Ventricular arrhythmia and Noonan Syndrome with LZTR1 Mutations: Expanding the Phenotype with a Case Report and Review of the Literature

Ventricular arrhythmia and Noonan Syndrome with LZTR1 Mutations: Expanding the Phenotype with a Case Report and Review of the Literature | 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 Ventricular arrhythmia and Noonan Syndrome with LZTR1 Mutations: Expanding the Phenotype with a Case Report and Review of the Literature Zhuyuan Liu, Yan Huang, Jinxi Wang, Jiayi Tong This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4122815/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Noonan syndrome (NS) is characterized by typical facial features, short stature, congenital heart defects and other comorbidities, which is caused by germline mutations in genes coding for components of the Ras-mitogen-activated protein kinase (RAS-MAPK) pathway. Noonan syndrome is an inherited disease involving multiple systems, but ventricular arrhythmia in Noonan syndrome is rarely reported. Methods Here we report a 15-years old patient with LZTR1-associated Noonan syndrome, who has congenital heart defect, ventricular arrhythmia, bundle branch block, pectus excavatum, costal eversion, scoliosis, myopia, growth retardation and hearing loss. Genetic testing revealed that the patient had a novel heterozygous variant c.313delT (p.trp105Glyfs*42) mutation in the LZTR1. Results We provide a review of the literature of LZTR1 mutations and find that approximately 6% of published cases have ventricular arrhythmia. Conclusions Our findings expand on the Noonan syndrome phenotype and suggest that mutations in the LZTR1 gene are involved in ventricular arrhythmia. Noonan syndrome ventricular arrhythmia LZTR1 Figures Figure 1 Introduction Noonan syndrome (NS) ,with a prevalence of 1 in 1000–2500 live birth, is a genetic multi-system disorder. Characteristic findings include typical craniofacial features, congenital heart disease, postnatal growth retardation, variable cognitive delay, cryptorchidism, skeletal, and other anomalies[1–3]. Mutiple genes have been found to cause Noonan syndrome, all linked to the RAS-MAPK signalling pathway, including PTPN11, SOS1, RAF1, RIT1, KRAS, NRAS, BRAF, SHOC2, CBL, MAP2K1, MAP2K2, LZTR1, SOS2, and PPP1CB[4]. Leucine zipperlike transcription regulator 1 (LZTR1), has been firstly associated with the etiology of Noonan syndrome in 2014. LZTR1 has been reported to enable the polyubiquitination and degradation of endogenous RAS, mediate RAS ubiquitination and MAPK pathway activation and inhibit MAPK signalling pathway[5, 6]. Examination of LZTR1 variants associated with Noonan syndrome suggest this gene is functionally-linked to the RAS/MAPK pathway by negatively controlling RAS protein levels and MAPK signalling[7]. So far, less than 50 cases of Noonan syndrome have been associated with LZTR1 variants, and no specific report is available in literature regarding the spectrum of ventricular arrhythmia in LZTR1 mutations. Here we present a Chinese family with Noonan Syndrome caused by a heterozygous variant in LZTR1, and hypothesize that mutations in LZTR1 could contribute to the development of ventricular arrhythmia. Materials and methods Whole exome sequencing After obtaining the informed consent from the proband and her family, whole exome sequencing (WES) analysis was performed on the proband. Exons were captured using Agilent SureSelect and Illumina sequencing platform was used for high-throughput sequencing. After the sequencing data was matched and analyzed by NextGENe software, the Ingenuity online software system was used for mutation screening and interpretation. The candidate mutations were validated by Sanger sequencing. Literature Review A Medline search was conducted to find previously reported patients with LZTR1-associated Noonan syndrome. All the available literature on LZTR1, Noonan syndrome and ventricular arrhythmia was reviewed. Clinical reports Patient 1 The proband (Fig. 1 , III-2), a 15-year-old girl, was admitted to our hospital because of congenital heart disease. As the first child of non-consanguineous parents, she was born at 38 weeks of gestation via caesarean. The birth weight was 3800g. No prenatal or birth complications were noted. She was found to have pectus excavatum, facial features (large eyes, low-set cupped ears) and congenital heart defects (left ventricular (LV) hypertrophy with left ventricular outfow tract obstruction) at 4 months of age. She showed feeding difficulty and mild growth retardation since then, and now her height,weight and body mass index (BMI) were 150cm (− 2SD), 39kg (− 2SD) and 17.3 kg/m2, according to the standard reference values [12]. Physical examination: She showed the following typical features of Noonan syndrome: low-set, oval-shaped, posteriorly rotated ears, a short neck, scoliosis, myopia and hearing loss.. Auxiliary examination: The IGF-1 level was 156 ng/mL(reference interval:191-496ng/mL). The electrocardiogram test showed left ventricular (LV) hypertrophy with left ventricular outflow tract obstruction. X-rays showed scoliosis and her bone age was 15 years old. In addition, the tumor markers, hormone levels of the adrenal gland, thyroid gland and gonad were normal. The electrocardiogram showed complicated ventricular arrhythmia and bundle branch block. No abnormalities were found during the ultrasound examination of liver, kidneys, uterus or ovaries. The exome sequencing revealed a mutation in LZTR1.She was diagnosed as Noonan syndrome according to the clinical manifestation and laboratory tests. Patient 2 (Fig. 1 , II-5) was the aunt of patient 1, she died suddenly at the age of 38. she was born at 38 weeks of gestation via vaginal delivery. No prenatal or birth complications were noted. She showed significant growth retardation since the newborn stage. When she was 38 years old, her height and weight were 140cm and 31.8kg. She showed typical phenotype of Noonan syndrome: downslanting palpebral fissures, low-set, oval-shaped, posteriorly rotated ears, a short broad nose with a depressed root and full tip, a deeply grooved and long philtrum, a short neck, scoliosis, and mild hypertrichosis. Unfortunately, she had no auxiliary examination.The patient was also diagnosed as Noonan syndrome clinically. Suspected patient 3 (Fig. 1 , II-2) was the mother of the proband and the old sisiter of patient2. Her height was 156cm. She showed the mild phenotype of Noonan syndrome: a short neck, She didn’t show mental retardation, nor did she have any diseases of the heart, genitourinary system and skeletal system. The exome sequencing revealed a mutation in LZTR1. Results Exome Sequencing We identified a heterozygous variant c.313delT, under accession number NM_006767.4 in the LZTR1 gene. No other variants were detected in the LZTR1 gene or in the other RASopathy genes in the proband. The splicing variant was ranked as “likely pathogenic” according to the 2015-ACMG Standards and Guidelines [17]. Sanger sequencing showed that the variant of the proband was inherited from the proband’s mother, but her father without Noonan syndrome didn’t carry the variant. Unfortunately, patients II-5 was already died, and patient II 3,4,6,III-1 rejected the genetic analysis. Literature Search A total of 61 reported cases of Noonan syndrome with LZTR1 mutations were identified in the literature (Table 1 ), A review of these reports yielded 3 patients with or without family with Noonan syndrome and ventricular arrhythmia (Table 2 ). Table 1 Previous published reports of LZTR1-mutation Noonan syndrome variants zygosity Mode of inheritance typical facial features congenital heart defects short stature Skeletal anomalies ventricular arrhythmia other c.742G > A (p.Gly248Arg) Heterozygous Maternal + pulmonary valve stenosis/atrial septal defect - + - + c.850C > T (p.Arg284Cys) Heterozygous Maternal + - + - - + c.859C > T (p.His287Tyr) Heterozygous De novo + pulmonary valve stenosis/atrial septal defect + - - + c.356A > G (p.Tyr119Cys) Heterozygous De novo + left ventricular hypertrophy - - - + c.740C > A (p.Ser247Asn) Heterozygous Maternal + mitral valve insufciency + + - + c.881G > T (p.Arg294Leu)/ c.2212C > T (p.Gln738*) Compound Compound heterozygous Maternal/paternal + transposition of the great vessels, pulmonary stenosis, interventricular and interatrial communication + + + c.2374T > G (p.Cys792Gly) Compound heterozygous Maternal/paternal Autosomal recessive + left ventricular outfow tract obstruction, atrial septal defect + - - - .850C > T (p.Arg284Cys) Heterozygous Maternal Dominant + - + + - + c.1149 + 1G > T Heterozygous Maternal Autosomal dominant + - + + + + c.1149 + 1G > T Compound heterozygous Maternal/paternal Autosomal recessive + severe hypertrophic cardiomyopathy, mild pulmonary valve stenosis, broad QRS complexes, left axis deviation, striking negative pattern in the left precordial leads, right bundle branch block - c.2070-2A > G/ c.1735G > A (p.Val579Met) Compound heterozygous Paternal/maternal Autosomal recessive - severe hypertrophic cardiomyopathy without obstruction, left axis deviation, negative pattern in the left precordial leads - - - + c.355T > C (p.Tyr119His) Not provided De novo + pulmonary valve stenosis/branch pulmonary arterystenosis, slight asymmetric hypertrophy of inteventricular sept + + c.1430C > T (p.Ala477Val)/ three LRP1 variants Heterozygous Paternal/maternal + - + + - + c.347C > T (p.Ala116Val) Heterozygous De novo + heart murmur, hypertrophic cardiomyopathy + + - + c.628C > T (p.Arg210*)/c.2220-17C > A (p.Tyr741Hisfs*89) Compound heterozygous Paternal/maternal Autosomal recessive + congenital heart defect or valvular disease - + - + c.2178C > A (p.Tyr726*)/ c.1943-256C > T Heterozygous Paternal/maternal Autosomal recessive + cardiomyopathy, congenital heart defect or valvular disease + + - + c.1943-256C > T; *70G > A/ c.1943-256C > T; *70G > A Homozygous Paternal/maternal, Autosomal recessive + cardiomyopathy + - - + c.1687G > C (p.Glu563Gln) Homozygous Paternal/maternal Autosomal recessive + cardiomyopathy, congenital heart defect or valvular disease + + - + c.2407-2A > G/ c.2090G > A (p.Arg697Gln) Compound heterozygous Paternal/maternal Autosomal recessive + cardiomyopathy, congenital heart defect or valvular disease + + - + c.27delG (p.Gln10fs*15)/ c.1149 + 1G > A Compound heterozygous Paternal/maternal Autosomal recessive + - + + - + c.361C > G (p.His121Asp)/ c.2264G > A (p.Arg755Gln) Compound heterozygous Paternal/maternal Autosomal recessive + cardiomyopathy, congenital heart defect or valvular disease + + - + c.508C > T (p.Arg170Trp); c.614T > C (p.Ile205Thr)/ c.508C > T (p.Arg170Trp); c.614T > C (p.Ile205Thr) Compound homozygous Paternal/maternal Autosomal recessive + cardiomyopathy, congenital heart defect or valvular disease + + - - c.650A > C (p.Glu217Ala)/ c.650A > C (p.Glu217Ala) Homozygous Paternal/maternal Autosomal recessive + congenital heart defect or valvular disease, developmental delay/intellectual disability + - - - c.2062C > G (p.Arg688Gly)/ c.1943-256C > T Heterozygous Paternal/maternalAutosomal recessive + cardiomyopathy + + - + c.2325 + 1G > A/ c.1943-256C > T Not provided Paternal/maternal Autosomal recessive + cardiomyopathy, congenital heart defect or valvular disease - + - + c.2462T > C (p.Ile821Thr)/ c.2462T > C (p.Ile821Thr) Homozygous Paternal/maternal Autosomal recessive + cardiomyopathy, congenital heart defect or valvular disease + + - - c.406T > C (p.Tyr136His) Heterozygous De novo Autosomal dominant + the cardiac segments, coarctation of the aorta + - - - c.434A > T (p.Asn145Ile) Heterozygous Maternal Autosomal dominant + mild pulmonary stenosis, mild left ventricular dilation with a normal pulmonary valve, right bundle branch block + + - + c.290G > T (p.Arg97Leu) Not provided De novo, Autosomal dominant + hypertrophic cardiomyopathy,ventricular septal defect,atrial septal defect, + + - + c.407A > G (p.Tyr136Cys) Not provided De novo Autosomal dominant + - + + - + c.731C > G (p.Ser244Cys) Not provided De novo Autosomal dominant + - + + - + c.742G > A (p.Gly248Arg) Not provided De novo Autosomal dominant + valvular heart disease + + - + c.1591G > A (p.Asp531Asn)/ c.628C > T (p.Arg210*) Compound heterozygous Autosomal recessive + hypertrophic cardiomyopathy, mitral valve prolapse + + - + c.1149 + 1G > T/ c.2062C > T (p.Arg688Cys) Compound heterozygous Autosomal recessive + - + + - + c.628C > T (p.Arg210*)/ c.1735G > A (p.Val579Met) Compound heterozygous Autosomal recessive + mitral valve regurgitation + + - + c.1311G > A (p.Trp437*)/ c.-38T > A Compound heterozygous Suspected autosomal recessive + left ventricle hypertrophy - - - + c.1407G > A (p.Trp469*)/ c.2246A > G (p.Tyr749Cys) Compound heterozygous Suspected autosomal recessive + severe hypertrophic cardiomyopathy + + - + c.1382C > A (p.Ala461Asp)/ c.1385T > C (p.Ile462Thr) Compound heterozygous Maternal/paternal Suspected autosomal recessive + cardiac hypertrophy, pulmonic stenosis + - - - c.848G > A (p.Arg283Gln) Heterozygous De novo + atrial septal defect, ventricular septal defect, pulmonary stenosis, patent ductus arteriosus + + - + c.742G > A (p.Gly248Arg) Heterozygous Maternal Suspected autosomal dominant + ventricular septal defect,anomalous origin of coronary artery, - - - + c.2102C > A (p.Pro701His)/ c.2069 + 2T > C Compound heterozygous Paternal/maternal Suspected autosomal recessive + hypertropic cardiomyopathy + + - + c.428A > G (p.Asn143Ser) Heterozygous Paternal + hypertropic cardiomyopathy + - - + c.606_650del (p.Met202fs) Heterozygous Paternal + hypertropic cardiomyopathy, atrial septal defect, pulmonary stenosis + - + - c.756_758del (p.Asn253del) Heterozygous De nov + hypertropic cardiomyopathy + + - + c.1660G > C (p.Ala554Pro) Heterozygous De nov + hypertropic cardiomyopathy, atrial septal defect + + - + c.742G > A (p.Gly248Arg) Heterozygous De novo + mild pulmonary supravalvular stenosis - - - + c.2074T > A (p.Phe692Leu) Homozygous Maternal/paternal + mild pulmonary supravalvular stenosis + - - + c.730T > C (p.Ser244Pro) Heterozygous Maternal + - + - - + c.313delT Heterozygous Autosomal dominant + hypertropic cardiomyopathy + + + + Table 2 Ventricular arrhythmia and Noonan Syndrome with LZTR1 Mutations variants zygosity Mode of inheritance Genealogy typical facial features congenital heart defects short stature Skeletal anomalies ventricular arrhythmia other c.1149 + 1G > T Heterozygous Maternal Autosomal dominant Proband + - + + + + Sibling + - + + - - Mother + - - - - - c.606_650del (p.Met202fs) Heterozygous Paternal + hypertropic cardiomyopathy, atrial septal defect, pulmonary stenosis + - + - c.313delT Heterozygous Autosomal dominant Proband + hypertropic cardiomyopathy + + + + Mother + - - - - - Aunt + - + + - + Discussion and conclusion Noonan syndrome (NS) is characterized by typical facial features, short stature, congenital heart defects and other comorbidities[8]. The diagnosis of Noonan syndrome mainly depends on its typical clinical manifestations. However, about 25% of patients cannot get a clear genetic diagnosis, so it is importnt to correctly understand and analyze its clinical manifestations. The typical feature of Noonan syndrome in cardiovascular system is including pulmonary valve defect, hypertrophic cardiomyopathy and atrial septal defect. But apart from structure disease, some patients with Noonan syndrome have other manifestations like ventricular arrhythmia. As previous studies reported, 2 patients with LZTR1 mutaitaon Noonan syndrome have been diagnosed with ventricular arrhythmia. In our study, the proband (III-2) was the third Noonan syndrome patient with LZTR1 mutation identified as having ventricular arrhythmia (Table 1 ). In this study, we performed WES for molecular diagnoses. The results showed that there was a heterozygous variant c.313delT, under accession number NM_006767.4 in the LZTR1 gene. It is a novel LZTR1 mutation, which is not included in the HGMD and gnomAD database. LZTR1 can prematurely terminate amino acid translation or affect mRNA expression, and can be classified as potentially pathogenic according to the ACMG mutation classification criteria. Based on variant c.313delT in the LZTR1 gene segregating with Noonan syndrome-related phenotype in multiple affected family members, we speculated that the pedigree presented as dominant inheritance. LZTR1 is a highly conserved gene and encodes a protein characterized by six tandemly arranged Kelch motifs at the N-terminus and two broad complex, tramtrack and bric-a-brac/Pox virus and zinc finger domains at the C-terminus[9]. LZTR1 is an important regulator of the normal cell cycle and a conserved regulator of RAS ubiquitination and signaling[10]. Previous studies have demonstrated that LZTR1 variants can be acquired via AR or AD inheritance. Our patients had the Noonan syndrome phenotype and the heterozygous variant inherited in the AD form. The phenotype of LZTR1 mutations was generally severe, with short stature, mental retardation, and heart defects[11]. Cardiac involvement was present in up to 82% of affected individuals, including pulmonary stenosis, hypertrophic cardiomyopathy, atrial septal defect, and ventricle septal defect, mitral valve insufciency, transposition of the great vessels, broad QRS complexes, left axis deviation, striking negative pattern in the left precordial leads, right bundle branch block and ventricular arrhythmia(Table 1 ). Ventricular arrhythmia is not typically considered part of Noonan syndrome[12–16]. Ventricular dysrhythmias have been increasingly recognized in Noonan syndrome in mutation in PTPN 11, SOS 1, RAF 1, KARS, NRAS, BRAF and MAP2K1. On the other hand, lethal ventricular dysrhythmias have only been presumed from cases of unexpected sudden death[17, 18]. The article about LZTR1 mutation and ventricular arrhythmia is rare. We report a 15-years-old girl with Noonan syndrome due to a LZTR1 mutation and ventricular arrhythmia and review all reported cases of Noonan syndrome to identify similar patients with ventricular arrhythmia. Including the present report, from a total of 49 cases of Noonan syndrome with LZTR1 mutations, 3 patients had Noonan syndrome and ventricular arrhythmia(Table 2 ). The association of LZTR1 mutations and ventricular arrhythmia is supported by the RAS/MAPK pathway’s involvement in the presence of cardiac electrophysiological abnormalities.These ventricular dysrhythmias have almost always occurred in the setting of hypertrophic cardiomyopathy or pulmonary stenosis[19–21]. Ventricular arrhythmia is common in RAS/MAPK-associated arrhythmia due to the aforementioned mechanisms and as well as hypertrophic cardiomyopathy-induced arrhythmia due to myocardial fibrosis and left atrial enlargement. As the downstream targets of the RAS/MAPK pathway, high levels of phosphorylation of mitogen-induced extracellular kinase (MEK) and extracellular signal-regulated kinase (ERK) regulate cellular proliferation, apoptosis, differentiation and migration of cardiomyocytes which lead to cardiac hypertrophy and arrhythmia in Noonan syndrome[22–24]. The activation of Ca2+/calcineurin causes arrhythmia and cardiac hypertrophy due to pathological cardiac remodeling[25].The types of arrhythmia in our patient were complicated with ventricular arrhythmia, which are common in RAS/MAPK-associated arrhythmia due to the aforementioned mechanisms and as well as hypertrophic cardiomyopathy-induced arrhythmia due to myocardial fibrosis and left atrial enlargement. While the family with LZTR1 mutation(c.1149 + 1G > T ) have ventricular arrhythmia,without hypertrophic cardiomyopathy manifestation. Therefore, it was difficult to determine whether the arrhythmia was associated with hypertrophic cardiomyopathy, Noonan syndrome-related or both. In summary, we have described a novel condition of Noonan syndrome, caused by a heterozygous variant in LZTR1(c.313delT, under accession number NM_006767.4), manifested normal Noonan syndrome performance and complicated ventricular arrhythmia and bundle branch block, which is different from previous reports, which improves our understanding of Noonan syndrome. Besides, we find that patients with Noonan syndrome may suffer ventricular arrhythmia at the same time, which will help us to enrich the clinical spectrum of Noonan syndrome. Abbreviations Noonan syndrome (NS) Ras-mitogen-activated protein kinase (RAS-MAPK) Leucine zipperlike transcription regulator 1 (LZTR1) Declarations Availability of data and materials: The data supporting the conclusions of this article is included within the article. Acknowledgements: We would like to express our gratitude to the proband and his family members who agreed to participate in this study. Funding: This work was supported by the Natural Science Foundation of Jiangsu Province(BK20190352) and National Natural Science