Successful Experience with High-Risk and Family Screening for Fabry Disease in Ninghai County, Zhejiang Province, Eastern China: Genotype‒Phenotype Analysis of the GLA IVS4+919G>A Variant

Successful Experience with High-Risk and Family Screening for Fabry Disease in Ninghai County, Zhejiang Province, Eastern China: Genotype‒Phenotype Analysis of the GLA IVS4+919G>A Variant | 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 Successful Experience with High-Risk and Family Screening for Fabry Disease in Ninghai County, Zhejiang Province, Eastern China: Genotype‒Phenotype Analysis of the GLA IVS4+919G>A Variant Zhuhui Ge, Jianhua Mao, Zhangqiao Dai, Xiaodan Pan, Keqiang Lin, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6363208/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 05 Feb, 2026 Read the published version in BMC Medical Genomics → Version 1 posted 14 You are reading this latest preprint version Abstract Background This study aimed to conduct high-risk and family screening for patients and to investigate the clinical phenotypes and genetic characteristics of patients with Fabry disease caused by the GLA IVS4 + 919G > A variant in China. Methods In a 31-month study, a pilot program was designed to assess high-risk screening for Fabry disease in 388 patients by measuring their dry blood spot (DBS) α-galactosidase A (α-GAL) activity, globotriaosylsphingosine (Lyso-GL-3), and GLA gene sequence from October 2021 to May 2024 at Ninghai First Hospital. Patients whose dried blood spot (DBS) α-GAL enzyme activity was low ( 1.10 ng/mL) underwent GLA genetic testing for diagnostic confirmation. Evaluation and family screening were carried out on the proband, and the clinical and genetic characteristics of Fabry disease caused by the GLA IVS4 + 919G > A variant were summarised. Results Before the pilot program was established, no patients were diagnosed with Fabry disease in the hospital. However, 31 months following the program’s implementation, 388 patients (233 males and 155 females) were recruited to meet the inclusion criteria for high-risk screening for Fabry disease, with a yield of diagnosis of 1.80% (7/388). A 9.8-year-old girl was screened because of a high-risk profile of severe pain in the extremities, and the other 6 males, who were diagnosed with Fabry disease, were screened because of unexplained left ventricular hypertrophy. All 7 diagnosed patients were carriers of the GLA IVS4 + 919G > A variant. Family screening of 7 probands revealed that 18 family members carried pathogenic variants, resulting in a diagnosis rate of 6.44% (25/388); 13 were clinically affected, 2 were asymptomatic carriers, and 3 declined further clinical assessment. Among the 25 patients, multiple affected organs and systems included the heart (60.00%), peripheral nerves (16.00%), kidney (36.00%), eye (20.00%), brain (12.00%), and gastrointestinal tract (24.00%). Conclusions Screening high-risk populations and family screening is critical for early diagnosis and timely intervention in patients with Fabry disease. The GLA IVS4 + 919G > A variant is associated with diverse phenotypes of Fabry disease and is highly prevalent in late-onset cases in Ninghai County, Zhejiang Province, Eastern China. Fabry disease High-risk screening Family screening Early diagnosis GLA gene variant IVS4 + 919G > A Figures Figure 1 Introduction Fabry disease (OMIM #301500) is a rare, X-linked lysosomal storage disorder caused by pathogenic variants in the GLA gene, resulting in a deficiency in α-Gal A activity. This deficiency leads to the progressive accumulation of globotriaosylceramide (GL-3) and globotriaosylsphingosine (Lyso-GL-3) in cells and multiple organ systems throughout the body [ 1 , 2 ], causing multiorgan pathology resulting in substantial mortality and a reduced life expectancy [ 3 ]. The clinical spectrum ranges from classic early-onset to atypical late-onset phenotypes. The clinical manifestations include renal insufficiency of unknown etiology, acroparesthesia, unexplained left ventricular hypertrophy (LVH), cardiac arrhythmia, unexplained stroke, angiokeratomas, sweating abnormalities, cornea verticillata, lenticular opacities, and unexplained gastrointestinal symptoms [ 1 ]. Owing to skewed X chromosome inactivation, heterozygous females generally present with milder clinical manifestations and a delayed age of onset relative to those of hemizygous males [ 1 , 2 ]. The early symptoms of patients with Fabry disease are nonspecific. Therefore, early diagnosis remains a clinical challenge. To enhance the early diagnosis of Fabry disease, some countries have systematically conducted high-risk, newborn, and genetic screening [ 2 , 4 ]. This study was designed to combine high-risk and family screening to increase the yield of diagnoses of Fabry disease presenting with different but relevant phenotypic traits (isolated or combined). Methods Experimental design The experimental design of our study involved collaboration across thirteen hospitals in Zhejiang Province. From October 2021 to May 2024, we analysed DBS samples collected from 388 high-risk individuals screened for Fabry disease at Ninghai First Hospital, and those patients met at least one of the following criteria: (a) unexplained chronic kidney disease (including unexplained proteinuria or haematuria); (b) unexplained stroke; (c) unexplained cardiovascular diseases (unexplained LVH or cardiac failure); (d) acroparesthesias (periodic crises of severe pain in the extremities); (e) clustered angiokeratoma; (f) hypo-anhidrosis; (g) cornea verticillata and lenticular opacities; and (h) abdominal pain or diarrhoea of unknown aetiology [ 2 ]. For males, the level of α-Gal A determined below normal ( 1.10 ng/mL) was tested via long-range PCR, the GLA of the gene was sequenced, and the level of α-Gal A was determined. For female children, a level of α-Gal A determined below normal or a level of lyso-GL-3 tested above normal was followed by long-range PCR and sequencing of the GLA gene. Family screening, including genetic testing, enzymatic activity measurement of the level of α-Gal A and the measurement of Lyso-GL-3, was offered to all the relatives of the probands. Patients who did not agree to undergo measurement of α-Gal A activity, Lyso-GL-3 and genetic analysis were excluded. This study was approved by the Ethical Committee of Ninghai First Hospital, Zhejiang Province, China (No. Nhyy-IEC-KY202304). Enzymatic activity measurement of α-Gal A The NeoLSD MSMS kit was used for the quantitative measurement of the activity of the enzyme GLA in dried blood spots (DSSs). A 3.2 mm (1/8 in) DBS was incubated in the buffer solution containing the internal standard and substrate provided by the kit at 37°C for 18.5 h. Then, water and NeoLSD Extraction Solution were added for extraction. Fifty microliters of the supernatant was transferred to a new well and dried with nitrogen. One hundred microliters of flow solvent was added to the well before it was run on a Waters UPLC/Xevo TQD MS/MS system. Data were obtained by using the multiple reaction monitoring (MRM) mode of the tandem mass spectrometry (MSMS) system. The enzymatic activity could be measured according to the signal response of the target analyte relative to the internal standard. Measurement of Lyso-GL-3 An HPLC‒MS/MS instrument was used for the quantitative measurement of Lyso-GL-3 in DBSs. Two 3.2 mm (1/8 in) DBSs were incubated in buffer solution containing an internal standard. The supernatant was transferred to a new well before being run on the HPLC‒MS/MS system. Data were obtained by using the multiple reaction monitoring (MRM) mode of the tandem mass spectrometry (MSMS) system. The standard curve was generated via data fitting of the standard. The x-axis represents the ratio of the peak area of the target analyte to that of the internal standard, and the y-axis represents the concentration. The concentration of the target analyte in the sample can be obtained by inputting the ratio of the peak area into the regression equation of the standard curve. Genetic test of GLA A sufficient amount of genomic DNA was extracted from dry blood through lysis solution and ground. The whole-genome sequence of the GLA gene was amplified via long-range PCR. The purified amplicons were processed to generate paired-end libraries and then sequenced on an Illumina NovaSeq platform. The data were processed and analysed to identify related variants. Data analysis and statistics SPSS 22.0 software was used for statistical processing and descriptive analysis, including the mean ± standard deviation (SD) and median. Changes in plasma α-Gal A activity between males and females with Fabry disease were analysed via t tests. α-Gal A activity and Lyso-GL-3 activity between males and females with Fabry disease were analysed via Fisher’s exact test, and differences were considered to be statistically significant when the p value was < 0.05. Results Patient characteristics From October 2021 to May 2024, a total of 388 individuals (233 males and 155 females; median age, 46.5 years) who met the eligibility criteria were enrolled. The patient group included 165 patients with unexplained chronic kidney disease, 58 patients with unexplained stroke, 114 patients with unexplained cardiovascular diseases, 38 patients with acroparesthesia, 4 patients with clustered angiokeratoma, 5 patients with hypo-anhidrosis, 1 patient with cornea verticillata and lenticular opacities, and 3 patients with abdominal pain or diarrhea of unknown etiology. Measurement of α-Gal A activity and Lyso-GL-3 We measured α-Gal A activity and Lyso-GL-3 via a DBS test. α-Gal A activity values 1.10 ng/mL were observed in 3 patients (3 females), α-Gal A activity values were low, and Lyso-GL-3 values increased in 17 patients (14 males and 3 females). Genetic tests and assays By sequencing the full-length sequence of the GLA gene, including the exon coding region and intron region, the GLA variant IVS4 + 919G > A was detected in 13 hemizygous males and 12 heterozygous females, including 7 probands, who were diagnosed with Fabry disease. According to the interpretation guidelines of the American Society of Medical Genetics and Genomics, this variant was rated as the pathogenic variant. Clinical characteristics of patients with the pathogenic GLA variant Through high-risk screening, we identified 7 probands with Fabry disease. Subsequent family screening of these probands revealed 18 family members carrying pathogenic variants; 13 were clinically affected, 2 were asymptomatic carriers, and 3 declined further clinical assessment. The clinical characteristics of the 25 patients (13 males and 12 females) carrying the pathogenic GLA variant IVS4 + 919G > A are summarised in Tables 1 and 2 ; the affected organs and systems included the kidney (36.00%), brain (12.00%), heart (60.00%), peripheral nerves (16.00%), eye (20.00%), gastrointestinal tract (24.0%), and hypertension (8.00%). Table 1 Clinical characteristics of patients with the GLA IVS4 + 919G > A variant Pt Gender Age α-Gal A Lyso-GL-3 Comorbidity years (µmol·L − 1 ·h − 1 ) (ng/mL) 1 F 9 1.09 <0.55 LVH, Acroparesthesias, Bile reflux gastritis 2 F 19 2.33 0.90 Decreased vision 3 M 50 0.71 3.06 LVH, Acroparesthesias 4 F 47 3.84 0.74 Decreased vision 5 M 13 0.87 0.78 Acroparesthesias 6 F 22 1.60 0.66 No symptoms 7 M 55 0.74 3.98 LVH, CAD, HUA, Chronic gastritis, Acroparesthesias, CKD 8 M 61 0.93 3.65 LVH, HUA, Conjunctival vessel tortuosity, CKD 结膜血管迂曲 9 M 72 0.72 3.79 LVH, Cerebral ischemic stroke, CKD 10 M 72 0.57 4.99 LVH, CKD 11 F 66 1.28 1.58 No symptoms 12 F 40 1.69 1.13 No symptoms 13 F 33 1.45 1.13 No symptoms 14 F 18 2.11 1.13 No symptoms 15 M 78 0.77 4.31 LVH, CAD, COPD, Strock, Arrhythmia(PVC), Hypertension, Gastroduodenal ulcer, CKD 16 F 56 2.05 1.12 Conjunctival vessel tortuosity, Arrhythmia (Sinus bradycardia) 17 F 60 3.52 <0.55 Conjunctival vessel tortuosity, Arrhythmia (Sinus bradycardia) 18 M 66 0.95 13.9 LVH, Pacemaker(Third-degree atrioventricular block), Hypertension, Duodenal bulb ulcer, CKD 19 M 68 0.49 8.25 LVH, Pacemaker(Third-degree atrioventricular block), CKD 20 M 45 0.69 4.79 CAD, Arrhythmia (Complete right bundle branch block) 21 F 70 0.67 <0.55 No symptoms 22 M 74 0.42 5.57 LVH, Cerebral ischemic stroke, CAD, HUA, Gastrectomy for gastric cancer, Chronic gastritis, CKD 23 F 44 3.15 4.10 Gastroduodenal ulcer 24 M 80 1.20 5.30 LVH, Pacemaker(Third-degree atrioventricular block), CAD, HUA, CKD 25 M 61 1.01 6.05 LVH, Arrhythmia (Sinus bradycardia), COPD, stroke F, Female; M, Male; α-Gal A activity, normal range(2.40 ~ 17.65)µmol·L − 1 ·h − 1 ; Lyso-GL-3, normal range༈<1.10 ng·mL − 1 ༉; LVH, Left ventricular hypertrophy; CAD, Coronary atherosclerotic heart disease; HUA, hyperuricemia; CKD, Chronic kidney disease; COPD, Chronic obstructive pulmonary disease; PVC, Premature ventricular complex Table 2 Clinical evaluation of cardiac status and renal function in patients with the GLA IVS4 + 919G > A variant Pt Gender Age Cardiac biomarkers Echocardiography renal function CTnI BNP IVST LVPWT LVEF LVMI Scr GFR years (µg/L) (ng/L) (mm) (mm) (%) (g/m 2.7 (µmol/L) (ml/min) 1 F 9 < 0.100 141 5.4 4.9 72 27.3 34 187 2 F 19 < 0.100 68 8 7 72 29.4 NA NA 3 M 50 < 0.100 320 12 11 68 48.5 63 109 4 F 47 < 0.100 89 10 8 66 44.5 NA NA 5 M 13 < 0.100 56 6 6 70 16.5 NA NA 6 F 22 < 0.100 70 8 7 69 27.9 NA NA 7 M 55 0.459 1290 20 17 56 86.0 99 73.58 8 M 61 < 0.100 16 12 12 61 43.6 82 88.59 9 M 72 < 0.100 512 14 13 66 68.1 80 84.48 10 M 72 < 0.100 173 12 12 54 63.6 84 79.64 11 F 66 < 0.100 77 10 11 51 62.0 57 92.76 15 M 78 0.151 347 13 12 65 68.2 138 41.6 16 F 56 < 0.100 479 9 9 67 43.7 63 94.8 17 F 60 < 0.100 21 9 9 68 40.7 62 95.3 18 M 66 0.661 506 21 12 59 82.8 83 83.69 19 M 68 < 0.100 1006 27 18 55 81.7 80 86.89 20 M 45 < 0.100 NA 10 10 68 52.5 