title: Whole-exome sequencing identifies Y1495X of SCN5A to be associated with familial conduction disease and sudden death.
abstract: SCN5A mutations have been reported to underlie a variety of inherited arrhythmias, while the complex overlapping phenotype, especially with congenital heart disease (CHD), is rarely reported. The 48-year-old proband underwent a recent syncope during rest. A CHD (tetralogy of Fallot) and conduction disease was revealed by echocardiogram and ultrasonic cardiogram examination. We combined whole-exome sequencing (WES) and bioinformatics strategies to identify the pathogenic gene for this autosomal-dominant cardiac conduction disease (CCD) in a multi-generation pedigree. We examined four members of this family, including three affected and one unaffected. A novel nonsense mutation (Y1495X) in SCN5A was identified in the affected family members. This mutation is predicted to generate a truncated SCN5A protein, which could result in the loss of sodium current, a defined mechanism of SCN5A related arrhythmias. Our study provides evidence that WES is a highly effective approach for genetic analyses of rare clinical phenotypes. Our study also offers accurate genetic testing information for those yet clinically negative relatives.
authors.affiliation: 1] Department of Cardiothoracic Surgery, the Second Xiangya Hospital of Central South University, Changsha, Hunan Province 410011, China [2] Clinical Center for Gene Diagnosis and Therapy of State Key Laboratory of Medical Genetics, the Second Xiangya Hospital of Central South University, Changsha, Hunan Province 410011, China.
authors.forename: Zhi-Ping
authors.initials: ZP
authors.lastname: Tan
authors.affiliation: Department of Cardiothoracic Surgery, the Second Xiangya Hospital of Central South University, Changsha, Hunan Province 410011, China.
authors.forename: Li
authors.initials: L
authors.lastname: Xie
authors.affiliation: Department of Cardiothoracic Surgery, the Second Xiangya Hospital of Central South University, Changsha, Hunan Province 410011, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Department of Cardiothoracic Surgery, the Second Xiangya Hospital of Central South University, Changsha, Hunan Province 410011, China.
authors.forename: Jin-Lan
authors.initials: JL
authors.lastname: Chen
authors.affiliation: Department of Cardiothoracic Surgery, the Second Xiangya Hospital of Central South University, Changsha, Hunan Province 410011, China.
authors.forename: Wei-Zhi
authors.initials: WZ
authors.lastname: Zhang
authors.affiliation: 1] Department of Cardiothoracic Surgery, the Second Xiangya Hospital of Central South University, Changsha, Hunan Province 410011, China [2] Clinical Center for Gene Diagnosis and Therapy of State Key Laboratory of Medical Genetics, the Second Xiangya Hospital of Central South University, Changsha, Hunan Province 410011, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: 1] Department of Cardiothoracic Surgery, the Second Xiangya Hospital of Central South University, Changsha, Hunan Province 410011, China [2] Clinical Center for Gene Diagnosis and Therapy of State Key Laboratory of Medical Genetics, the Second Xiangya Hospital of Central South University, Changsha, Hunan Province 410011, China.
authors.forename: Jin-Fu
authors.initials: JF
authors.lastname: Yang
authors.affiliation: 1] Department of Cardiothoracic Surgery, the Second Xiangya Hospital of Central South University, Changsha, Hunan Province 410011, China [2] Clinical Center for Gene Diagnosis and Therapy of State Key Laboratory of Medical Genetics, the Second Xiangya Hospital of Central South University, Changsha, Hunan Province 410011, China.
authors.forename: Yi-Feng
authors.initials: YF
authors.lastname: Yang
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001145:Arrhythmias, Cardiac / Q000209:etiology* / Q000235:genetics*; D053840:Brugada Syndrome; D000075224:Cardiac Conduction System Disease; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense / Q000235:genetics; D003645:Death, Sudden / Q000209:etiology*; D059472:Exome / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006329:Heart Conduction System / Q000002:abnormalities*; D006801:Humans; D008297:Male; D008875:Middle Aged; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D012964:Sodium / Q000378:metabolism
chemical_list: D018389:Codon, Nonsense; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D012964:Sodium