Foundation of China(82302875). Competing interests : The authors declare that they have no competing interests. Authors contributions: Liu zhuyuan: concept, design, definition of intellectual content, manuscript preparation, manuscript editing Yan Huang: literature search. Jinxi Wang: data acquisition, Jiayi Tong: manuscript review, the integrity of the work as a whole from inception to published article. Consent for publication: This patients’ guardian provided written informed consent for his personal and clinical details to be published in this study. There are no identifying images in this case. Ethics approval and consent to participate: This patients’ guardian provided oral and signed written informed consent to use his clinical materials in this study. The study was conducted in accordance with the principles contained in the Declaration of Helsinki and the ethical standards of the institutional and national research committee. References Sun L, Xie YM, Wang SS, Zhang ZW: Cardiovascular Abnormalities and Gene Mutations in Children With Noonan Syndrome . Front Genet 2022, 13 :915129.10.3389/fgene.2022.915129 Tiemens DK, Kleimeier L, Leenders E, Wingbermuhle E, Roelofs RL, Sibbles B, Oostwegel FSM, Vroonland E, van Leeuwen C, Niessen H et al : The most important problems and needs of rasopathy patients with a noonan syndrome spectrum disorder . Orphanet J Rare Dis 2023, 18 (1):198.10.1186/s13023-023-02818-y Wingbermuhle E, Roelofs RL, Oomens W, Kramer J, Draaisma JMT, Leenders E, Kleefstra T, Kessels RPC, Egger JIM: Cognitive Phenotype and Psychopathology in Noonan Syndrome Spectrum Disorders through Various Ras/MAPK Pathway Associated Gene Variants . J Clin Med 2022, 11 (16).10.3390/jcm11164735 El Bouchikhi I, Belhassan K, Moufid FZ, Iraqui Houssaini M, Bouguenouch L, Samri I, Atmani S, Ouldim K: Noonan syndrome-causing genes: Molecular update and an assessment of the mutation rate . Int J Pediatr Adolesc Med 2016, 3 (4):133-142.10.1016/j.ijpam.2016.06.003 Abe T, Umeki I, Kanno SI, Inoue SI, Niihori T, Aoki Y: LZTR1 facilitates polyubiquitination and degradation of RAS-GTPases . Cell Death Differ 2020, 27 (3):1023-1035.10.1038/s41418-019-0395-5 Bigenzahn JW, Collu GM, Kartnig F, Pieraks M, Vladimer GI, Heinz LX, Sedlyarov V, Schischlik F, Fauster A, Rebsamen M et al : LZTR1 is a regulator of RAS ubiquitination and signaling . Science 2018, 362 (6419):1171-1177.10.1126/science.aap8210 De Ridder W, van Engelen B, van Alfen N: Neurological features of Noonan syndrome and related RASopathies: Pain and nerve enlargement characterized by nerve ultrasound . Am J Med Genet A 2022, 188 (6):1801-1807.10.1002/ajmg.a.62714 Farncombe KM, Thain E, Barnett-Tapia C, Sadeghian H, Kim RH: LZTR1 molecular genetic overlap with clinical implications for Noonan syndrome and schwannomatosis . BMC Med Genomics 2022, 15 (1):160.10.1186/s12920-022-01304-x Jacquinet A, Bonnard A, Capri Y, Martin D, Sadzot B, Bianchi E, Servais L, Sacre JP, Cave H, Verloes A: Oligo-astrocytoma in LZTR1-related Noonan syndrome . Eur J Med Genet 2020, 63 (1):103617.10.1016/j.ejmg.2019.01.007 Guemes M, Martin-Rivada A, Ortiz-Cabrera NV, Martos-Moreno GA, Pozo-Roman J, Argente J: LZTR1: Genotype Expansion in Noonan Syndrome . Horm Res Paediatr 2019, 92 (4):269-275.10.1159/000502741 Steklov M, Pandolfi S, Baietti MF, Batiuk A, Carai P, Najm P, Zhang M, Jang H, Renzi F, Cai Y et al : Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination . Science 2018, 362 (6419):1177-1182.10.1126/science.aap7607 Chinton J, Huckstadt V, Mucciolo M, Lepri F, Novelli A, Gravina LP, Obregon MG: Providing more evidence on LZTR1 variants in Noonan syndrome patients . Am J Med Genet A 2020, 182 (2):409-414.10.1002/ajmg.a.61445 Jenkins J, Barnes A, Birnbaum B, Papagiannis J, Thiffault I, Saunders CJ: LZTR1-Related Hypertrophic Cardiomyopathy Without Typical Noonan Syndrome Features . Circ Genom Precis Med 2020, 13 (2):e002690.10.1161/CIRCGEN.119.002690 Johnston JJ, van der Smagt JJ, Rosenfeld JA, Pagnamenta AT, Alswaid A, Baker EH, Blair E, Borck G, Brinkmann J, Craigen W et al : Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants . Genet Med 2018, 20 (10):1175-1185.10.1038/gim.2017.249 Li X, Yao R, Tan X, Li N, Ding Y, Li J, Chang G, Chen Y, Ma L, Wang J et al : Molecular and phenotypic spectrum of Noonan syndrome in Chinese patients . Clin Genet 2019, 96 (4):290-299.10.1111/cge.13588 Magotteaux S, Farhat N, Jacquinet A, Seghaye MC: [Complex congenital heart disease : about a case of Noonan syndrome] . Rev Med Liege 2023, 78 (3):130-136 Aly SA, Boyer KM, Muller BA, Marini D, Jones CH, Nguyen HH: Complicated ventricular arrhythmia and hematologic myeloproliferative disorder in RIT1-associated Noonan syndrome: Expanding the phenotype and review of the literature . Mol Genet Genomic Med 2020, 8 (7):e1253.10.1002/mgg3.1253 Carcavilla A, Cambra A, Santome JL, Seidel V, Cruz J, Alonso M, Pozo J, Valenzuela I, Guillen-Navarro E, Santos-Simarro F et al : Genotypic Findings in Noonan and Non-Noonan RASopathies and Patient Eligibility for Growth Hormone Treatment . J Clin Med 2023, 12 (15).10.3390/jcm12155003 Pagnamenta AT, Kaisaki PJ, Bennett F, Burkitt-Wright E, Martin HC, Ferla MP, Taylor JM, Gompertz L, Lahiri N, Tatton-Brown K et al : Delineation of dominant and recessive forms of LZTR1-associated Noonan syndrome . Clin Genet 2019, 95 (6):693-703.10.1111/cge.13533 Sewduth RN, Pandolfi S, Steklov M, Sheryazdanova A, Zhao P, Criem N, Baietti MF, Lechat B, Quarck R, Impens F et al : The Noonan Syndrome Gene Lztr1 Controls Cardiovascular Function by Regulating Vesicular Trafficking . Circ Res 2020, 126 (10):1379-1393.10.1161/CIRCRESAHA.119.315730 Nakagama Y, Takeda N, Ogawa S, Takeda H, Furutani Y, Nakanishi T, Sato T, Hirata Y, Oka A, Inuzuka R: Noonan syndrome-associated biallelic LZTR1 mutations cause cardiac hypertrophy and vascular malformations in zebrafish . Mol Genet Genomic Med 2020, 8 (3):e1107.10.1002/mgg3.1107 Umeki I, Niihori T, Abe T, Kanno SI, Okamoto N, Mizuno S, Kurosawa K, Nagasaki K, Yoshida M, Ohashi H et al : Delineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1-PPP1CB complexes . Hum Genet 2019, 138 (1):21-35.10.1007/s00439-018-1951-7 Yu QX, Zhen L, Lin XM, Wen YJ, Li DZ: Prenatal diagnosis of autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants presented with thick nuchal translucency and cardiac abnormalities . Prenat Diagn 2023, 43 (13):1662-1665.10.1002/pd.6462 Zhao X, Li Z, Wang L, Lan Z, Lin F, Zhang W, Su Z: A Chinese family with Noonan syndrome caused by a heterozygous variant in LZTR1: a case report and literature review . BMC Endocr Disord 2021, 21 (1):2.10.1186/s12902-020-00666-6 Limongelli G, Sarkozy A, Pacileo G, Calabro P, Digilio MC, Maddaloni V, Gagliardi G, Di Salvo G, Iacomino M, Marino B et al : Genotype-phenotype analysis and natural history of left ventricular hypertrophy in LEOPARD syndrome . Am J Med Genet A 2008, 146A (5):620-628.10.1002/ajmg.a.32206 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-4122815","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":282273755,"identity":"f384cdc4-1b02-426f-b94b-a44b60284eb7","order_by":0,"name":"Zhuyuan Liu","email":"","orcid":"","institution":"Zhongda Hospital Southeast University","correspondingAuthor":false,"prefix":"","firstName":"Zhuyuan","middleName":"","lastName":"Liu","suffix":""},{"id":282273756,"identity":"4a1290fc-ae5c-46d0-a038-94f0d88d2896","order_by":1,"name":"Yan Huang","email":"","orcid":"","institution":"Fuwai Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yan","middleName":"","lastName":"Huang","suffix":""},{"id":282273757,"identity":"9a080524-2698-4d6b-9c0a-0468f72a48ed","order_by":2,"name":"Jinxi Wang","email":"","orcid":"","institution":"Fuwai Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jinxi","middleName":"","lastName":"Wang","suffix":""},{"id":282273758,"identity":"de4165bf-00e0-49f7-9032-afe09db028ed","order_by":3,"name":"Jiayi Tong","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4klEQVRIie3RsQrCMBCA4QuBdgl2jSjtK7S4+jAJQl0UHDsItlTiYMVXcXRsLXSKu4NDuuiqm5Oos2Lq5pBvvp/kOADD+EOWs77kjPSxZyeJYtFUn7RoHijVDe0gK1NfyUqfuMB6gervHDgMRbue4wYfgzykbJR3UMxFxGMLnMWSfU9wXFEmjz0bCnHg2y5Qud9oXikE5dlpgJLkmUgLfDrWJQOL8ns5i0skJlzgJkmIfUZKDBUS0CyhEilGQhxkKH0uVRHtLt46g+L2OqV3rq+3aOo6i9X35A35bdwwDMP46AGsZU0v7q9OoQAAAABJRU5ErkJggg==","orcid":"","institution":"Zhongda Hospital Southeast University","correspondingAuthor":true,"prefix":"","firstName":"Jiayi","middleName":"","lastName":"Tong","suffix":""}],"badges":[],"createdAt":"2024-03-18 11:28:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4122815/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4122815/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":53579457,"identity":"3f5e4f0b-0ee9-4a99-8d40-01d8854d38d3","added_by":"auto","created_at":"2024-03-27 17:22:48","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":38015,"visible":true,"origin":"","legend":"\u003cp\u003ethe pedigree of the proband and her family\u003c/p\u003e","description":"","filename":"FIGURE1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4122815/v1/e15e90cdc156f3c735b2f5fc.jpg"},{"id":54009861,"identity":"b4839292-4823-469e-b868-89b28d1b3673","added_by":"auto","created_at":"2024-04-03 10:30:12","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":895391,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4122815/v1/2692b006-82bb-4ae0-8c9e-68ca7f3c9f45.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Ventricular arrhythmia and Noonan Syndrome with LZTR1 Mutations: Expanding the Phenotype with a Case Report and Review of the Literature","fulltext":[{"header":"Introduction","content":"\u003cp\u003eNoonan syndrome (NS) ,with a prevalence of 1 in 1000\u0026ndash;2500 live birth, is a genetic multi-system disorder. Characteristic findings include typical craniofacial features, congenital heart disease, postnatal growth retardation, variable cognitive delay, cryptorchidism, skeletal, and other anomalies[1\u0026ndash;3].\u003c/p\u003e \u003cp\u003eMutiple genes have been found to cause Noonan syndrome, all linked to the RAS-MAPK signalling pathway, including PTPN11, SOS1, RAF1, RIT1, KRAS, NRAS, BRAF, SHOC2, CBL, MAP2K1, MAP2K2, LZTR1, SOS2, and PPP1CB[4]. Leucine zipperlike transcription regulator 1 (LZTR1), has been firstly associated with the etiology of Noonan syndrome in 2014.