82 99.12 22 M 74 < 0.1008 3419 24 9 38 98.4 150 38.96 23 F 44 NA NA 9 8 68 30.9 47 115.36 24 M 80 0.273 2745 11 11 46 98.6 112 53.00 25 M 61 0.353 517 23 18 64 95.6 74 94.64 F, Female; M, Male; CTnI, Troponin I(normal range 0.000 ~ 0.100 µg·L − 1 );BNP, B-type natriuretic peptide༈normal range 0 ~ 100 pg·ml − 1 ༉; IVST, Interventricular septal thickness; LVPWT, Left ventricular posterior wall thickness; LVEF, Left ventricular ejection fraction; LVMI, Left ventricular mass index༈left ventricular hypertrophy was defined as LVMI > 51 g/m 2.7 in males and LVMI > 48 g/m 2.7 in females༉; NA, Not available. Among 25 patients (average age, 51.16 ± 21.52 years), α-Gal A activity was within the normal reference range (2 females), α-Gal A activity was significantly reduced in 5 patients, falling below the standard reference (1 male and 4 females), Lyso-GL-3 levels were abnormally elevated in one patient (1 female), and both α-Gal A activity and Lyso-GL-3 were abnormally altered in 17 patients (11 males and 6 females). There were significant differences in α-Gal A activity (t = 4.655, p < 0.05) between 12 females and 13 males. In our cohort, normal α-Gal A activity or Lyso-GL-3 levels were observed more frequently in females than in males, as shown in Table 3 . Table 3 Baseline α-Gal A and Lyso-GL-3 data of males and females with Fabry disease. Gender Age α-Gal A α-Gal A Lyso-GL-3 (1.10 ng·mL − 1 ) M (n = 13) 61.15 0.775 ± 0.217 13 12 F (n = 12) 40.33 2.065 ± 0.989 9 6 P value 0.012 0.001 0.096 0.027 *Probability values refer to t-test and Fisher’s exact test as appropriate, significance at p < 0.05, F, Female; M, Male Proband 1 was a 9-year-old girl with pain in both lower limbs, and cardiovascular magnetic resonance imaging revealed that the ventricular septum was thick. The α-Gal A activity was below the normal range, Lyso-GL-3 was within the normal range, and genetic analysis revealed a heterozygous pathogenic variant in GLA IVS4 + 919G > A, which has been reported previously [1] . Through family screening, 4 family members (proband’s father, elder sister, elder male cousin and elder female cousin) were diagnosed with Fabry disease, and a family member (proband’s fifth aunt) carried the GLA variant with no symptoms. The age at diagnosis ranged from 9.0 years old to 50.0 years old in this Fabry disease family (Fig. 1 A). Proband 2 was a 55-year-old male with LVH, acroparesthesia, and gastrointestinal disorders, and he also suffered from coronary spastic angina. The level of α-Gal A was markedly low, and genetic analysis revealed a hemizygous pathogenic variant in GLA IVS4 + 919G > A. Family screening for Fabry disease led to a diagnosis of 7 family members (3 elder brothers, one elder sister, 2 nieces and one granddaughter). The age at diagnosis ranged from 18.0 years old to 72.0 years old in this Fabry disease family (Fig. 1 B). Proband 3 was a 78-year-old male with LVH, ischemic stroke, acroparesthesia, kidney disease, and gastrointestinal disorders, and he also suffered from hypertensive disease and coronary spastic angina. The level of α-Gal A was markedly low, Lyso-GL-3 was above the normal range, and genetic analysis revealed a hemizygous pathogenic variant in GLA IVS4 + 919G > A. Family screening identified the GLA pathogenic variant in the proband’s elder daughter (diagnosed with Fabry disease) and younger daughter (an asymptomatic carrier). The age at diagnosis ranged from 56.0 years to 78.0 years (Fig. 1 C). Proband 4 was a 66-year-old male with LVH, hypertensive disease, and gastrointestinal disorders; he also experienced acute irreversible visual loss of his left eye due to ophthalmic artery occlusion and underwent pacemaker implantation. The level of α-Gal A was low, Lyso-GL-3 was above normal, and genetic analysis revealed a hemizygous pathogenic variant in GLA IVS4 + 919G > A. The age at diagnosis was 66.0 years (Fig. 1 D). Proband 5 was a 6-year-old male with LVH, kidney disease and gastrointestinal disorders, and he also underwent pacemaker implantation. The level of α-Gal A was markedly low, and that of Lyso-GL-3 was above normal. Genetic analysis revealed a hemizygous pathogenic variant in GLA IVS4 + 919G > A. Since Fabry disease is inherited in an X-linked manner, the sons of proband 5 are expected to be normal. However, the proband′s son strongly urged family screening because of coronary atherosclerotic heart disease (CAD) and arrhythmia (complete right bundle branch block); subsequently, genetic analysis revealed GLA IVS4 + 919G > A in the proband′s son and the proband′s wife. Thus, the proband′s son inherited it from his mother (the proband’s wife). All three patients were heterozygous for the GLA IVS4 + 919G > A variant. The age at diagnosis ranged from 45.0 years old to 70.0 years old (Fig. 1 E). Proband 6 was a 74-year-old male with LVH, kidney disease, ischaemic stroke and gastrointestinal disorders. The level of α-Gal A was markedly low, Lyso-GL-3 was above standard, and genetic analysis revealed a hemizygous pathogenic variant in GLA IVS4 + 919G > A. Family screening indicated that his daughter was diagnosed with Fabry disease. The age at diagnosis ranged from 44.0 years to 74.0 years (Fig. 1 F). Proband 7 was an 80-year-old male with LVH, kidney disease, ischaemic stroke and gastrointestinal disorders. The level of α-Gal A was markedly low, Lyso-GL-3 was above normal, and genetic analysis revealed a hemizygous pathogenic variant in GLA IVS4 + 919G > A. Family screening indicated that his brother was diagnosed with Fabry disease. The age at diagnosis ranged from 61.0 years to 80.0 years (Fig. 1 G). Among 25 patients with Fabry disease and 2 patients with the GLA IVS4 + 919G > A variant, proband 1 and his father were treated regularly via enzyme replacement therapy (ERT); after 4 months of ERT, the pain in both lower limbs of proband 1 improved, and her father received ERT from September 2023. The levels of Lyso-GL-3 decreased from baseline values of 3.06 ng/mL to 2.20 ng/mL after 4 months of treatment. After the diagnosis of Fabry disease, proband 7 and the brother of proband 7 underwent pretreatment evaluation and were treated with ERT regularly. The levels of Lyso-GL-3 decreased from baseline values of 6.05 ng/mL and 5.30 ng/mL to 4.58 ng/mL and 5.07 ng/mL, respectively. Other patients have not initiated ERT and only receive different degrees of symptomatic treatment. Discussion Fabry disease patients with rare genetic diseases and nonspecific symptoms often experience substantial diagnostic delays, sometimes more than a decade [ 4 ]. If Fabry disease is not treated in time, end-organ damage significantly impairs quality of life and reduces life expectancy [ 4 , 5 ]. To improve the diagnostic yield of Fabry disease, high-risk screening, family screening, and newborn screening programs have been adopted in some countries and regions. In this study, 388 cases of high-risk screening combined with family screening for Fabry disease were conducted from October 2021 to May 2024, and a total of 13 male hemizygotes and 12 female heterozygotes were detected, resulting in a diagnosis rate of 6.44%. Some studies have screened for Fabry disease in different populations (i.e., dialysis patients, LVHs, strokes, and newborns), and the prevalence of Fabry disease is 0.41% (0.33% for males and 0.10% for females) in dialysis patients. In addition, the prevalence of Fabry disease is at least 0.94% for both genders in LVH, and the prevalence of Fabry disease in premature stroke patients is 0.20% (0.13% for males and 0.14% for females) [ 6 , 7 ]. Newborn screening studies have reported that the prevalence of Fabry disease is unexpectedly high, reaching 0.04% for infants in the Chinese Taiwan population (Table 4) [ 8 – 20 ]. Compared with prior studies, the screening strategy implemented in this study demonstrated an enhanced diagnostic yield of Fabry disease and superior cost-effectiveness, and our data demonstrate a substantially higher prevalence of Fabry disease than previously reported. However, this study revealed that the majority of females with Fabry disease had an insignificant increase in Lyso-GL-3 levels, except for proband 1; the other female patients were successfully diagnosed through family screening in this study; these findings suggest that genetic testing is superior to Lyso-GL-3 quantification for early diagnosis of late-onset Fabry disease in females, mainly due to the limited sensitivity of Lyso-GL-3 in heterozygous individuals with skewed X inactivation. The international Fabry Family Screening Advisory Board, consisting of 19 Fabry experts from 15 countries, shared their experiences with family screening for Fabry disease and the difficulties in their respective countries. Family screening of 365 probands with Fabry disease revealed that 1,744 family members carried pathogenic GLA variants; in other words, each proband affected 4.8 family members on average [ 4 ]. Although family screening is the most effective strategy for identifying undiagnosed Fabry patients, it is not universally accepted because of logistics economics and the numerous geographic, societal, and cultural barriers that limit the adoption of family genetic screening [ 4 ]. In a retrospective study of 83 consecutive patients with Fabry disease, pedigree analysis followed by cascade genetic testing identified 165 previously undiagnosed Fabry disease cases among 331 at-risk family members [ 5 ]. The primary barriers to family-based cascade screening are ineffective communication among relatives and geographical dispersion of families, which hinders coordinated genetic testing efforts [ 4 , 5 ]. Table 4 Summary of global studies on Fabry cases with the IVS4+919G>A variant Pub year Region No. of screening Pop Inclusion criteria No. of FD No. of Cases with IVS4+919G>A Ref 2017 Japan 177 LVH consecutive unrelated male patients with HCM, the diagnosis of HCM was based on echocardiographic demonstration of unexplained LVH, i.e., maximum LV wall thickness ≥ 15 mm 2 (1.13%) 1 (0.56%) [11] 2020 Canada and Chinese Hongkong 266 LVH Inclusion criteria for the study included the following: 1) ability to provide informed consent, 2) LVH based on echocardiography. Participants were excluded from the study if other known causes of hypertrophic remodelling were present in their clinical history, such as the following: 1) uncontrolled hypertension, 2) hemodynamically stable aortic valvular stenosis, 3) coarctation of the aorta, 4) cardiac amyloidosis, and 5) previously diagnosed hypertrophic cardiomyopathy. Patients who were pregnant or suspected to be pregnant were also excluded 5 (1.88%) 5 (1.88%) [14] 2021 Hongkong, China 499 LVH Adult (age ≥18 years) Han Chinese subjects with LVH, defined as a maximal interventricular septal (IVST) and/or posterior wall thickness (PWT) ≥13 mm on echocardiography, were identified from our echo lab and prospectively recruited for Fabry screening in this study. Exclusion criteria were LVH caused by known sarcomere gene mutation, infiltrating cardiomyopathies (e.g., amyloidosis), athletic heart, noncompaction cardiomyopathy, and other non-Fabry metabolic or syndromic conditions associated with LVH. 8 (1.60%) 8 (1.60%) [15] 2024 Hongkong, China 426 LVH Adult (aged ≥18 years) consecutive patients with LVH were recruited for Fabry screening if they had maximal left ventricular (septal and/or posterior) wall thickness ≥13 mm, as determined by transthoracic echocardiography. Patients with abnormal loading conditions, namely, hypertension and aortic stenosis, were included in the study. Exclusion criteria included those with a diagnosis of HCM (i.e., increased LV wall thickness of ≥13 mm not solely explained by abnormal loading conditions or those with known sarcomere mutations), other infiltrative cardiomyopathies (e.g., cardiac amyloidosis), LV noncompaction, athlete’s heart, morbid obesity, and other non-Fabry infiltrative cardiomyopathies associated with LVH. 4 (0.94%) 3 (0.70%) [19] 2018 Taiwan, China 1000 Stroke Young stroke patients were aged 18–55 years 2 (0.20%) 2 (0.20%) [13] 2018 Taiwan, China 1012 CKD Patients at different CKD stages and not on dialysis with unknown etiology 6 (0.59%) 3 (0.30%) [12] 2023 Taiwan, China 1812 ESRD Male patients from Pre-End Stage Renal Disease Program, hemodialysis, peritoneal dialysis, and kidney transplant programs. Patients aged younger than 20 years were excluded. 