural effects of the variant alleles. Mol Genet Metab. 2004;83:28\u0026ndash;37.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChilds B, Nyhan WL, Borden M, Bard L, Cooke RE. Idiopathic hyperglycinemia and hyperglycinuria: a new disorder of amino acid metabolism. I Pediatr. 1961;27:522\u0026ndash;58.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJurecki E, Ueda K, Frazier D, Rohr F, Thompson A, Hussa C, et al. Nutrition management guideline for propionic acidemia: An evidence- and consensus-based approach. Mol Genet Metab. 2019;126:341\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eScott Schwoerer J, Clowes Candadai S, Held PK. Long-term outcomes in Amish patients diagnosed with propionic acidemia. Mol Genet Metab Rep. 2018;16:36\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eForny P, Horster F, Ballhausen D, Chakrapani A, Chapman KA, Dionisi-Vici C, et al. Guidelines for the diagnosis and management of methylmalonic acidaemia and propionic acidaemia: First revision. J Inherit Metab Dis. 2021;44:566\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKim SN, Ryu KH, Lee EH, Kim JS, Hahn SH. Molecular analysis of PCCB gene in Korean patients with propionic acidemia. Mol Genet Metab. 2002;77:209\u0026ndash;16.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYorifuji T, Kawai M, Muroi J, Mamada M, Kurokawa K, Shigematsu Y, et al. Unexpectedly high prevalence of the mild form of propionic acidemia in Japan: presence of a common mutation and possible clinical implications. Hum Genet. 2002;111:161\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu Y, Chen Z, Dong H, Ding Y, He R, Kang L, et al. Analysis of the relationship between phenotypes and genotypes in 60 Chinese patients with propionic acidemia: a fourteen-year experience at a tertiary hospital. Orphanet J Rare Dis. 2022;17:135.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"propionic acidemia, mutation, newborn screening, tandem mass spectrometry","lastPublishedDoi":"10.21203/rs.3.rs-3819961/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3819961/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003ePropionic acidemia (PA) is an inherited organic acid metabolic disease involving multiple physiological systems with variable manifestations. The causative genes, \u003cem\u003ePCCA\u003c/em\u003e and \u003cem\u003ePCCB\u003c/em\u003e, carry a wide range of mutations. The present study aimed to investigate the phenotype and genotype features of PA in Chinese patients.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe enrolled 133 PA patients who were treated during the past 17 years. We investigated their clinical data in detail, including national newborn screening (NBS) status and disease onset, biochemical metabolites, gene variations, and recent prognosis, to investigate the phenotype and genotype features.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAmong the 133 PA patients, 36 patients were diagnosed thanks to NBS expanded by tandem mass spectrometry (MS/MS). The median onset time was four months old, with symptoms involving multiple systems without specificity. The blood propionylcarnitine/ acetylcarnitine (C3/C2) ratio and urine 3-hydroxypropionic acid (3-OHPA) levels decreased after treatment. The overall prognosis of was poor, with 25.5% being healthy (34/133), 36.1% having developmental delays (48/133), 24.1% dying (32/133) and 14.3% being lost to follow-up (19/133). In the \u003cem\u003ePCCA\u003c/em\u003e gene of 49 patients, 60 variants were detected, including 43 new variations. The variations c.2002G\u0026thinsp;\u0026gt;\u0026thinsp;A, c.229C\u0026thinsp;\u0026gt;\u0026thinsp;T, and c.1118T\u0026thinsp;\u0026gt;\u0026thinsp;A were the three most frequent variations. In the \u003cem\u003ePCCB\u003c/em\u003e gene of 80 patients, 64 variants were detected, including 40 new variations. The variations c.1087T\u0026thinsp;\u0026gt;\u0026thinsp;C, c.838dup, and c.1228C\u0026thinsp;\u0026gt;\u0026thinsp;T were the three most frequent variations.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003ePA is a serious organic acidemia with early onset and nonspecific symptoms. The overall prognosis is poor. There are wide and relative common variations in Chinese patients in causative genes.\u003c/p\u003e","manuscriptTitle":"Evaluation of the Clinical, Biochemical, Genotype, and Prognosis of Propionic Acidemia in 133 Patients from China","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-16 19:43:08","doi":"10.21203/rs.3.rs-3819961/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"948e75e4-5005-4944-8a53-bf77f0c1c140","owner":[],"postedDate":"January 16th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-05-05T11:35:56+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-16 19:43:08","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3819961","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3819961","identity":"rs-3819961","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}