\u003c/p\u003e \u003cp\u003eLZTR1 has been reported to enable the polyubiquitination and degradation of endogenous RAS, mediate RAS ubiquitination and MAPK pathway activation and inhibit MAPK signalling pathway[5, 6]. Examination of LZTR1 variants associated with Noonan syndrome suggest this gene is functionally-linked to the RAS/MAPK pathway by negatively controlling RAS protein levels and MAPK signalling[7].\u003c/p\u003e \u003cp\u003eSo far, less than 50 cases of Noonan syndrome have been associated with LZTR1 variants, and no specific report is available in literature regarding the spectrum of ventricular arrhythmia in LZTR1 mutations. Here we present a Chinese family with Noonan Syndrome caused by a heterozygous variant in LZTR1, and hypothesize that mutations in LZTR1 could contribute to the development of ventricular arrhythmia.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eWhole exome sequencing\u003c/h2\u003e\n \u003cp\u003eAfter obtaining the informed consent from the proband and her family, whole exome sequencing (WES) analysis was performed on the proband. Exons were captured using Agilent SureSelect and Illumina sequencing platform was used for high-throughput sequencing. After the sequencing data was matched and analyzed by NextGENe software, the Ingenuity online software system was used for mutation screening and interpretation. The candidate mutations were validated by Sanger sequencing.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n \u003ch2\u003eLiterature Review\u003c/h2\u003e\n \u003cp\u003eA Medline search was conducted to find previously reported patients with LZTR1-associated Noonan syndrome. All the available literature on LZTR1, Noonan syndrome and ventricular arrhythmia was reviewed.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n \u003ch2\u003eClinical reports\u003c/h2\u003e\n \u003cp\u003ePatient 1 The proband (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, III-2), a 15-year-old girl, was admitted to our hospital because of congenital heart disease. As the first child of non-consanguineous parents, she was born at 38 weeks of gestation via caesarean. The birth weight was 3800g. No prenatal or birth complications were noted. She was found to have pectus excavatum, facial features (large eyes, low-set cupped ears) and congenital heart defects (left ventricular (LV) hypertrophy with left ventricular outfow tract obstruction) at 4 months of age. She showed feeding difficulty and mild growth retardation since then, and now her height,weight and body mass index (BMI) were 150cm (\u0026minus;\u0026thinsp;2SD), 39kg (\u0026minus;\u0026thinsp;2SD) and 17.3 kg/m2, according to the standard reference values [12].\u003c/p\u003e\n \u003cp\u003ePhysical examination: She showed the following typical features of Noonan syndrome: low-set, oval-shaped, posteriorly rotated ears, a short neck, scoliosis, myopia and hearing loss..\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n \u003cp\u003eAuxiliary examination: The IGF-1 level was 156 ng/mL(reference interval:191-496ng/mL). The electrocardiogram test showed left ventricular (LV) hypertrophy with left ventricular outflow tract obstruction. X-rays showed scoliosis and her bone age was 15 years old. In addition, the tumor markers, hormone levels of the adrenal gland, thyroid gland and gonad were normal. The electrocardiogram showed complicated ventricular arrhythmia and bundle branch block. No abnormalities were found during the ultrasound examination of liver, kidneys, uterus or ovaries. The exome sequencing revealed a mutation in LZTR1.She was diagnosed as Noonan syndrome according to the clinical manifestation and laboratory tests.\u003c/p\u003e\n \u003cp\u003ePatient 2 (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, II-5) was the aunt of patient 1, she died suddenly at the age of 38. she was born at 38 weeks of gestation via vaginal delivery. No prenatal or birth complications were noted. She showed significant growth retardation since the newborn stage. When she was 38 years old, her height and weight were 140cm and 31.8kg. She showed typical phenotype of Noonan syndrome: downslanting palpebral fissures, low-set, oval-shaped, posteriorly rotated ears, a short broad nose with a depressed root and full tip, a deeply grooved and long philtrum, a short neck, scoliosis, and mild hypertrichosis. Unfortunately, she had no auxiliary examination.The patient was also diagnosed as Noonan syndrome clinically.\u003c/p\u003e\n \u003cp\u003eSuspected patient 3 (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e, II-2) was the mother of the proband and the old sisiter of patient2. Her height was 156cm. She showed the mild phenotype of Noonan syndrome: a short neck, She didn\u0026rsquo;t show mental retardation, nor did she have any diseases of the heart, genitourinary system and skeletal system. The exome sequencing revealed a mutation in LZTR1.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eExome Sequencing\u003c/h2\u003e \u003cp\u003eWe identified a heterozygous variant c.313delT, under accession number NM_006767.4 in the LZTR1 gene. No other variants were detected in the LZTR1 gene or in the other RASopathy genes in the proband. The splicing variant was ranked as \u0026ldquo;likely pathogenic\u0026rdquo; according to the 2015-ACMG Standards and Guidelines [17]. Sanger sequencing showed that the variant of the proband was inherited from the proband\u0026rsquo;s mother, but her father without Noonan syndrome didn\u0026rsquo;t carry the variant. Unfortunately, patients II-5 was already died, and patient II 3,4,6,III-1 rejected the genetic analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eLiterature Search\u003c/h2\u003e \u003cp\u003eA total of 61 reported cases of Noonan syndrome with LZTR1 mutations were identified in the literature (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), A review of these reports yielded 3 patients with or without family with Noonan syndrome and ventricular arrhythmia (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\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\u003ePrevious published reports of LZTR1-mutation Noonan syndrome\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003evariants\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ezygosity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMode of inheritance\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003etypical facial features\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003econgenital heart defects\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eshort stature\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSkeletal anomalies\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eventricular arrhythmia\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eother\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.742G\u0026thinsp;\u0026gt;\u0026thinsp;A (p.Gly248Arg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHeterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMaternal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003epulmonary valve stenosis/atrial septal defect\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\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+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.850C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Arg284Cys)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHeterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMaternal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\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+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.859C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.His287Tyr)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHeterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDe novo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003epulmonary valve\u003c/p\u003e \u003cp\u003estenosis/atrial septal defect\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\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+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.356A\u0026thinsp;\u0026gt;\u0026thinsp;G (p.Tyr119Cys)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHeterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDe novo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eleft ventricular hypertrophy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\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+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.740C\u0026thinsp;\u0026gt;\u0026thinsp;A (p.Ser247Asn)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHeterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMaternal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003emitral valve insufciency\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\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+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.881G\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Arg294Leu)/ c.2212C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Gln738*)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCompound Compound\u003c/p\u003e \u003cp\u003eheterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMaternal/paternal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003etransposition of the great vessels, pulmonary stenosis, interventricular and interatrial communication\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.2374T\u0026thinsp;\u0026gt;\u0026thinsp;G (p.Cys792Gly)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCompound heterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMaternal/paternal\u003c/p\u003e \u003cp\u003eAutosomal recessive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eleft ventricular outfow tract obstruction, atrial septal defect\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\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-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e.850C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Arg284Cys)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHeterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMaternal\u003c/p\u003e \u003cp\u003eDominant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\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+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.1149\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHeterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMaternal\u003c/p\u003e \u003cp\u003eAutosomal dominant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\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+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.1149\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCompound heterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMaternal/paternal\u003c/p\u003e \u003cp\u003eAutosomal recessive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003esevere hypertrophic cardiomyopathy, mild pulmonary valve stenosis, broad QRS complexes, left axis deviation, striking negative pattern in the left precordial leads, right bundle branch block\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.2070-2A\u0026thinsp;\u0026gt;\u0026thinsp;G/ c.1735G\u0026thinsp;\u0026gt;\u0026thinsp;A (p.Val579Met)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCompound heterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePaternal/maternal\u003c/p\u003e \u003cp\u003eAutosomal recessive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003esevere hypertrophic cardiomyopathy without obstruction, left axis deviation, negative pattern in the left precordial leads\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\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+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.355T\u0026thinsp;\u0026gt;\u0026thinsp;C (p.Tyr119His)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNot provided\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDe novo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003epulmonary valve stenosis/branch pulmonary arterystenosis, slight asymmetric hypertrophy of inteventricular sept\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.1430C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Ala477Val)/\u003c/p\u003e \u003cp\u003ethree \u003cem\u003eLRP1\u003c/em\u003e variants\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHeterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePaternal/maternal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\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+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.347C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Ala116Val)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHeterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDe novo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eheart murmur, hypertrophic cardiomyopathy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\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+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.628C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Arg210*)/c.2220-17C\u0026thinsp;\u0026gt;\u0026thinsp;A (p.Tyr741Hisfs*89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCompound heterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePaternal/maternal\u003c/p\u003e \u003cp\u003eAutosomal recessive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003econgenital heart defect or valvular disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\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+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.2178C\u0026thinsp;\u0026gt;\u0026thinsp;A (p.Tyr726*)/ c.1943-256C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHeterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePaternal/maternal\u003c/p\u003e \u003cp\u003eAutosomal recessive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ecardiomyopathy, congenital heart defect or valvular disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\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+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.1943-256C\u0026thinsp;\u0026gt;\u0026thinsp;T; *70G\u0026thinsp;\u0026gt;\u0026thinsp;A/ c.1943-256C\u0026thinsp;\u0026gt;\u0026thinsp;T; *70G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHomozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePaternal/maternal, Autosomal recessive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ecardiomyopathy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\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+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.1687G\u0026thinsp;\u0026gt;\u0026thinsp;C (p.Glu563Gln)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHomozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePaternal/maternal\u003c/p\u003e \u003cp\u003eAutosomal recessive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ecardiomyopathy, congenital heart defect or valvular disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\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+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.2407-2A\u0026thinsp;\u0026gt;\u0026thinsp;G/ c.2090G\u0026thinsp;\u0026gt;\u0026thinsp;A (p.Arg697Gln)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCompound heterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePaternal/maternal\u003c/p\u003e \u003cp\u003eAutosomal recessive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ecardiomyopathy, congenital heart defect or valvular disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\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+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.27delG (p.Gln10fs*15)/ c.1149\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCompound heterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePaternal/maternal\u003c/p\u003e \u003cp\u003eAutosomal recessive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\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+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.361C\u0026thinsp;\u0026gt;\u0026thinsp;G (p.His121Asp)/ c.2264G\u0026thinsp;\u0026gt;\u0026thinsp;A (p.Arg755Gln)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCompound heterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePaternal/maternal\u003c/p\u003e \u003cp\u003eAutosomal recessive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ecardiomyopathy, congenital heart defect or valvular disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\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+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.508C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Arg170Trp); c.614T\u0026thinsp;\u0026gt;\u0026thinsp;C (p.Ile205Thr)/\u003c/p\u003e \u003cp\u003ec.508C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Arg170Trp); c.614T\u0026thinsp;\u0026gt;\u0026thinsp;C (p.Ile205Thr)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCompound homozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePaternal/maternal\u003c/p\u003e \u003cp\u003eAutosomal recessive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ecardiomyopathy, congenital heart defect or valvular disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\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-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.650A\u0026thinsp;\u0026gt;\u0026thinsp;C (p.Glu217Ala)/ c.650A\u0026thinsp;\u0026gt;\u0026thinsp;C (p.Glu217Ala)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHomozygous\u003c/p\u003e \u003cp\u003ePaternal/maternal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAutosomal recessive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003econgenital heart defect or valvular disease, developmental delay/intellectual disability\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\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-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.2062C\u0026thinsp;\u0026gt;\u0026thinsp;G (p.Arg688Gly)/ c.1943-256C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHeterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePaternal/maternalAutosomal recessive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ecardiomyopathy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\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+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.2325\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;A/ c.1943-256C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNot provided\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePaternal/maternal\u003c/p\u003e \u003cp\u003eAutosomal recessive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ecardiomyopathy, congenital heart defect or valvular disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\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+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.2462T\u0026thinsp;\u0026gt;\u0026thinsp;C (p.Ile821Thr)/ c.2462T\u0026thinsp;\u0026gt;\u0026thinsp;C (p.Ile821Thr)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHomozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePaternal/maternal\u003c/p\u003e \u003cp\u003eAutosomal recessive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ecardiomyopathy, congenital heart defect or valvular disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\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-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.406T\u0026thinsp;\u0026gt;\u0026thinsp;C (p.Tyr136His)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHeterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDe novo\u003c/p\u003e \u003cp\u003eAutosomal dominant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ethe cardiac segments, coarctation of the aorta\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\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-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.434A\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Asn145Ile)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHeterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMaternal\u003c/p\u003e \u003cp\u003eAutosomal dominant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003emild pulmonary stenosis, mild left ventricular dilation with a normal pulmonary valve, right bundle branch block\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\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+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.290G\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Arg97Leu)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNot provided\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDe novo, Autosomal dominant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ehypertrophic cardiomyopathy,ventricular septal defect,atrial septal