3 (0.16%) 2 (0.11%) [16] 2024 Zhejiang, China* 244 ESRD patients under dialysis 1 (0.41%) 1 (0.41%) [20] 2009 Taiwan, China 171,977 NBS NA 74 (1/2324) 63 (1/2730) [8] 2013 Japan 21170 NBS NA 3 (1/7057) 1 (1/21170) [10] 2024 Nanjing, China 17171 NBS NA 13 (1/1321) 6 (1/2862) [17] 2024 Shanghai, China 50108 NBS NA 8 (1/6264) 1 (1/50108) [18] *Notes: In the 2024 Zhejiang study, family screening of the index patient (41 family members) yielded 11 FD patients: FD, Fabry disease; Pub, Publication; Pop, Population; LVH, left ventricular hypertrophy; CKD, chronic kidney disease; ESRD, end-stage renal disease; NBS, newborn screening; Ref, reference; NA, not available. Among the patients included in this study, 25 patients had a previously reported GLA IVS4 + 919G > A pathogenic variant located in the Xq22.1 region. This variant was first discovered in Kyushu, Japan [ 21 ], has a high frequency in Chinese Taiwan populations and has been linked to late-onset Fabry disease [ 22 ]; the incidence of this specific variant is as high as 80% in patients with Fabry disease in Taiwan, China. Patients with the GLA IVS4 + 919G > A variant, including mainland China, Chinese Taiwan, Japan, Singapore, Vietnam and Malaysia, who were of Chinese ancestry, were subsequently investigated [ 14 , 23 ]. In contrast, this variant is very rare in other ethnic populations. This study identified 25 Fabry disease patients harboring the GLA IVS4 + 919G > A variant in Ninghai County, Zhejiang Province, China. The clustering of cases along coastal regions suggests that this variant may represent a regional founder mutation, potentially linked to historical population migration patterns and originating from the common ancestor, which was traced to Chinese ancestors more than 800 years ago via genetic assessments of the common haplotype [ 23 ]. The sequence of the patient’s intron 4 contains a single G-to-A transversion at IVS4 + 919G > A, causing an increase in alternatively spliced genes; it has been proven that this sequence is related to cardiac diseases, such as LVH, valve regurgitation, cardiac failure, arrhythmia, and myocardial ischemia, described as a cardiac variant of Fabry disease [ 11 , 21 , 24 ]. Recent studies suggest that the phenotypes of Fabry disease with the variant IVS4 + 919G > A are diverse; several studies have shown that insidious and irreversible organ injury may progress silently [ 25 , 26 ], including renal, cardiovascular, cerebrovascular, gastrointestinal, respiratory, and ocular manifestations (Table 5) [ 11 , 13 – 15 , 20 , 27 – 31 ]. In this study, the clinical manifestations of 25 patients with Fabry disease identified through high-risk and family screening included LVH, pain in the lower limbs, stroke, chronic kidney disease, gastrointestinal symptoms, and conjunctival vessel tortuosity. Ten patients had LVH, among whom, proband 4 and proband 5 had implanted pacemakers; proband 1 experienced pain in both lower limbs as the first initial symptom. Cardiac magnetic resonance imaging (MRI) revealed that the ventricular septum was thick, which indicates that patients with Fabry disease may have experienced heart injury in childhood. To the best of our knowledge, there is limited literature on patients with a known intronic variant, IVS4 + 919G > A, combined with peripheral nerve pain. Family genetic screening identified 2 affected relatives, the son of proband 5 and his wife, who were also diagnosed with Fabry disease with the GLA IVS4 + 919G > A variant. To date, it has been unexpectedly and rarely reported. The clinical characteristics of Fabry disease are heterogeneous; therefore, to reduce the chance of missing a diagnosis of Fabry disease, the proband’s relatives should be asked to provide more detailed information, and family genetic screening should be offered to all the relatives of the probands [ 5 , 32 ]. Table 5 Systematic review of Fabry disease cases with the IVS4+919G>A variant in China Publication Year Region No. of Cases with IVS4+919G>A cases Extracardiac involvement of IVS4+919G>A cases Ref 2010 Taiwan, China 94 Microalbuminuria in 17 cases；At least one ocular manifestation consistent with Fabry disease in 41cases [28] 2013 Taiwan, China 21 Elevated urine ACR in 6 cases; Abnormal eGFR in 1 case；Cerebrovascular disorders in 1 case; cornea verticillata in 2 cases; Fabry cataract in 5 cases [27] 2014 Taiwan, China 22 ESRD in 1 case; Chronic renal insufficiency in 1 case [29] 2016 Taiwan, China 26 Infarctions in 9 cases；pulvinar sign in 8 cases [30] 2024 Zhejiang, China 12 Renal involvement in 9 case（75.00%）, among them, 9 with albuminuria or hematuria, 1 with ESRD; abnormal brain MRI in 4 cases [31] 2024 Zhejiang, China 6 Pain in both lower limbs in 1 case [20] ACR, albumin-to-creatine ratio; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; Ref, reference. Currently, ERT is available for treatment to prevent multiple organ and system damage that occurs in Fabry disease. In May 2018, Fabry disease was listed as the first batch of rare diseases in China [ 33 ]. Agalsidase alfa and agalsidase beta were approved by China's National Medical Products Administration [ 34 ]. The inclusion of Fabry disease therapies in Zhejiang Province's rare disease reimbursement drug list enables timely treatment initiation, significantly reducing the risk of irreversible organ damage through early intervention [ 2 , 29 , 35 ]. Proband 1 and his father underwent pretreatment ERT and successfully received an intravenous infusion of agalsidase beta, and the pain in both lower limbs was alleviated. In conclusion, the integration of targeted high-risk population screening with family screening significantly improves the early diagnosis of Fabry disease. Patients harboring the GLA IVS4 + 919G > A variant exhibit a heterogeneous phenotype, with multisystem involvement extending beyond classical cardiac manifestations to include renal disease, stroke, respiratory symptoms, gastrointestinal symptoms and ocular symptoms. This study identified the GLA IVS4 + 919G > A variant as a cause of Fabry disease in a patient who presented with lower limb pain as the initial symptom, expanding the known phenotypic spectrum. Furthermore, our data confirm the high prevalence of this variant in Ninghai County, Zhejiang Province, Eastern China, suggesting a potential regional founder effect. Abbreviations DBS: Dried blood spots; α-Gal A: α-Galactosidase A; Lyso-GL-3: globotriaosylsphingosine; LVH: left ventricular hypertrophy; CAD: coronary atherosclerotic heart disease; ERT: enzyme replacement therapy; HUA: hyperuricemia; CKD: chronic kidney disease; COPD: chronic obstructive pulmonary disease; PVC: premature ventricular complex; cTnI: troponin I; BNP: B-type natriuretic peptide; IVST: interventricular septal thickness; LVPWT: left ventricular posterior wall thickness; LVEF: left ventricular ejection fraction; LVMI: left ventricular mass index. Declarations Acknowledgements The authors sincerely thank all the patients and their families who participated in this study. Author contributions Each author has participated sufficiently in the work to take public responsibility for the content. JHM and ZHL participated in the conception and design of the study; ZHG, ZQD, XDP, KQL, MJY, TTL, HBZ, HLG, GYG and ZGH conducted the data acquisition, analysis, and interpretation; ZHG drafted the article and provided intellectual content of critical importance to the work described; and JHM revised the article. All the authors approved the final manuscript. Funding This study was supported by the Ninghai County Science and Technology Plan Project (No. 202325) Date availability Statement The raw sequence data reported in this paper have been deposited in the Genome Sequence Archive (Genomics, Proteomics & Bioinformatics 2021) in National Genomics Data Center (Nucleic Acids Res 2024), China National Center for Bioinformation / Beijing Institute of Genomics, Chinese Academy of Sciences (GSA-Human: HRA011136) that are publicly accessible at https://ngdc.cncb.ac.cn/gsa-human. Ethics approval and consent to participate All procedures performed in studies involving human participants were performed in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Ethics approval for this study was granted by the Ethics Board of Ninghai First Hospital (project number: Nhyy-IEC-KY202304). Informed consent was obtained from all individual participants included in the study. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. Author details 1 Department of Paediatrics, Ninghai First Hospital, Ninghai, Zhejiang Province, China. 2 Department of Nephrology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang Province, China. 3 Department of Nephrology, Ninghai First Hospital, Ninghai, Zhejiang Province, China. 4 Department of Cardiology, Ninghai First Hospital, Ninghai, Zhejiang Province, China. 5 Department of Infections Disease, Ninghai First Hospital, Ninghai, Zhejiang Province, China. 6 Department of Physiatry, Ninghai First Hospital, Ninghai, Zhejiang Province, China. 7 Department of Cardiac ultrasound, Ninghai First Hospital, Ninghai, Zhejiang Province, China. References Mehta A, Hughes DA. Fabry disease [M/OL]. 2nd ed. Seattle (WA): University of Washington, Seattle, 2002: 1‑36[2023‑03‑09]. https://www. ncbi. nlm. NIH. Gov/books/NBK1292. Chinese Fabry disease expert panel. Expert consensus for diagnosis and treatment of Fabry disease in China (2021) [J]. Chin J Intern Med, 2021,60(4):321-330. Wanner C, Arad M, Baron R, et al. European expert consensus statement on therapeutic goals in Fabry disease[J]. Mol Genet Metab, 2018,124(3):189-203. Germain D P, Moiseev S, Suarez-Obando F, et al. The benefits and challenges of family genetic testing in rare genetic diseases-lessons from Fabry disease[J]. Mol Genet Genomic Med, 2021,9(5):e1666. Moiseev S, Tao E, Moiseev A, et al. The Benefits of Family Screening in Rare Diseases: Genetic Testing Reveals 165 New Cases of Fabry Disease among At-Risk Family Members of 83 Index Patients[J]. Genes (Basel), 2022,13(9). Linthorst G E, Bouwman M G, Wijburg F A, et al. Screening for Fabry disease in high-risk populations: a systematic review[J]. J Med Genet, 2010,47(4):217-222. Doheny D, Srinivasan R, Pagant S, et al. Fabry Disease: prevalence of affected males and heterozygotes with pathogenic GLA mutations identified by screening renal, cardiac and stroke clinics, 1995-2017[J]. J Med Genet, 2018,55(4):261-268. Hwu W L, Chien Y H, Lee N C, et al. Newborn screening for Fabry disease in Taiwan reveals a high incidence of the later-onset GLA mutation c.936+919G>A (IVS4+919G>A)[J]. Hum Mutat, 2009,30(10):1397-1405. Lu Y H, Huang P H, Wang L Y, et al. Improvement in the sensitivity of newborn screening for Fabry disease among females through the use of a high-throughput and cost-effective method, DNA mass spectrometry[J]. J Hum Genet, 2018,63(1):1-8. Inoue T, Hattori K, Ihara K, et al. Newborn screening for Fabry disease in Japan: prevalence and genotypes of Fabry disease in a pilot study[J]. J Hum Genet, 2013,58(8):548-552. Kubo T, Ochi Y, Baba Y, et al. Prevalence and clinical features of Fabry disease in Japanese male patients with diagnosis of hypertrophic cardiomyopathy[J]. J Cardiol, 2017,69(1):302-307. Lin C J, Chien Y H, Lai T S, et al. The results of Fabry Disease Screening in Male Pre-End Stage Renal Disease Patients with Unknown Etiology Found Through the Platform of a Chronic Kidney Disease Education Program in a Northern Taiwan Medical Center[J]. Kidney Blood Press Res, 2018,43(5):1636-1645. Lee T H, Yang J T, Lee J D, et al. Genomic screening of Fabry disease in young stroke patients: the Taiwan experience and a review of the literature[J]. Eur J Neurol, 2019,26(3):553-555. Sadasivan C, Chow J, Sheng B, et al. Screening for Fabry Disease in patients with unexplained left ventricular hypertrophy[J]. PLoS One, 2020,15(9):e239675. Fan Y, Chan T N, Chow J, et al. High Prevalence of Late-Onset Fabry Cardiomyopathy in a Cohort of 499 Non-Selective Patients with Left Ventricular Hypertrophy: The Asian Fabry Cardiomyopathy High-Risk Screening Study (ASIAN-FAME)[J]. J Clin Med, 2021,10(10). Shih C Y, You Z H, Tsai S F, et al. Diagnosis and Management of Fabry Disease in High-Risk Renal Disease Patients in Taiwan: A Single Center Study[J]. Transplant Proc, 2023,55(4):788-791. Sun Y, Guan X W, Wang Y Y, et al. Newborn genetic screening for Fabry disease: Insights from a retrospective analysis in Nanjing, China[J]. Clin Chim Acta, 2024,557:117889. Chang S, Zhan X, Liu Y, et al. Newborn Screening for 6 Lysosomal Storage Disorders in China[J]. JAMA Netw Open, 2024,7(5):e2410754. Leung S P, Dougherty S, Zhang X Y, et al. The Asian Fabry Cardiomyopathy High-Risk Screening Study 2 (ASIAN-FAME-2): Prevalence of Fabry Disease in Patients with Left Ventricular Hypertrophy[J]. J Clin Med, 2024,13(13). Chen B R, Tong M Q, Lu Z H, et al, High-risk screening combined with family screening for Fabry disease in adult hemodialysis population-a family report of GLA IVS4+919 G>A mutation in Fabry disease[J]. Clin J of Nephrol, 2024,40(1):18-23. Ishii S, Nakao S, Minamikawa-Tachino R, et al. Alternative splicing in the alpha-galactosidase A gene: increased exon inclusion results in the Fabry cardiac phenotype[J]. Am J Hum Genet, 2002,70(4):994-1002. Lin H Y, Chong K W, Hsu J H, et al. High incidence of the cardiac variant of Fabry disease was revealed by newborn screening in the Taiwan Chinese population[J]. Circ Cardiovasc Genet, 2009,2(5):450-456. Liang K H, Lu Y H, Niu C W, et al. The Fabry disease-causing mutation, GLA IVS4+919G>A, originated in Mainland China more than 800 years ago[J]. J Hum Genet, 2020,65(7):619-625. Hsu T R, Chang F P, Chu T H, et al. Correlations between Endomyocardial Biopsies and Cardiac Manifestations in Taiwanese Patients with the Chinese Hotspot IVS4+919G>A Mutation: Data from the Fabry Outcome Survey[J]. Int J Mol Sci, 2017,18(1). Hsu T R, Hung S C, Chang F P, et al. Later Onset Fabry Disease, Cardiac Damage Progress in Silence: Experience With a Highly Prevalent Mutation[J]. J Am Coll Cardiol, 2016,68(23):2554-2563. Hsu T R, Niu D M. Fabry disease: Review and experience during newborn screening[J]. Trends Cardiovasc Med, 2018,28(4):274-281. Lin H Y, Liu H C, Huang Y H, et al. Effects of enzyme replacement therapy for cardiac-type Fabry patients with a Chinese hotspot late-onset Fabry mutation (IVS4+919G>A)[J]. BMJ Open, 2013,3(7). Lin H Y, Huang C H, Yu H C, et al. Enzyme assay and clinical assessment in subjects with a Chinese hotspot late-onset Fabry mutation (IVS4 + 919G-->A)[J]. J Inherit Metab Dis, 2010,33(5):619-624. Hsu T R, Sung S H, Chang F P, et al. Endomyocardial biopsies in patients with left ventricular hypertrophy and a common Chinese later-onset Fabry mutation (IVS4 + 919G > A)[J]. Orphanet J Rare Dis, 2014,9:96. Lee H J, Hung S C, Hsu T R, et al. Brain MR Imaging Findings of Cardiac-Type Fabry Disease with an IVS4+919G>A Mutation[J]. AJNR Am J Neuroradiol, 2016,37(6):1044-1049. Ge Z H, Lu Z H, Pan X D, et al. Genotype-phenotype analysis of Fabry disease caused by GLA gene variation in a pedigree[J]. Chin J Pediatr, 2024,62(4):345-350. Favalli V, Disabella E, Molinaro M, et al. Genetic Screening of Anderson-Fabry Disease in Probands Referred From Multispecialty Clinics[J]. J Am Coll Cardiol, 2016,68(10):1037-1050. National Health Commission, Ministry of Science and Technology, Ministry of Industry and Information Technology, et al. Circular on publishing the first batch of rare diseases catalogue[Z]. Gazette of the State Council of the People's Republic of China, 2018(5):15-19. Chen N. Fabry disease: timely diagnosis and treatment, improve clinical outcome[J]. Zhonghua Nei Ke Za Zhi, 2021,60(4):299-301. Zhejiang Healthcare Security Administration, Zhejiang Provincial Department of Finance, Health Commission of Zhejiang Province, et al. Circular on the establishment of drug guarantee mechanism for rare diseases in Zhejiang Province[Z]. Gazette of Zhejiang Provincial People's Government, 2020(02):33-35. Additional Declarations No competing interests reported. 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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-6363208","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":446143072,"identity":"c1d98f8f-8423-4605-aca3-8eb0d6aff099","order_by":0,"name":"Zhuhui Ge","email":"","orcid":"","institution":"Ninghai First Hospital","correspondingAuthor":false,"prefix":"","firstName":"Zhuhui","middleName":"","lastName":"Ge","suffix":""},{"id":446143074,"identity":"84652014-0933-4d41-9819-a1a20018a91f","order_by":1,"name":"Jianhua 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16:53:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6363208/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6363208/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12920-026-02314-9","type":"published","date":"2026-02-05T15:57:55+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":82121992,"identity":"e633c47b-a940-485a-9553-9dbabe0a38b3","added_by":"auto","created_at":"2025-05-07 03:25:40","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":102247,"visible":true,"origin":"","legend":"\u003cp\u003ePedigrees of families with Fabry disease. (A) Pedigree of Proband 1’s family. (B) Pedigree of Proband 2’s family. (C) Pedigree of Proband 3’sfamily. (D) Pedigree of Proband 4’s family. (E) Pedigree of Proband 5’s family. (F) Pedigree of Proband 6’s family. (G) Pedigree of Proband 7’s family\u003c/p\u003e","description":"","filename":"OnlineFig1.png","url":"https://assets-eu.researchsquare.com/files/rs-6363208/v1/189f31c3659568a5e8614865.png"},{"id":102234023,"identity":"eccd5003-9783-436f-a7cb-db0dba226f35","added_by":"auto","created_at":"2026-02-09 16:04:12","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1297452,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6363208/v1/3b96aac0-9d98-49aa-9ae8-bc487296a395.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Successful Experience with High-Risk and Family Screening for Fabry Disease in Ninghai County, Zhejiang Province, Eastern China: Genotype‒Phenotype Analysis of the GLA IVS4+919G\u003eA Variant","fulltext":[{"header":"Introduction","content":"\u003cp\u003eFabry disease (OMIM #301500) is a rare, X-linked lysosomal storage disorder caused by pathogenic variants in the \u003cem\u003eGLA\u003c/em\u003e gene, resulting in a deficiency in α-Gal A activity. This deficiency leads to the progressive accumulation of globotriaosylceramide (GL-3) and globotriaosylsphingosine (Lyso-GL-3) in cells and multiple organ systems throughout the body [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], causing multiorgan pathology resulting in substantial mortality and a reduced life expectancy [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The clinical spectrum ranges from classic early-onset to atypical late-onset phenotypes. The clinical manifestations include renal insufficiency of unknown etiology, acroparesthesia, unexplained left ventricular hypertrophy (LVH), cardiac arrhythmia, unexplained stroke, angiokeratomas, sweating abnormalities, cornea verticillata, lenticular opacities, and unexplained gastrointestinal symptoms [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Owing to skewed X chromosome inactivation, heterozygous females generally present with milder clinical manifestations and a delayed age of onset relative to those of hemizygous males [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe early symptoms of patients with Fabry disease are nonspecific. Therefore, early diagnosis remains a clinical challenge. To enhance the early diagnosis of Fabry disease, some countries have systematically conducted high-risk, newborn, and genetic screening [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. This study was designed to combine high-risk and family screening to increase the yield of diagnoses of Fabry disease presenting with different but relevant phenotypic traits (isolated or combined).\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eExperimental design\u003c/h2\u003e \u003cp\u003eThe experimental design of our study involved collaboration across thirteen hospitals in Zhejiang Province. From October 2021 to May 2024, we analysed DBS samples collected from 388 high-risk individuals screened for Fabry disease at Ninghai First Hospital, and those patients met at least one of the following criteria: (a) unexplained chronic kidney disease (including unexplained proteinuria or haematuria); (b) unexplained stroke; (c) unexplained cardiovascular diseases (unexplained LVH or cardiac failure); (d) acroparesthesias (periodic crises of severe pain in the extremities); (e) clustered angiokeratoma; (f) hypo-anhidrosis; (g) cornea verticillata and lenticular opacities; and (h) abdominal pain or diarrhoea of unknown aetiology [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. For males, the level of α-Gal A determined below normal (\u0026lt;\u0026thinsp;2.40 \u0026micro;mol\u0026middot;L\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e\u0026middot;h\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) was followed by long-range PCR and sequencing of the \u003cem\u003eGLA\u003c/em\u003e gene, and the level of lyso-GL-3 was tested. For female adults, a level of lyso-GL-3 above normal (\u0026gt;\u0026thinsp;1.10 ng/mL) was tested via long-range PCR, the \u003cem\u003eGLA\u003c/em\u003e of the gene was sequenced, and the level of α-Gal A was determined. For female children, a level of α-Gal A determined below normal or a level of lyso-GL-3 tested above normal was followed by long-range PCR and sequencing of the \u003cem\u003eGLA\u003c/em\u003e gene. Family screening, including genetic testing, enzymatic activity measurement of the level of α-Gal A and the measurement of Lyso-GL-3, was offered to all the relatives of the probands. Patients who did not agree to undergo measurement of α-Gal A activity, Lyso-GL-3 and genetic analysis were excluded. This study was approved by the Ethical Committee of Ninghai First Hospital, Zhejiang Province, China (No. Nhyy-IEC-KY202304).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEnzymatic activity measurement of α-Gal A\u003c/h3\u003e\n\u003cp\u003eThe NeoLSD MSMS kit was used for the quantitative measurement of the activity of the enzyme GLA in dried blood spots (DSSs). A 3.2 mm (1/8 in) DBS was incubated in the buffer solution containing the internal standard and substrate provided by the kit at 37\u0026deg;C for 18.5 h. Then, water and NeoLSD Extraction Solution were added for extraction. Fifty microliters of the supernatant was transferred to a new well and dried with nitrogen. One hundred microliters of flow solvent was added to the well before it was run on a Waters UPLC/Xevo TQD MS/MS system. Data were obtained by using the multiple reaction monitoring (MRM) mode of the tandem mass spectrometry (MSMS) system. The enzymatic activity could be measured according to the signal response of the target analyte relative to the internal standard.\u003c/p\u003e\n\u003ch3\u003eMeasurement of Lyso-GL-3\u003c/h3\u003e\n\u003cp\u003eAn HPLC‒MS/MS instrument was used for the quantitative measurement of Lyso-GL-3 in DBSs. Two 3.2 mm (1/8 in) DBSs were incubated in buffer solution containing an internal standard. The supernatant was transferred to a new well before being run on the HPLC‒MS/MS system. Data were obtained by using the multiple reaction monitoring (MRM) mode of the tandem mass spectrometry (MSMS) system. The standard curve was generated via data fitting of the standard. The x-axis represents the ratio of the peak area of the target analyte to that of the internal standard, and the y-axis represents the concentration. The concentration of the target analyte in the sample can be obtained by inputting the ratio of the peak area into the regression equation of the standard curve.\u003c/p\u003e \u003cp\u003e \u003cb\u003eGenetic test of\u003c/b\u003e \u003cb\u003eGLA\u003c/b\u003e\u003c/p\u003e \u003cp\u003eA sufficient amount of genomic DNA was extracted from dry blood through lysis solution and ground. The whole-genome sequence of the \u003cem\u003eGLA\u003c/em\u003e gene was amplified via long-range PCR. The purified amplicons were processed to generate paired-end libraries and then sequenced on an Illumina NovaSeq platform. The data were processed and analysed to identify related variants.\u003c/p\u003e\n\u003ch3\u003eData analysis and statistics\u003c/h3\u003e\n\u003cp\u003eSPSS 22.0 software was used for statistical processing and descriptive analysis, including the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD) and median. Changes in plasma α-Gal A activity between males and females with Fabry disease were analysed via t tests. α-Gal A activity and Lyso-GL-3 activity between males and females with Fabry disease were analysed via Fisher\u0026rsquo;s exact test, and differences were considered to be statistically significant when the p value was \u0026lt;\u0026thinsp;0.05.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003eFrom October 2021 to May 2024, a total of 388 individuals (233 males and 155 females; median age, 46.5 years) who met the eligibility criteria were enrolled. The patient group included 165 patients with unexplained chronic kidney disease, 58 patients with unexplained stroke, 114 patients with unexplained cardiovascular diseases, 38 patients with acroparesthesia, 4 patients with clustered angiokeratoma, 5 patients with hypo-anhidrosis, 1 patient with cornea verticillata and lenticular opacities, and 3 patients with abdominal pain or diarrhea of unknown etiology.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eMeasurement of α-Gal A activity and Lyso-GL-3\u003c/h3\u003e\n\u003cp\u003eWe measured α-Gal A activity and Lyso-GL-3 via a DBS test. α-Gal A activity values\u0026thinsp;\u0026lt;\u0026thinsp;2.40 \u0026micro;mol/(L\u0026middot;h) were observed in 33 patients (25 males and 8 females), Lyso-GL-3 values\u0026thinsp;\u0026gt;\u0026thinsp;1.10 ng/mL were observed in 3 patients (3 females), α-Gal A activity values were low, and Lyso-GL-3 values increased in 17 patients (14 males and 3 females).\u003c/p\u003e\n\u003ch3\u003eGenetic tests and assays\u003c/h3\u003e\n\u003cp\u003eBy sequencing the full-length sequence of the \u003cem\u003eGLA\u003c/em\u003e gene, including the exon coding region and intron region, the \u003cem\u003eGLA\u003c/em\u003e variant IVS4\u0026thinsp;+\u0026thinsp;919G\u0026thinsp;\u0026gt;\u0026thinsp;A was detected in 13 hemizygous males and 12 heterozygous females, including 7 probands, who were diagnosed with Fabry disease. According to the interpretation guidelines of the American Society of Medical Genetics and Genomics, this variant was rated as the pathogenic variant.\u003c/p\u003e \u003cp\u003e \u003cb\u003eClinical characteristics of patients with the pathogenic\u003c/b\u003e \u003cb\u003eGLA\u003c/b\u003e \u003cb\u003evariant\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThrough high-risk screening, we identified 7 probands with Fabry disease. Subsequent family screening of these probands revealed 18 family members carrying pathogenic variants; 13 were clinically affected, 2 were asymptomatic carriers, and 3 declined further clinical assessment. The clinical characteristics of the 25 patients (13 males and 12 females) carrying the pathogenic \u003cem\u003eGLA\u003c/em\u003e variant IVS4\u0026thinsp;+\u0026thinsp;919G\u0026thinsp;\u0026gt;\u0026thinsp;A are summarised in Tables\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e; the affected organs and systems included the kidney (36.00%), brain (12.00%), heart (60.00%), peripheral nerves (16.00%), eye (20.00%), gastrointestinal tract (24.0%), and hypertension (8.00%).\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\u003eClinical characteristics of patients with the GLA IVS4\u0026thinsp;+\u0026thinsp;919G\u0026thinsp;\u0026gt;\u0026thinsp;A variant\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePt\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eα-Gal A\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLyso-GL-3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eComorbidity\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eyears\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(\u0026micro;mol\u0026middot;L\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e\u0026middot;h\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(ng/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;0.