defect,\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\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+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.407A\u0026thinsp;\u0026gt;\u0026thinsp;G (p.Tyr136Cys)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNot provided\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDe novo\u003c/p\u003e \u003cp\u003eAutosomal dominant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\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+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.731C\u0026thinsp;\u0026gt;\u0026thinsp;G (p.Ser244Cys)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNot provided\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDe novo\u003c/p\u003e \u003cp\u003eAutosomal dominant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\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+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.742G\u0026thinsp;\u0026gt;\u0026thinsp;A (p.Gly248Arg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNot provided\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDe novo\u003c/p\u003e \u003cp\u003eAutosomal dominant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003evalvular heart disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\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+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.1591G\u0026thinsp;\u0026gt;\u0026thinsp;A (p.Asp531Asn)/ c.628C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Arg210*)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCompound heterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAutosomal recessive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ehypertrophic cardiomyopathy, mitral valve prolapse\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\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+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.1149\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;T/ c.2062C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Arg688Cys)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCompound heterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAutosomal recessive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\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+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.628C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Arg210*)/ c.1735G\u0026thinsp;\u0026gt;\u0026thinsp;A (p.Val579Met)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCompound heterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAutosomal recessive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003emitral valve regurgitation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\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+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.1311G\u0026thinsp;\u0026gt;\u0026thinsp;A (p.Trp437*)/\u003c/p\u003e \u003cp\u003ec.-38T\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCompound heterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSuspected autosomal recessive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eleft ventricle hypertrophy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\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+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.1407G\u0026thinsp;\u0026gt;\u0026thinsp;A (p.Trp469*)/ c.2246A\u0026thinsp;\u0026gt;\u0026thinsp;G (p.Tyr749Cys)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCompound heterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSuspected autosomal recessive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003esevere hypertrophic cardiomyopathy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\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+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.1382C\u0026thinsp;\u0026gt;\u0026thinsp;A (p.Ala461Asp)/ c.1385T\u0026thinsp;\u0026gt;\u0026thinsp;C (p.Ile462Thr)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCompound heterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMaternal/paternal\u003c/p\u003e \u003cp\u003eSuspected autosomal recessive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ecardiac hypertrophy, pulmonic stenosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\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-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.848G\u0026thinsp;\u0026gt;\u0026thinsp;A (p.Arg283Gln)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHeterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDe novo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eatrial septal defect, ventricular septal defect, pulmonary stenosis, patent ductus arteriosus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\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+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.742G\u0026thinsp;\u0026gt;\u0026thinsp;A (p.Gly248Arg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHeterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMaternal\u003c/p\u003e \u003cp\u003eSuspected autosomal dominant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eventricular septal defect,anomalous origin of coronary artery,\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\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+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.2102C\u0026thinsp;\u0026gt;\u0026thinsp;A (p.Pro701His)/ c.2069\u0026thinsp;+\u0026thinsp;2T\u0026thinsp;\u0026gt;\u0026thinsp;C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCompound heterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePaternal/maternal\u003c/p\u003e \u003cp\u003eSuspected autosomal recessive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ehypertropic cardiomyopathy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\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+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.428A\u0026thinsp;\u0026gt;\u0026thinsp;G (p.Asn143Ser)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHeterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePaternal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ehypertropic cardiomyopathy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\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+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.606_650del (p.Met202fs)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHeterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePaternal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ehypertropic cardiomyopathy, atrial septal defect, pulmonary stenosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\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-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.756_758del (p.Asn253del)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHeterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDe nov\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ehypertropic cardiomyopathy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\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+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.1660G\u0026thinsp;\u0026gt;\u0026thinsp;C (p.Ala554Pro)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHeterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDe nov\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ehypertropic cardiomyopathy, atrial septal defect\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\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+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.742G\u0026thinsp;\u0026gt;\u0026thinsp;A (p.Gly248Arg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHeterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDe novo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003emild pulmonary supravalvular stenosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\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+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.2074T\u0026thinsp;\u0026gt;\u0026thinsp;A (p.Phe692Leu)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHomozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMaternal/paternal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003emild pulmonary supravalvular stenosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\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+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.730T\u0026thinsp;\u0026gt;\u0026thinsp;C (p.Ser244Pro)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHeterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMaternal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\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+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.313delT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHeterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAutosomal dominant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ehypertropic cardiomyopathy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\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+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\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\u003eVentricular arrhythmia and Noonan Syndrome with LZTR1 Mutations\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003evariants\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ezygosity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMode of inheritance\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGenealogy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003etypical facial features\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003econgenital heart defects\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eshort stature\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eSkeletal anomalies\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eventricular arrhythmia\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eother\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003ec.1149\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eHeterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eMaternal\u003c/p\u003e \u003cp\u003eAutosomal