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLVH, Acroparesthesias, Bile reflux gastritis\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\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eDecreased vision\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\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLVH, Acroparesthesias\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\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eDecreased vision\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\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAcroparesthesias\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\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo symptoms\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\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLVH, CAD, HUA, Chronic gastritis, Acroparesthesias, CKD\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\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLVH, HUA, Conjunctival vessel tortuosity, CKD\u003c/p\u003e \u003cp\u003e结膜血管迂曲\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\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLVH, Cerebral ischemic stroke, CKD\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\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLVH, CKD\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\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo symptoms\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\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo symptoms\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\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo symptoms\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\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo symptoms\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\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLVH, CAD, COPD, Strock, Arrhythmia(PVC), Hypertension, Gastroduodenal ulcer, CKD\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eConjunctival vessel tortuosity, Arrhythmia (Sinus bradycardia)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eF\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\u003e3.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;0.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eConjunctival vessel tortuosity, Arrhythmia (Sinus bradycardia)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLVH, Pacemaker(Third-degree atrioventricular block), Hypertension, Duodenal bulb ulcer, CKD\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLVH, Pacemaker(Third-degree atrioventricular block), CKD\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCAD, Arrhythmia (Complete right bundle branch block)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;0.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNo symptoms\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLVH, Cerebral ischemic stroke, CAD, HUA, Gastrectomy for gastric cancer, Chronic gastritis, CKD\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eGastroduodenal ulcer\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLVH, Pacemaker(Third-degree atrioventricular block), CAD, HUA, CKD\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLVH, Arrhythmia (Sinus bradycardia), COPD, stroke\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eF, Female; M, Male; α-Gal A activity, normal range(2.40\u0026thinsp;~\u0026thinsp;17.65)\u0026micro;mol\u0026middot;L\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e\u0026middot;h\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e; Lyso-GL-3, normal range༈\u0026lt;1.10 ng\u0026middot;mL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e༉; LVH, Left ventricular hypertrophy; CAD, Coronary atherosclerotic heart disease; HUA, hyperuricemia; CKD, Chronic kidney disease; COPD, Chronic obstructive pulmonary disease; PVC, Premature ventricular complex\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\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\u003eClinical evaluation of cardiac status and renal function in patients with the GLA IVS4\u0026thinsp;+\u0026thinsp;919G\u0026thinsp;\u0026gt;\u0026thinsp;A variant\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"11\"\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 \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePt\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eCardiac biomarkers\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c9\" namest=\"c6\"\u003e \u003cp\u003eEchocardiography\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e \u003cp\u003erenal function\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCTnI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBNP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eIVST\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eLVPWT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eLVEF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eLVMI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eScr\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eGFR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eyears\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(\u0026micro;g/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(ng/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e(mm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e(mm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e(g/m\u003csup\u003e2.7\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e(\u0026micro;mol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e(ml/min)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e141\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e27.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e187\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\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e29.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eNA\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\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e320\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e48.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e109\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e 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align=\"left\" colname=\"c10\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eNA\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\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.459\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1290\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e 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align=\"left\" colname=\"c8\"\u003e \u003cp\u003e66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e68.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e84.48\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\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e173\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e63.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e79.64\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\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e 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colname=\"c5\"\u003e \u003cp\u003e479\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e43.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e94.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eF\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\u0026lt;\u0026thinsp;0.100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e40.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e95.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.661\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e506\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e82.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e83.69\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e81.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e86.89\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e52.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e99.12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.1008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3419\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e98.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e150\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e38.96\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e30.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e115.36\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.273\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2745\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e98.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e112\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e53.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.353\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e517\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e95.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e94.64\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"11\"\u003eF, Female; M, Male; CTnI, Troponin I(normal range 0.000\u0026thinsp;~\u0026thinsp;0.100 \u0026micro;g\u0026middot;L\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e);BNP, B-type natriuretic peptide༈normal range 0\u0026thinsp;~\u0026thinsp;100 pg\u0026middot;ml\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e༉; IVST, Interventricular septal thickness; LVPWT, Left ventricular posterior wall thickness; LVEF, Left ventricular ejection fraction; LVMI, Left ventricular mass index༈left ventricular hypertrophy was defined as LVMI\u0026thinsp;\u0026gt;\u0026thinsp;51 g/m\u003csup\u003e2.7\u003c/sup\u003e in males and LVMI\u0026thinsp;\u0026gt;\u0026thinsp;48 g/m\u003csup\u003e2.7\u003c/sup\u003e in females༉; NA, Not available.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAmong 25 patients (average age, 51.16\u0026thinsp;\u0026plusmn;\u0026thinsp;21.52 years), α-Gal A activity was within the normal reference range (2 females), α-Gal A activity was significantly reduced in 5 patients, falling below the standard reference (1 male and 4 females), Lyso-GL-3 levels were abnormally elevated in one patient (1 female), and both α-Gal A activity and Lyso-GL-3 were abnormally altered in 17 patients (11 males and 6 females). There were significant differences in α-Gal A activity (t\u0026thinsp;=\u0026thinsp;4.655, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) between 12 females and 13 males. In our cohort, normal α-Gal A activity or Lyso-GL-3 levels were observed more frequently in females than in males, as shown in 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\u003eBaseline α-Gal A and Lyso-GL-3 data of males and females with Fabry disease.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" 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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eα-Gal A\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eα-Gal A\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLyso-GL-3\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e(\u0026lt;2.40 \u0026micro;mol\u0026middot;L\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e\u0026middot;h\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e(\u0026gt;1.10 ng\u0026middot;mL\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eM (n\u0026thinsp;=\u0026thinsp;13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e61.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.775\u0026thinsp;\u0026plusmn;\u0026thinsp;0.217\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eF (n\u0026thinsp;=\u0026thinsp;12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e40.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.065\u0026thinsp;\u0026plusmn;\u0026thinsp;0.989\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.096\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.027\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e*Probability values refer to t-test and Fisher\u0026rsquo;s exact test as appropriate, significance at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05, F, Female; M, Male\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eProband 1 was a 9-year-old girl with pain in both lower limbs, and cardiovascular magnetic resonance imaging revealed that the ventricular septum was thick. The α-Gal A activity was below the normal range, Lyso-GL-3 was within the normal range, and genetic analysis revealed a heterozygous pathogenic variant in \u003cem\u003eGLA\u003c/em\u003e IVS4\u0026thinsp;+\u0026thinsp;919G\u0026thinsp;\u0026gt;\u0026thinsp;A, which has been reported previously\u003csup\u003e[1]\u003c/sup\u003e. Through family screening, 4 family members (proband\u0026rsquo;s father, elder sister, elder male cousin and elder female cousin) were diagnosed with Fabry disease, and a family member (proband\u0026rsquo;s fifth aunt) carried the \u003cem\u003eGLA\u003c/em\u003e variant with no symptoms. The age at diagnosis ranged from 9.0 years old to 50.0 years old in this Fabry disease family (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eProband 2 was a 55-year-old male with LVH, acroparesthesia, and gastrointestinal disorders, and he also suffered from coronary spastic angina. The level of α-Gal A was markedly low, and genetic analysis revealed a hemizygous pathogenic variant in \u003cem\u003eGLA\u003c/em\u003e IVS4\u0026thinsp;+\u0026thinsp;919G\u0026thinsp;\u0026gt;\u0026thinsp;A. Family screening for Fabry disease led to a diagnosis of 7 family members (3 elder brothers, one elder sister, 2 nieces and one granddaughter). The age at diagnosis ranged from 18.0 years old to 72.0 years old in this Fabry disease family (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB).\u003c/p\u003e \u003cp\u003eProband 3 was a 78-year-old male with LVH, ischemic stroke, acroparesthesia, kidney disease, and gastrointestinal disorders, and he also suffered from hypertensive disease and coronary spastic angina. The level of α-Gal A was markedly low, Lyso-GL-3 was above the normal range, and genetic analysis revealed a hemizygous pathogenic variant in \u003cem\u003eGLA\u003c/em\u003e IVS4\u0026thinsp;+\u0026thinsp;919G\u0026thinsp;\u0026gt;\u0026thinsp;A. Family screening identified the \u003cem\u003eGLA\u003c/em\u003e pathogenic variant in the proband\u0026rsquo;s elder daughter (diagnosed with Fabry disease) and younger daughter (an asymptomatic carrier). The age at diagnosis ranged from 56.0 years to 78.0 years (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC).\u003c/p\u003e \u003cp\u003eProband 4 was a 66-year-old male with LVH, hypertensive disease, and gastrointestinal disorders; he also experienced acute irreversible visual loss of his left eye due to ophthalmic artery occlusion and underwent pacemaker implantation. The level of α-Gal A was low, Lyso-GL-3 was above normal, and genetic analysis revealed a hemizygous pathogenic variant in \u003cem\u003eGLA\u003c/em\u003e IVS4\u0026thinsp;+\u0026thinsp;919G\u0026thinsp;\u0026gt;\u0026thinsp;A. The age at diagnosis was 66.0 years (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eD).\u003c/p\u003e \u003cp\u003eProband 5 was a 6-year-old male with LVH, kidney disease and gastrointestinal disorders, and he also underwent pacemaker implantation. The level of α-Gal A was markedly low, and that of Lyso-GL-3 was above normal. Genetic analysis revealed a hemizygous pathogenic variant in \u003cem\u003eGLA\u003c/em\u003e IVS4\u0026thinsp;+\u0026thinsp;919G\u0026thinsp;\u0026gt;\u0026thinsp;A. Since Fabry disease is inherited in an X-linked manner, the sons of proband 5 are expected to be normal. However, the proband\u0026prime;s son strongly urged family screening because of coronary atherosclerotic heart disease (CAD) and arrhythmia (complete right bundle branch block); subsequently, genetic analysis revealed \u003cem\u003eGLA\u003c/em\u003e IVS4\u0026thinsp;+\u0026thinsp;919G\u0026thinsp;\u0026gt;\u0026thinsp;A in the proband\u0026prime;s son and the proband\u0026prime;s wife. Thus, the proband\u0026prime;s son inherited it from his mother (the proband\u0026rsquo;s wife). All three patients were heterozygous for the \u003cem\u003eGLA\u003c/em\u003e IVS4\u0026thinsp;+\u0026thinsp;919G\u0026thinsp;\u0026gt;\u0026thinsp;A variant. The age at diagnosis ranged from 45.0 years old to 70.0 years old (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eE).\u003c/p\u003e \u003cp\u003eProband 6 was a 74-year-old male with LVH, kidney disease, ischaemic stroke and gastrointestinal disorders. The level of α-Gal A was markedly low, Lyso-GL-3 was above standard, and genetic analysis revealed a hemizygous pathogenic variant in \u003cem\u003eGLA\u003c/em\u003e IVS4\u0026thinsp;+\u0026thinsp;919G\u0026thinsp;\u0026gt;\u0026thinsp;A. Family screening indicated that his daughter was diagnosed with Fabry disease. The age at diagnosis ranged from 44.0 years to 74.0 years (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eF).\u003c/p\u003e \u003cp\u003eProband 7 was an 80-year-old male with LVH, kidney disease, ischaemic stroke and gastrointestinal disorders. The level of α-Gal A was markedly low, Lyso-GL-3 was above normal, and genetic analysis revealed a hemizygous pathogenic variant in \u003cem\u003eGLA\u003c/em\u003e IVS4\u0026thinsp;+\u0026thinsp;919G\u0026thinsp;\u0026gt;\u0026thinsp;A. Family screening indicated that his brother was diagnosed with Fabry disease. The age at diagnosis ranged from 61.0 years to 80.0 years (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eG).\u003c/p\u003e \u003cp\u003eAmong 25 patients with Fabry disease and 2 patients with the \u003cem\u003eGLA\u003c/em\u003e IVS4\u0026thinsp;+\u0026thinsp;919G\u0026thinsp;\u0026gt;\u0026thinsp;A variant, proband 1 and his father were treated regularly via enzyme replacement therapy (ERT); after 4 months of ERT, the pain in both lower limbs of proband 1 improved, and her father received ERT from September 2023. The levels of Lyso-GL-3 decreased from baseline values of 3.06 ng/mL to 2.20 ng/mL after 4 months of treatment. After the diagnosis of Fabry disease, proband 7 and the brother of proband 7 underwent pretreatment evaluation and were treated with ERT regularly. The levels of Lyso-GL-3 decreased from baseline values of 6.05 ng/mL and 5.30 ng/mL to 4.58 ng/mL and 5.07 ng/mL, respectively. Other patients have not initiated ERT and only receive different degrees of symptomatic treatment.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eFabry disease patients with rare genetic diseases and nonspecific symptoms often experience substantial diagnostic delays, sometimes more than a decade [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. If Fabry disease is not treated in time, end-organ damage significantly impairs quality of life and reduces life expectancy [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. To improve the diagnostic yield of Fabry disease, high-risk screening, family screening, and newborn screening programs have been adopted in some countries and regions. In this study, 388 cases of high-risk screening combined with family screening for Fabry disease were conducted from October 2021 to May 2024, and a total of 13 male hemizygotes and 12 female heterozygotes were detected, resulting in a diagnosis rate of 6.44%. Some studies have screened for Fabry disease in different populations (i.e., dialysis patients, LVHs, strokes, and newborns), and the prevalence of Fabry disease is 0.41% (0.33% for males and 0.10% for females) in dialysis patients. In addition, the prevalence of Fabry disease is at least 0.94% for both genders in LVH, and the prevalence of Fabry disease in premature stroke patients is 0.20% (0.13% for males and 0.14% for females) [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Newborn screening studies have reported that the prevalence of Fabry disease is unexpectedly high, reaching 0.04% for infants in the Chinese Taiwan population (Table\u0026nbsp;4) [\u003cspan additionalcitationids=\"CR9 CR10 CR11 CR12 CR13 CR14 CR15 CR16 CR17 CR18 CR19\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Compared with prior studies, the screening strategy implemented in this study demonstrated an enhanced diagnostic yield of Fabry disease and superior cost-effectiveness, and our data demonstrate a substantially higher prevalence of Fabry disease than previously reported. However, this study revealed that the majority of females with Fabry disease had an insignificant increase in Lyso-GL-3 levels, except for proband 1; the other female patients were successfully diagnosed through family screening in this study; these findings suggest that genetic testing is superior to Lyso-GL-3 quantification for early diagnosis of late-onset Fabry disease in females, mainly due to the limited sensitivity of Lyso-GL-3 in heterozygous individuals with skewed X inactivation. The international Fabry Family Screening Advisory Board, consisting of 19 Fabry experts from 15 countries, shared their experiences with family screening for Fabry disease and the difficulties in their respective countries. Family screening of 365 probands with Fabry disease revealed that 1,744 family members carried pathogenic \u003cem\u003eGLA\u003c/em\u003e variants; in other words, each proband affected 4.8 family members on average [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Although family screening is the most effective strategy for identifying undiagnosed Fabry patients, it is not universally accepted because of logistics economics and the numerous geographic, societal, and cultural barriers that limit the adoption of family genetic screening [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. In a retrospective study of 83 consecutive patients with Fabry disease, pedigree analysis followed by cascade genetic testing identified 165 previously undiagnosed Fabry disease cases among 331 at-risk family members [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The primary barriers to family-based cascade screening are ineffective communication among relatives and geographical dispersion of families, which hinders coordinated genetic testing efforts [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e\u003cstrong\u003eTable\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e4\u003c/strong\u003e Summary of global studies on Fabry cases with the IVS4+919G\u0026gt;A variant\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"1130\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003ePub year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003eRegion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003eNo. of screening\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003ePop\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 531px;\"\u003e\n \u003cp\u003eInclusion criteria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003eNo. of FD\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003eNo. of\u003c/p\u003e\n \u003cp\u003eCases with IVS4+919G\u0026gt;A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003eRef\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003eJapan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e177\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003eLVH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 531px;\"\u003e\n \u003cp\u003econsecutive unrelated male patients with HCM, the diagnosis of HCM was based on echocardiographic demonstration of unexplained LVH, i.e., maximum LV wall thickness \u0026ge; 15 mm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e2 (1.13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e1 (0.56%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e[11]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003eCanada and\u003c/p\u003e\n \u003cp\u003eChinese Hongkong\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e266\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003eLVH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 531px;\"\u003e\n \u003cp\u003eInclusion criteria for the study included the following: 1) ability to provide informed consent, 2) LVH based on echocardiography. Participants were excluded from the study if other known causes of hypertrophic remodelling were present in their clinical history, such as the following: 1) uncontrolled hypertension, 2) hemodynamically stable aortic valvular stenosis, 3) coarctation of the aorta, 4) cardiac amyloidosis, and 5) previously diagnosed hypertrophic cardiomyopathy. Patients who were pregnant or suspected to be pregnant were also excluded\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e5 (1.88%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e5 (1.88%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e[14]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003eHongkong, China\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e499\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003eLVH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 531px;\"\u003e\n \u003cp\u003eAdult (age \u0026ge;18 years) Han Chinese subjects with LVH, defined as a maximal interventricular septal (IVST) and/or posterior wall thickness (PWT) \u0026ge;13 mm on echocardiography, were identified from our echo lab and prospectively recruited for Fabry screening in this study. Exclusion criteria were LVH caused by known sarcomere gene mutation, infiltrating cardiomyopathies (e.g., amyloidosis), athletic heart, noncompaction cardiomyopathy, and other non-Fabry metabolic or syndromic conditions associated with LVH.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e8 (1.60%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e8 (1.60%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e[15]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003eHongkong, China\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e426\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003eLVH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 531px;\"\u003e\n \u003cp\u003eAdult (aged \u0026ge;18 years) consecutive patients with LVH were recruited for Fabry screening if they had maximal left ventricular (septal and/or posterior) wall thickness \u0026ge;13 mm, as determined by transthoracic echocardiography. Patients with abnormal loading conditions, namely, hypertension and aortic stenosis, were included in the study. Exclusion criteria included those with a diagnosis of HCM (i.e., increased LV wall thickness of \u0026ge;13 mm not solely explained by abnormal loading conditions or those with known sarcomere mutations), other infiltrative cardiomyopathies (e.g., cardiac amyloidosis), LV noncompaction, athlete\u0026rsquo;s heart, morbid obesity, and other non-Fabry infiltrative cardiomyopathies associated with LVH.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e4 (0.94%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e3 (0.70%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e[19]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003eTaiwan, China\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e1000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003eStroke\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 531px;\"\u003e\n \u003cp\u003eYoung stroke patients were aged 18\u0026ndash;55 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e2 (0.20%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e2 (0.20%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e[13]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003eTaiwan, China\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e1012\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003eCKD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 531px;\"\u003e\n \u003cp\u003ePatients at different CKD stages and not on dialysis with unknown etiology\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e6 (0.59%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e3 (0.30%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e[12]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003eTaiwan, China\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e1812\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003eESRD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 531px;\"\u003e\n \u003cp\u003eMale patients from Pre-End Stage Renal Disease Program, hemodialysis, peritoneal dialysis, and kidney transplant programs. Patients aged younger than 20 years were excluded.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e3 (0.16%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e2 (0.11%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e[16]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003eZhejiang, China*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e244\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003eESRD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 531px;\"\u003e\n \u003cp\u003epatients under dialysis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e1 (0.41%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e1 (0.41%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e[20]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2009\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003eTaiwan, China\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e171,977\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003eNBS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 531px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e74 (1/2324)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e63 (1/2730)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e[8]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2013\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003eJapan\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e21170\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003eNBS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 531px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e3 (1/7057)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e1 (1/21170)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e[10]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003eNanjing, China\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e17171\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003eNBS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 531px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e13 (1/1321)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e6 (1/2862)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e[17]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 47px;\"\u003e\n \u003cp\u003e2024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003eShanghai, China\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 70px;\"\u003e\n \u003cp\u003e50108\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003eNBS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 531px;\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 102px;\"\u003e\n \u003cp\u003e8 (1/6264)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106px;\"\u003e\n \u003cp\u003e1 (1/50108)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 97px;\"\u003e\n \u003cp\u003e[18]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*Notes: In the 2024 Zhejiang study, family screening of the index patient (41 family members) yielded 11 FD patients: FD, Fabry disease; Pub, Publication; Pop, Population; LVH, left ventricular hypertrophy; CKD, chronic kidney disease; ESRD, end-stage renal disease; NBS, newborn screening; Ref, reference; NA, not available.\u003c/p\u003e\u003cp\u003eAmong the patients included in this study, 25 patients had a previously reported \u003cem\u003eGLA\u003c/em\u003e IVS4\u0026thinsp;+\u0026thinsp;919G\u0026thinsp;\u0026gt;\u0026thinsp;A pathogenic variant located in the Xq22.1 region. This variant was first discovered in Kyushu, Japan [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], has a high frequency in Chinese Taiwan populations and has been linked to late-onset Fabry disease [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]; the incidence of this specific variant is as high as 80% in patients with Fabry disease in Taiwan, China. Patients with the \u003cem\u003eGLA\u003c/em\u003e IVS4\u0026thinsp;+\u0026thinsp;919G\u0026thinsp;\u0026gt;\u0026thinsp;A variant, including mainland China, Chinese Taiwan, Japan, Singapore, Vietnam and Malaysia, who were of Chinese ancestry, were subsequently investigated [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. In contrast, this variant is very rare in other ethnic populations. This study identified 25 Fabry disease patients harboring the \u003cem\u003eGLA\u003c/em\u003e IVS4\u0026thinsp;+\u0026thinsp;919G\u0026thinsp;\u0026gt;\u0026thinsp;A variant in Ninghai County, Zhejiang Province, China. The clustering of cases along coastal regions suggests that this variant may represent a regional founder mutation, potentially linked to historical population migration patterns and originating from the common ancestor, which was traced to Chinese ancestors more than 800 years ago via genetic assessments of the common haplotype [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The sequence of the patient\u0026rsquo;s intron 4 contains a single G-to-A transversion at IVS4\u0026thinsp;+\u0026thinsp;919G\u0026thinsp;\u0026gt;\u0026thinsp;A, causing an increase in alternatively spliced genes; it has been proven that this sequence is related to cardiac diseases, such as LVH, valve regurgitation, cardiac failure, arrhythmia, and myocardial ischemia, described as a cardiac variant of Fabry disease [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRecent studies suggest that the phenotypes of Fabry disease with the variant IVS4\u0026thinsp;+\u0026thinsp;919G\u0026thinsp;\u0026gt;\u0026thinsp;A are diverse; several studies have shown that insidious and irreversible organ injury may progress silently [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], including renal, cardiovascular, cerebrovascular, gastrointestinal, respiratory, and ocular manifestations (Table\u0026nbsp;5) [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan additionalcitationids=\"CR28 CR29 CR30\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. In this study, the clinical manifestations of 25 patients with Fabry disease identified through high-risk and family screening included LVH, pain in the lower limbs, stroke, chronic kidney disease, gastrointestinal symptoms, and conjunctival vessel tortuosity. Ten patients had LVH, among whom, proband 4 and proband 5 had implanted pacemakers; proband 1 experienced pain in both lower limbs as the first initial symptom. Cardiac magnetic resonance imaging (MRI) revealed that the ventricular septum was thick, which indicates that patients with Fabry disease may have experienced heart injury in childhood. To the best of our knowledge, there is limited literature on patients with a known intronic variant, IVS4\u0026thinsp;+\u0026thinsp;919G\u0026thinsp;\u0026gt;\u0026thinsp;A, combined with peripheral nerve pain. Family genetic screening identified 2 affected relatives, the son of proband 5 and his wife, who were also diagnosed with Fabry disease with the \u003cem\u003eGLA\u003c/em\u003e IVS4\u0026thinsp;+\u0026thinsp;919G\u0026thinsp;\u0026gt;\u0026thinsp;A variant. To date, it has been unexpectedly and rarely reported. The clinical characteristics of Fabry disease are heterogeneous; therefore, to reduce the chance of missing a diagnosis of Fabry disease, the proband\u0026rsquo;s relatives should be asked to provide more detailed information, and family genetic screening should be offered to all the relatives of the probands [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e\u003cstrong\u003eTable\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;5\u003c/strong\u003e Systematic review of Fabry disease cases with the IVS4+919G\u0026gt;A variant in China\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003ePublication Year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003eRegion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26px;\"\u003e\n \u003cp\u003eNo. of Cases with IVS4+919G\u0026gt;A cases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 41px;\"\u003e\n \u003cp\u003eExtracardiac involvement of IVS4+919G\u0026gt;A cases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003eRef\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e2010\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003eTaiwan, China\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26px;\"\u003e\n \u003cp\u003e94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 41px;\"\u003e\n \u003cp\u003eMicroalbuminuria in 17 cases；At least one ocular\u003cbr\u003emanifestation consistent with Fabry disease in 41cases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e[28]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e2013\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003eTaiwan, China\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26px;\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 41px;\"\u003e\n \u003cp\u003eElevated urine ACR in 6 cases; Abnormal eGFR in 1 case；Cerebrovascular disorders in 1 case; cornea verticillata in 2 cases; Fabry cataract in 5 cases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e[27]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e2014\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003eTaiwan, China\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26px;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 41px;\"\u003e\n \u003cp\u003eESRD in 1 case; Chronic renal insufficiency in 1 case\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e[29]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e2016\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003eTaiwan, China\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26px;\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 41px;\"\u003e\n \u003cp\u003eInfarctions in 9 cases；pulvinar sign in 8 cases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e[30]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e2024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003eZhejiang, China\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 41px;\"\u003e\n \u003cp\u003eRenal involvement in 9 case（75.00%）, among them, 9 with albuminuria or hematuria, 1 with ESRD; abnormal brain MRI in 4 cases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e[31]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e2024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003eZhejiang, China\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 26px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 41px;\"\u003e\n \u003cp\u003ePain in both lower limbs in 1 case\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e[20]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eACR, albumin-to-creatine ratio; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; Ref, reference.\u003c/p\u003e\u003cp\u003eCurrently, ERT is available for treatment to prevent multiple organ and system damage that occurs in Fabry disease. In May 2018, Fabry disease was listed as the first batch of rare diseases in China [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Agalsidase alfa and agalsidase beta were approved by China's National Medical Products Administration [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. The inclusion of Fabry disease therapies in Zhejiang Province's rare disease reimbursement drug list enables timely treatment initiation, significantly reducing the risk of irreversible organ damage through early intervention [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Proband 1 and his father underwent pretreatment ERT and successfully received an intravenous infusion of agalsidase beta, and the pain in both lower limbs was alleviated.\u003c/p\u003e \u003cp\u003eIn conclusion, the integration of targeted high-risk population screening with family screening significantly improves the early diagnosis of Fabry disease. Patients harboring the \u003cem\u003eGLA\u003c/em\u003e IVS4\u0026thinsp;+\u0026thinsp;919G\u0026thinsp;\u0026gt;\u0026thinsp;A variant exhibit a heterogeneous phenotype, with multisystem involvement extending beyond classical cardiac manifestations to include renal disease, stroke, respiratory symptoms, gastrointestinal symptoms and ocular symptoms. This study identified the \u003cem\u003eGLA\u003c/em\u003e IVS4\u0026thinsp;+\u0026thinsp;919G\u0026thinsp;\u0026gt;\u0026thinsp;A variant as a cause of Fabry disease in a patient who presented with lower limb pain as the initial symptom, expanding the known phenotypic spectrum. Furthermore, our data confirm the high prevalence of this variant in Ninghai County, Zhejiang Province, Eastern China, suggesting a potential regional founder effect.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eDBS: Dried blood spots; \u0026alpha;-Gal A: \u0026alpha;-Galactosidase A; Lyso-GL-3: globotriaosylsphingosine; LVH: left ventricular hypertrophy; CAD: coronary atherosclerotic heart disease; ERT: enzyme replacement therapy; HUA: hyperuricemia; CKD: chronic kidney disease; COPD: chronic obstructive pulmonary disease; PVC: premature ventricular complex; cTnI: troponin I; BNP: B-type natriuretic peptide; IVST: interventricular septal thickness; LVPWT: left ventricular posterior wall thickness; LVEF: left ventricular ejection fraction; LVMI: left ventricular mass index.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors sincerely thank all the patients and their families who participated in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEach author has participated sufficiently in the work to take public responsibility for the content. JHM and ZHL participated in the conception and design of the study; ZHG, ZQD, XDP, KQL, MJY, TTL, HBZ, HLG, GYG and ZGH conducted the data acquisition, analysis, and interpretation; ZHG drafted the article and provided intellectual content of critical importance to the work described; and JHM revised the article. All the authors approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by\u0026nbsp;the Ninghai County Science and Technology Plan Project (No. 202325)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDate availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe raw sequence data reported in this paper have been deposited in the Genome Sequence Archive (Genomics, Proteomics \u0026amp; Bioinformatics 2021) in National Genomics Data Center (Nucleic Acids Res 2024), China National Center for Bioinformation / Beijing Institute of Genomics, Chinese Academy of Sciences (GSA-Human: HRA011136) that are publicly accessible at https://ngdc.cncb.ac.cn/gsa-human.