dominant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eProband\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\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+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSibling\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\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-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMother\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\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-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ec.606_650del (p.Met202fs)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHeterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePaternal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ehypertropic cardiomyopathy, atrial septal defect, pulmonary stenosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\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+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003ec.313delT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eHeterozygous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eAutosomal dominant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eProband\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ehypertropic cardiomyopathy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\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+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMother\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\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-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAunt\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\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-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion and conclusion","content":"\u003cp\u003eNoonan syndrome (NS) is characterized by typical facial features, short stature, congenital heart defects and other comorbidities[8]. The diagnosis of Noonan syndrome mainly depends on its typical clinical manifestations. However, about 25% of patients cannot get a clear genetic diagnosis, so it is importnt to correctly understand and analyze its clinical manifestations. The typical feature of Noonan syndrome in cardiovascular system is including pulmonary valve defect, hypertrophic cardiomyopathy and atrial septal defect. But apart from structure disease, some patients with Noonan syndrome have other manifestations like ventricular arrhythmia. As previous studies reported, 2 patients with LZTR1 mutaitaon Noonan syndrome have been diagnosed with ventricular arrhythmia. In our study, the proband (III-2) was the third Noonan syndrome patient with LZTR1 mutation identified as having ventricular arrhythmia (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn this study, we performed WES for molecular diagnoses. The results showed that there was a heterozygous variant c.313delT, under accession number NM_006767.4 in the LZTR1 gene. It is a novel LZTR1 mutation, which is not included in the HGMD and gnomAD database. LZTR1 can prematurely terminate amino acid translation or affect mRNA expression, and can be classified as potentially pathogenic according to the ACMG mutation classification criteria. Based on variant c.313delT in the LZTR1 gene segregating with Noonan syndrome-related phenotype in multiple affected family members, we speculated that the pedigree presented as dominant inheritance. LZTR1 is a highly conserved gene and encodes a protein characterized by six tandemly arranged Kelch motifs at the N-terminus and two broad complex, tramtrack and bric-a-brac/Pox virus and zinc finger domains at the C-terminus[9]. LZTR1 is an important regulator of the normal cell cycle and a conserved regulator of RAS ubiquitination and signaling[10]. Previous studies have demonstrated that LZTR1 variants can be acquired via AR or AD inheritance. Our patients had the Noonan syndrome phenotype and the heterozygous variant inherited in the AD form.\u003c/p\u003e \u003cp\u003eThe phenotype of LZTR1 mutations was generally severe, with short stature, mental retardation, and heart defects[11]. Cardiac involvement was present in up to 82% of affected individuals, including pulmonary stenosis, hypertrophic cardiomyopathy, atrial septal defect, and ventricle septal defect, mitral valve insufciency, transposition of the great vessels, broad QRS complexes, left axis deviation, striking negative pattern in the left precordial leads, right bundle branch block and ventricular arrhythmia(Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Ventricular arrhythmia is not typically considered part of Noonan syndrome[12\u0026ndash;16]. Ventricular dysrhythmias have been increasingly recognized in Noonan syndrome in mutation in PTPN 11, SOS 1, RAF 1, KARS, NRAS, BRAF and MAP2K1. On the other hand, lethal ventricular dysrhythmias have only been presumed from cases of unexpected sudden death[17, 18]. The article about LZTR1 mutation and ventricular arrhythmia is rare. We report a 15-years-old girl with Noonan syndrome due to a LZTR1 mutation and ventricular arrhythmia and review all reported cases of Noonan syndrome to identify similar patients with ventricular arrhythmia. Including the present report, from a total of 49 cases of Noonan syndrome with LZTR1 mutations, 3 patients had Noonan syndrome and ventricular arrhythmia(Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe association of LZTR1 mutations and ventricular arrhythmia is supported by the RAS/MAPK pathway\u0026rsquo;s involvement in the presence of cardiac electrophysiological abnormalities.These ventricular dysrhythmias have almost always occurred in the setting of hypertrophic cardiomyopathy or pulmonary stenosis[19\u0026ndash;21]. Ventricular arrhythmia is common in RAS/MAPK-associated arrhythmia due to the aforementioned mechanisms and as well as hypertrophic cardiomyopathy-induced arrhythmia due to myocardial fibrosis and left atrial enlargement. As the downstream targets of the RAS/MAPK pathway, high levels of phosphorylation of mitogen-induced extracellular kinase (MEK) and extracellular signal-regulated kinase (ERK) regulate cellular proliferation, apoptosis, differentiation and migration of cardiomyocytes which lead to cardiac hypertrophy and arrhythmia in Noonan syndrome[22\u0026ndash;24]. The activation of Ca2+/calcineurin causes arrhythmia and cardiac hypertrophy due to pathological cardiac remodeling[25].The types of arrhythmia in our patient were complicated with ventricular arrhythmia, which are common in RAS/MAPK-associated arrhythmia due to the aforementioned mechanisms and as well as hypertrophic cardiomyopathy-induced arrhythmia due to myocardial fibrosis and left atrial enlargement. While the family with LZTR1 mutation(c.1149\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;T ) have ventricular arrhythmia,without hypertrophic cardiomyopathy manifestation. Therefore, it was difficult to determine whether the arrhythmia was associated with hypertrophic cardiomyopathy, Noonan syndrome-related or both.\u003c/p\u003e \u003cp\u003eIn summary, we have described a novel condition of Noonan syndrome, caused by a heterozygous variant in LZTR1(c.313delT, under accession number NM_006767.4), manifested normal Noonan syndrome performance and complicated ventricular arrhythmia and bundle branch block, which is different from previous reports, which improves our understanding of Noonan syndrome. Besides, we find that patients with Noonan syndrome may suffer ventricular arrhythmia at the same time, which will help us to enrich the clinical spectrum of Noonan syndrome.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eNoonan syndrome (NS)\u003c/p\u003e\n\u003cp\u003eRas-mitogen-activated protein kinase (RAS-MAPK)\u003c/p\u003e\n\u003cp\u003eLeucine zipperlike transcription regulator 1 (LZTR1)\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data supporting the conclusions of this article is included within the article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to express our gratitude to the proband and his family members who agreed to participate in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Natural Science Foundation of Jiangsu Province(BK20190352) and National Natural Science Foundation of China(82302875).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLiu zhuyuan: concept, design, definition of intellectual content, manuscript preparation, manuscript editing\u003c/p\u003e\n\u003cp\u003eYan Huang: literature search.\u003c/p\u003e\n\u003cp\u003eJinxi Wang: data acquisition,\u003c/p\u003e\n\u003cp\u003eJiayi Tong: manuscript review, the integrity of the work as a whole from inception to published article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis patients\u0026rsquo; guardian provided written informed consent for his personal and clinical details to be published in this study. There are no identifying images in this case.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis patients\u0026rsquo; guardian provided oral and signed written informed consent to use his clinical materials in this study. The study was conducted in accordance with the principles contained in the Declaration of Helsinki and the ethical standards of the institutional and national research committee.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSun L, Xie YM, Wang SS, Zhang ZW: \u003cstrong\u003eCardiovascular Abnormalities and Gene Mutations in Children With Noonan Syndrome\u003c/strong\u003e. \u003cem\u003eFront Genet \u003c/em\u003e2022, \u003cstrong\u003e13\u003c/strong\u003e:915129.10.3389/fgene.2022.915129\u003c/li\u003e\n\u003cli\u003eTiemens DK, Kleimeier L, Leenders E, Wingbermuhle E, Roelofs RL, Sibbles B, Oostwegel FSM, Vroonland E, van Leeuwen C, Niessen H\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eThe most important problems and needs of rasopathy patients with a noonan syndrome spectrum disorder\u003c/strong\u003e. \u003cem\u003eOrphanet J Rare Dis \u003c/em\u003e2023, \u003cstrong\u003e18\u003c/strong\u003e(1):198.10.1186/s13023-023-02818-y\u003c/li\u003e\n\u003cli\u003eWingbermuhle E, Roelofs RL, Oomens W, Kramer J, Draaisma JMT, Leenders E, Kleefstra T, Kessels RPC, Egger JIM: \u003cstrong\u003eCognitive Phenotype and Psychopathology in Noonan Syndrome Spectrum Disorders through Various Ras/MAPK Pathway Associated Gene Variants\u003c/strong\u003e. \u003cem\u003eJ Clin Med \u003c/em\u003e2022, \u003cstrong\u003e11\u003c/strong\u003e(16).10.3390/jcm11164735\u003c/li\u003e\n\u003cli\u003eEl Bouchikhi I, Belhassan K, Moufid FZ, Iraqui Houssaini M, Bouguenouch L, Samri I, Atmani S, Ouldim K: \u003cstrong\u003eNoonan syndrome-causing genes: Molecular update and an assessment of the mutation rate\u003c/strong\u003e. \u003cem\u003eInt J Pediatr Adolesc Med \u003c/em\u003e2016, \u003cstrong\u003e3\u003c/strong\u003e(4):133-142.10.1016/j.ijpam.2016.06.003\u003c/li\u003e\n\u003cli\u003eAbe T, Umeki I, Kanno SI, Inoue SI, Niihori T, Aoki Y: \u003cstrong\u003eLZTR1 facilitates polyubiquitination and degradation of RAS-GTPases\u003c/strong\u003e. \u003cem\u003eCell Death Differ \u003c/em\u003e2020, \u003cstrong\u003e27\u003c/strong\u003e(3):1023-1035.10.1038/s41418-019-0395-5\u003c/li\u003e\n\u003cli\u003eBigenzahn JW, Collu GM, Kartnig F, Pieraks M, Vladimer GI, Heinz LX, Sedlyarov V, Schischlik F, Fauster A, Rebsamen M\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eLZTR1 is a regulator of RAS ubiquitination and signaling\u003c/strong\u003e. \u003cem\u003eScience \u003c/em\u003e2018, \u003cstrong\u003e362\u003c/strong\u003e(6419):1171-1177.10.1126/science.aap8210\u003c/li\u003e\n\u003cli\u003eDe Ridder W, van Engelen B, van Alfen N: \u003cstrong\u003eNeurological features of Noonan syndrome and related RASopathies: Pain and nerve enlargement characterized by nerve ultrasound\u003c/strong\u003e. \u003cem\u003eAm J Med Genet A \u003c/em\u003e2022, \u003cstrong\u003e188\u003c/strong\u003e(6):1801-1807.10.1002/ajmg.a.62714\u003c/li\u003e\n\u003cli\u003eFarncombe KM, Thain E, Barnett-Tapia C, Sadeghian H, Kim RH: \u003cstrong\u003eLZTR1 molecular genetic overlap with clinical implications for Noonan syndrome and schwannomatosis\u003c/strong\u003e. \u003cem\u003eBMC Med Genomics \u003c/em\u003e2022, \u003cstrong\u003e15\u003c/strong\u003e(1):160.10.1186/s12920-022-01304-x\u003c/li\u003e\n\u003cli\u003eJacquinet A, Bonnard A, Capri Y, Martin D, Sadzot B, Bianchi E, Servais L, Sacre JP, Cave H, Verloes A: \u003cstrong\u003eOligo-astrocytoma in LZTR1-related Noonan syndrome\u003c/strong\u003e. \u003cem\u003eEur J Med Genet \u003c/em\u003e2020, \u003cstrong\u003e63\u003c/strong\u003e(1):103617.10.1016/j.ejmg.2019.01.007\u003c/li\u003e\n\u003cli\u003eGuemes M, Martin-Rivada A, Ortiz-Cabrera NV, Martos-Moreno GA, Pozo-Roman J, Argente J: \u003cstrong\u003eLZTR1: Genotype Expansion in Noonan Syndrome\u003c/strong\u003e. \u003cem\u003eHorm Res Paediatr \u003c/em\u003e2019, \u003cstrong\u003e92\u003c/strong\u003e(4):269-275.10.1159/000502741\u003c/li\u003e\n\u003cli\u003eSteklov M, Pandolfi S, Baietti MF, Batiuk A, Carai P, Najm P, Zhang M, Jang H, Renzi F, Cai Y\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eMutations in LZTR1 drive human disease by dysregulating RAS ubiquitination\u003c/strong\u003e. \u003cem\u003eScience \u003c/em\u003e2018, \u003cstrong\u003e362\u003c/strong\u003e(6419):1177-1182.10.1126/science.aap7607\u003c/li\u003e\n\u003cli\u003eChinton J, Huckstadt V, Mucciolo M, Lepri F, Novelli A, Gravina LP, Obregon MG: \u003cstrong\u003eProviding more evidence on LZTR1 variants in Noonan syndrome patients\u003c/strong\u003e. \u003cem\u003eAm J Med Genet A \u003c/em\u003e2020, \u003cstrong\u003e182\u003c/strong\u003e(2):409-414.10.1002/ajmg.a.61445\u003c/li\u003e\n\u003cli\u003eJenkins J, Barnes A, Birnbaum B, Papagiannis J, Thiffault I, Saunders CJ: \u003cstrong\u003eLZTR1-Related Hypertrophic Cardiomyopathy Without Typical Noonan Syndrome Features\u003c/strong\u003e. \u003cem\u003eCirc Genom Precis Med \u003c/em\u003e2020, \u003cstrong\u003e13\u003c/strong\u003e(2):e002690.10.1161/CIRCGEN.119.002690\u003c/li\u003e\n\u003cli\u003eJohnston JJ, van der Smagt JJ, Rosenfeld JA, Pagnamenta AT, Alswaid A, Baker EH, Blair E, Borck G, Brinkmann J, Craigen W\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eAutosomal recessive Noonan syndrome associated with biallelic LZTR1 variants\u003c/strong\u003e. \u003cem\u003eGenet Med \u003c/em\u003e2018, \u003cstrong\u003e20\u003c/strong\u003e(10):1175-1185.10.1038/gim.2017.249\u003c/li\u003e\n\u003cli\u003eLi X, Yao R, Tan X, Li N, Ding Y, Li J, Chang G, Chen Y, Ma L, Wang J\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eMolecular and phenotypic spectrum of Noonan syndrome in Chinese patients\u003c/strong\u003e. \u003cem\u003eClin Genet \u003c/em\u003e2019, \u003cstrong\u003e96\u003c/strong\u003e(4):290-299.10.1111/cge.13588\u003c/li\u003e\n\u003cli\u003eMagotteaux S, Farhat N, Jacquinet A, Seghaye MC: \u003cstrong\u003e[Complex congenital heart disease : about a case of Noonan syndrome]\u003c/strong\u003e. \u003cem\u003eRev Med Liege \u003c/em\u003e2023, \u003cstrong\u003e78\u003c/strong\u003e(3):130-136\u003c/li\u003e\n\u003cli\u003eAly SA, Boyer KM, Muller BA, Marini D, Jones CH, Nguyen HH: \u003cstrong\u003eComplicated ventricular arrhythmia and hematologic myeloproliferative disorder in RIT1-associated Noonan syndrome: Expanding the phenotype and review of the literature\u003c/strong\u003e. \u003cem\u003eMol Genet Genomic Med \u003c/em\u003e2020, \u003cstrong\u003e8\u003c/strong\u003e(7):e1253.10.1002/mgg3.1253\u003c/li\u003e\n\u003cli\u003eCarcavilla A, Cambra A, Santome JL, Seidel V, Cruz J, Alonso M, Pozo J, Valenzuela I, Guillen-Navarro E, Santos-Simarro F\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eGenotypic Findings in Noonan and Non-Noonan RASopathies and Patient Eligibility for Growth Hormone Treatment\u003c/strong\u003e. \u003cem\u003eJ Clin Med \u003c/em\u003e2023, \u003cstrong\u003e12\u003c/strong\u003e(15).10.3390/jcm12155003\u003c/li\u003e\n\u003cli\u003ePagnamenta AT, Kaisaki PJ, Bennett F, Burkitt-Wright E, Martin HC, Ferla MP, Taylor JM, Gompertz L, Lahiri N, Tatton-Brown K\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eDelineation of dominant and recessive forms of LZTR1-associated Noonan syndrome\u003c/strong\u003e. \u003cem\u003eClin Genet \u003c/em\u003e2019, \u003cstrong\u003e95\u003c/strong\u003e(6):693-703.10.1111/cge.13533\u003c/li\u003e\n\u003cli\u003eSewduth RN, Pandolfi S, Steklov M, Sheryazdanova A, Zhao P, Criem N, Baietti MF, Lechat B, Quarck R, Impens F\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eThe Noonan Syndrome Gene Lztr1 Controls Cardiovascular Function by Regulating Vesicular Trafficking\u003c/strong\u003e. \u003cem\u003eCirc Res \u003c/em\u003e2020, \u003cstrong\u003e126\u003c/strong\u003e(10):1379-1393.10.1161/CIRCRESAHA.119.315730\u003c/li\u003e\n\u003cli\u003eNakagama Y, Takeda N, Ogawa S, Takeda H, Furutani Y, Nakanishi T, Sato T, Hirata Y, Oka A, Inuzuka R: \u003cstrong\u003eNoonan syndrome-associated biallelic LZTR1 mutations cause cardiac hypertrophy and vascular malformations in zebrafish\u003c/strong\u003e. \u003cem\u003eMol Genet Genomic Med \u003c/em\u003e2020, \u003cstrong\u003e8\u003c/strong\u003e(3):e1107.10.1002/mgg3.1107\u003c/li\u003e\n\u003cli\u003eUmeki I, Niihori T, Abe T, Kanno SI, Okamoto N, Mizuno S, Kurosawa K, Nagasaki K, Yoshida M, Ohashi H\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eDelineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1-PPP1CB complexes\u003c/strong\u003e. \u003cem\u003eHum Genet \u003c/em\u003e2019, \u003cstrong\u003e138\u003c/strong\u003e(1):21-35.10.1007/s00439-018-1951-7\u003c/li\u003e\n\u003cli\u003eYu QX, Zhen L, Lin XM, Wen YJ, Li DZ: \u003cstrong\u003ePrenatal diagnosis of autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants presented with thick nuchal translucency and cardiac abnormalities\u003c/strong\u003e. \u003cem\u003ePrenat Diagn \u003c/em\u003e2023, \u003cstrong\u003e43\u003c/strong\u003e(13):1662-1665.10.1002/pd.6462\u003c/li\u003e\n\u003cli\u003eZhao X, Li Z, Wang L, Lan Z, Lin F, Zhang W, Su Z: \u003cstrong\u003eA Chinese family with Noonan syndrome caused by a heterozygous variant in LZTR1: a case report and literature review\u003c/strong\u003e. \u003cem\u003eBMC Endocr Disord \u003c/em\u003e2021, \u003cstrong\u003e21\u003c/strong\u003e(1):2.10.1186/s12902-020-00666-6\u003c/li\u003e\n\u003cli\u003eLimongelli G, Sarkozy A, Pacileo G, Calabro P, Digilio MC, Maddaloni V, Gagliardi G, Di Salvo G, Iacomino M, Marino B\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eGenotype-phenotype analysis and natural history of left ventricular hypertrophy in LEOPARD syndrome\u003c/strong\u003e. \u003cem\u003eAm J Med Genet A \u003c/em\u003e2008, \u003cstrong\u003e146A\u003c/strong\u003e(5):620-628.10.1002/ajmg.a.32206\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Noonan syndrome, ventricular arrhythmia, LZTR1","lastPublishedDoi":"10.21203/rs.3.rs-4122815/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4122815/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eNoonan syndrome (NS) is characterized by typical facial features, short stature, congenital heart defects and other comorbidities, which is caused by germline mutations in genes coding for components of the Ras-mitogen-activated protein kinase (RAS-MAPK) pathway. Noonan syndrome is an inherited disease involving multiple systems, but ventricular arrhythmia in Noonan syndrome is rarely reported.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eHere we report a 15-years old patient with LZTR1-associated Noonan syndrome, who has congenital heart defect, ventricular arrhythmia, bundle branch block, pectus excavatum, costal eversion, scoliosis, myopia, growth retardation and hearing loss. Genetic testing revealed that the patient had a novel heterozygous variant c.313delT (p.trp105Glyfs*42) mutation in the LZTR1.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eWe provide a review of the literature of LZTR1 mutations and find that approximately 6% of published cases have ventricular arrhythmia.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eOur findings expand on the Noonan syndrome phenotype and suggest that mutations in the LZTR1 gene are involved in ventricular arrhythmia.\u003c/p\u003e","manuscriptTitle":"Ventricular arrhythmia and Noonan Syndrome with LZTR1 Mutations: Expanding the Phenotype with a Case Report and Review of the Literature","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-27 17:22:40","doi":"10.21203/rs.3.rs-4122815/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"629db16b-282b-4800-a6b6-8bd7af1107ef","owner":[],"postedDate":"March 27th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-04-03T10:22:04+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-27 17:22:40","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4122815","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4122815","identity":"rs-4122815","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}