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll procedures performed in studies involving human participants were performed in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Ethics approval for this study was granted by the Ethics Board of Ninghai First Hospital (project number: Nhyy-IEC-KY202304). 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\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor details\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003eDepartment of Paediatrics, Ninghai First Hospital, Ninghai, Zhejiang Province, China.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e2\u003c/sup\u003eDepartment of Nephrology, Children\u0026apos;s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang Province, China.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e3\u003c/sup\u003eDepartment of Nephrology, Ninghai First Hospital, Ninghai, Zhejiang Province, China.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e4\u003c/sup\u003eDepartment of Cardiology, Ninghai First Hospital, Ninghai, Zhejiang Province, China.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e5\u003c/sup\u003eDepartment of Infections Disease, Ninghai First Hospital, Ninghai, Zhejiang Province, China.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e6\u003c/sup\u003eDepartment of Physiatry, Ninghai First Hospital, Ninghai, Zhejiang Province, China.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e7\u003c/sup\u003eDepartment of Cardiac ultrasound, Ninghai First Hospital, Ninghai, Zhejiang Province, China.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMehta A, Hughes DA. 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J Hum Genet, 2018,63(1):1-8.\u003c/li\u003e\n\u003cli\u003eInoue T, Hattori K, Ihara K, et al. Newborn screening for Fabry disease in Japan: prevalence and genotypes of Fabry disease in a pilot study[J]. J Hum Genet, 2013,58(8):548-552.\u003c/li\u003e\n\u003cli\u003eKubo T, Ochi Y, Baba Y, et al. Prevalence and clinical features of Fabry disease in Japanese male patients with diagnosis of hypertrophic cardiomyopathy[J]. J Cardiol, 2017,69(1):302-307.\u003c/li\u003e\n\u003cli\u003eLin C J, Chien Y H, Lai T S, et al. The results of Fabry Disease Screening in Male Pre-End Stage Renal Disease Patients with Unknown Etiology Found Through the Platform of a Chronic Kidney Disease Education Program in a Northern Taiwan Medical Center[J]. Kidney Blood Press Res, 2018,43(5):1636-1645.\u003c/li\u003e\n\u003cli\u003eLee T H, Yang J T, Lee J D, et al. Genomic screening of Fabry disease in young stroke patients: the Taiwan experience and a review of the literature[J]. 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Newborn Screening for 6 Lysosomal Storage Disorders in China[J]. JAMA Netw Open, 2024,7(5):e2410754.\u003c/li\u003e\n\u003cli\u003eLeung S P, Dougherty S, Zhang X Y, et al. The Asian Fabry Cardiomyopathy High-Risk Screening Study 2 (ASIAN-FAME-2): Prevalence of Fabry Disease in Patients with Left Ventricular Hypertrophy[J]. J Clin Med, 2024,13(13).\u003c/li\u003e\n\u003cli\u003eChen B R, Tong M Q, Lu Z H, et al, High-risk screening combined with family screening for Fabry disease in adult hemodialysis population-a family report of GLA IVS4+919 G\u0026gt;A mutation in Fabry disease[J]. Clin J of Nephrol, 2024,40(1):18-23.\u003c/li\u003e\n\u003cli\u003eIshii S, Nakao S, Minamikawa-Tachino R, et al. Alternative splicing in the alpha-galactosidase A gene: increased exon inclusion results in the Fabry cardiac phenotype[J]. Am J Hum Genet, 2002,70(4):994-1002.\u003c/li\u003e\n\u003cli\u003eLin H Y, Chong K W, Hsu J H, et al. High incidence of the cardiac variant of Fabry disease was revealed by newborn screening in the Taiwan Chinese population[J]. Circ Cardiovasc Genet, 2009,2(5):450-456.\u003c/li\u003e\n\u003cli\u003eLiang K H, Lu Y H, Niu C W, et al. The Fabry disease-causing mutation, GLA IVS4+919G\u0026gt;A, originated in Mainland China more than 800 years ago[J]. J Hum Genet, 2020,65(7):619-625.\u003c/li\u003e\n\u003cli\u003eHsu T R, Chang F P, Chu T H, et al. Correlations between Endomyocardial Biopsies and Cardiac Manifestations in Taiwanese Patients with the Chinese Hotspot IVS4+919G\u0026gt;A Mutation: Data from the Fabry Outcome Survey[J]. Int J Mol Sci, 2017,18(1).\u003c/li\u003e\n\u003cli\u003eHsu T R, Hung S C, Chang F P, et al. Later Onset Fabry Disease, Cardiac Damage Progress in Silence: Experience With a Highly Prevalent Mutation[J]. J Am Coll Cardiol, 2016,68(23):2554-2563.\u003c/li\u003e\n\u003cli\u003eHsu T R, Niu D M. Fabry disease: Review and experience during newborn screening[J]. Trends Cardiovasc Med, 2018,28(4):274-281.\u003c/li\u003e\n\u003cli\u003eLin H Y, Liu H C, Huang Y H, et al. Effects of enzyme replacement therapy for cardiac-type Fabry patients with a Chinese hotspot late-onset Fabry mutation (IVS4+919G\u0026gt;A)[J]. BMJ Open, 2013,3(7).\u003c/li\u003e\n\u003cli\u003eLin H Y, Huang C H, Yu H C, et al. Enzyme assay and clinical assessment in subjects with a Chinese hotspot late-onset Fabry mutation (IVS4 + 919G--\u0026gt;A)[J]. J Inherit Metab Dis, 2010,33(5):619-624.\u003c/li\u003e\n\u003cli\u003eHsu T R, Sung S H, Chang F P, et al. Endomyocardial biopsies in patients with left ventricular hypertrophy and a common Chinese later-onset Fabry mutation (IVS4 + 919G \u0026gt; A)[J]. Orphanet J Rare Dis, 2014,9:96.\u003c/li\u003e\n\u003cli\u003eLee H J, Hung S C, Hsu T R, et al. Brain MR Imaging Findings of Cardiac-Type Fabry Disease with an IVS4+919G\u0026gt;A Mutation[J]. AJNR Am J Neuroradiol, 2016,37(6):1044-1049.\u003c/li\u003e\n\u003cli\u003eGe Z H, Lu Z H, Pan X D, et al. Genotype-phenotype analysis of Fabry disease caused by GLA gene variation in a pedigree[J]. Chin J Pediatr, 2024,62(4):345-350.\u003c/li\u003e\n\u003cli\u003eFavalli V, Disabella E, Molinaro M, et al. Genetic Screening of Anderson-Fabry Disease in Probands Referred From Multispecialty Clinics[J]. J Am Coll Cardiol, 2016,68(10):1037-1050.\u003c/li\u003e\n\u003cli\u003eNational Health Commission, Ministry of Science and Technology, Ministry of Industry and Information Technology, et al. Circular on publishing the first batch of rare diseases catalogue[Z]. Gazette of the State Council of the People\u0026apos;s Republic of China, 2018(5):15-19.\u003c/li\u003e\n\u003cli\u003eChen N. Fabry disease: timely diagnosis and treatment, improve clinical outcome[J]. Zhonghua Nei Ke Za Zhi, 2021,60(4):299-301.\u003c/li\u003e\n\u003cli\u003eZhejiang Healthcare Security Administration, Zhejiang Provincial Department of Finance, Health Commission of Zhejiang Province, et al. Circular on the establishment of drug guarantee mechanism for rare diseases in Zhejiang Province[Z]. Gazette of Zhejiang Provincial People\u0026apos;s Government, 2020(02):33-35.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-medical-genomics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mgnm","sideBox":"Learn more about [BMC Medical Genomics](http://bmcmedgenomics.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/mgnm/default.aspx","title":"BMC Medical Genomics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Fabry disease, High-risk screening, Family screening, Early diagnosis, GLA gene variant, IVS4 + 919G \u003e A","lastPublishedDoi":"10.21203/rs.3.rs-6363208/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6363208/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThis study aimed to conduct high-risk and family screening for patients and to investigate the clinical phenotypes and genetic characteristics of patients with Fabry disease caused by the \u003cem\u003eGLA\u003c/em\u003e IVS4\u0026thinsp;+\u0026thinsp;919G\u0026thinsp;\u0026gt;\u0026thinsp;A variant in China.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eIn a 31-month study, a pilot program was designed to assess high-risk screening for Fabry disease in 388 patients by measuring their dry blood spot (DBS) α-galactosidase A (α-GAL) activity, globotriaosylsphingosine (Lyso-GL-3), and \u003cem\u003eGLA\u003c/em\u003e gene sequence from October 2021 to May 2024 at Ninghai First Hospital. Patients whose dried blood spot (DBS) α-GAL enzyme activity was low (\u0026lt;\u0026thinsp;2.40 \u0026micro;mol\u0026middot;L\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e\u0026middot;h\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) or whose Lyso-GL-3 level was high (\u0026gt;\u0026thinsp;1.10 ng/mL) underwent GLA genetic testing for diagnostic confirmation. Evaluation and family screening were carried out on the proband, and the clinical and genetic characteristics of Fabry disease caused by the \u003cem\u003eGLA\u003c/em\u003e IVS4\u0026thinsp;+\u0026thinsp;919G\u0026thinsp;\u0026gt;\u0026thinsp;A variant were summarised.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eBefore the pilot program was established, no patients were diagnosed with Fabry disease in the hospital. However, 31 months following the program\u0026rsquo;s implementation, 388 patients (233 males and 155 females) were recruited to meet the inclusion criteria for high-risk screening for Fabry disease, with a yield of diagnosis of 1.80% (7/388). A 9.8-year-old girl was screened because of a high-risk profile of severe pain in the extremities, and the other 6 males, who were diagnosed with Fabry disease, were screened because of unexplained left ventricular hypertrophy. All 7 diagnosed patients were carriers of the \u003cem\u003eGLA\u003c/em\u003e IVS4\u0026thinsp;+\u0026thinsp;919G\u0026thinsp;\u0026gt;\u0026thinsp;A variant. Family screening of 7 probands revealed that 18 family members carried pathogenic variants, resulting in a diagnosis rate of 6.44% (25/388); 13 were clinically affected, 2 were asymptomatic carriers, and 3 declined further clinical assessment. Among the 25 patients, multiple affected organs and systems included the heart (60.00%), peripheral nerves (16.00%), kidney (36.00%), eye (20.00%), brain (12.00%), and gastrointestinal tract (24.00%).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eScreening high-risk populations and family screening is critical for early diagnosis and timely intervention in patients with Fabry disease. The \u003cem\u003eGLA\u003c/em\u003e IVS4\u0026thinsp;+\u0026thinsp;919G\u0026thinsp;\u0026gt;\u0026thinsp;A variant is associated with diverse phenotypes of Fabry disease and is highly prevalent in late-onset cases in Ninghai County, Zhejiang Province, Eastern China.\u003c/p\u003e","manuscriptTitle":"Successful Experience with High-Risk and Family Screening for Fabry Disease in Ninghai County, Zhejiang Province, Eastern China: Genotype‒Phenotype Analysis of the GLA IVS4+919G\u0026gt;A Variant","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-07 03:25:36","doi":"10.21203/rs.3.rs-6363208/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-10-23T06:34:39+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-21T10:53:19+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"229824788677373718747593918474318585575","date":"2025-10-20T11:23:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"121021850441124037644343659983761948912","date":"2025-10-16T18:41:59+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"298124840341928018446419127346916566165","date":"2025-10-16T05:08:14+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-29T23:24:50+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"82599703237352125438931087094265851383","date":"2025-07-29T06:41:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"308602428938934805846742061789907099526","date":"2025-07-25T20:00:30+00:00","index":"hide","fulltext":""},{"type":"editorInvited","content":"","date":"2025-07-04T11:49:32+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"167013082718501279592448516158931408316","date":"2025-04-25T09:26:41+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-04-22T07:12:08+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-04-21T11:27:50+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-04-18T16:45:59+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Medical Genomics","date":"2025-04-18T16:44:51+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-medical-genomics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"mgnm","sideBox":"Learn more about [BMC Medical Genomics](http://bmcmedgenomics.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/mgnm/default.aspx","title":"BMC Medical Genomics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"dc0faa53-ffac-4d35-8d93-0ed7fd87ca55","owner":[],"postedDate":"May 7th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-02-09T16:01:16+00:00","versionOfRecord":{"articleIdentity":"rs-6363208","link":"https://doi.org/10.1186/s12920-026-02314-9","journal":{"identity":"bmc-medical-genomics","isVorOnly":false,"title":"BMC Medical Genomics"},"publishedOn":"2026-02-05 15:57:55","publishedOnDateReadable":"February 5th, 2026"},"versionCreatedAt":"2025-05-07 03:25:36","video":"","vorDoi":"10.1186/s12920-026-02314-9","vorDoiUrl":"https://doi.org/10.1186/s12920-026-02314-9","workflowStages":[]},"version":"v1","identity":"rs-6363208","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6363208","identity":"rs-6363208","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}