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A mutation in the CACNA1C gene leads to early repolarization syndrome with incomplete penetrance: A Chinese family study.

ABSTRACT: Early repolarization syndrome (ERS) may be a near-Mendelian or an oligogenic disease; however, no direct evidence has been provided to support this theory.We described a large Chinese family with nocturnal sudden cardiac death induced by ERS in most of the young male adults. One missense mutation (p.Q1916R) was found in the major subunit of the L-type calcium channel gene CACNA1C by the direct sequencing of candidate genes. A concomitant gain-of-function variant in the sodium channel gene SCN5A (p.R1193Q) was found to rescue the phenotype of the female CACNA1C-Q1916R mutation carriers, which led to the incomplete penetrance. The functional studies, via the exogenous expression approach, revealed that the CACNA1C-Q1916R mutation led to a decreasing L-type calcium current and the protein expression defect. The decreased calcium current produced by the mutant channel was improved by isoproterenol but exacerbated by testosterone. The effects of CACNA1C-Q1916R mutation and testosterone on cellular electrophysiology were further confirmed by the human ventricular action potential simulation.Our results demonstrated that the loss-of-function CACNA1C-Q1916R mutation contributed to ERS-related sudden cardiac death, and the phenotypic incomplete penetrance was modified by the SCN5A-R1193Q variant and sex. These findings suggest that phenotypes of ERS are modified by multiple genetic factors, which supports the theory that ERS may be an oligogenic disease.

SUBMITTER: Liu X

PROVIDER: S-EPMC5426766 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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A mutation in the CACNA1C gene leads to early repolarization syndrome with incomplete penetrance: A Chinese family study.

Liu Xin X Shen Yang Y Xie Jinyan J Bao Huihui H Cao Qing Q Wan Rong R Xu Xiaoming X Zhou Hui H Huang Lin L Xu Zhenyan Z Zhu Wengen W Hu Jinzhu J Cheng Xiaoshu X Hong Kui K

PloS one 20170511 5

<h4>Background</h4>Early repolarization syndrome (ERS) may be a near-Mendelian or an oligogenic disease; however, no direct evidence has been provided to support this theory.<h4>Methods and results</h4>We described a large Chinese family with nocturnal sudden cardiac death induced by ERS in most of the young male adults. One missense mutation (p.Q1916R) was found in the major subunit of the L-type calcium channel gene CACNA1C by the direct sequencing of candidate genes. A concomitant gain-of-fun ...[more]

PMID: 28493952

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Project description:BackgroundSyndactyly (SD) refers to a deformity caused by the fusion and limb differentiation disorder of soft tissues and/or skeletons to varying extents between adjacent fingers (toes). The main features of this disease are phenotypic heterogeneity and genetic heterogeneity. In this study, we examined four generations of a Chinese Mongolian with different phenotypes of syndactylia and analysed and identified the pathogenic genetic variants of SD by exon sequencing.MethodsThe clinical phenotypes of patients were analysed, and the hands and feet were examined by X-ray. The pedigree was drawn, and the family data were analysed. Peripheral blood was collected from the family members, and genomic DNA was extracted. The candidate genes of SD were identified by exon sequencing, and the mutation sites of the captured candidate genes were amplified by PCR and verified by Sanger sequencing.ResultsThe family has congenital syndactyly, which is an autosomal dominant disease. At present, this condition has been passed down for 4 generations and was identified in 9 patients, including 4 males and 5 females. Five patients, I2, II4, III5, III,7 and III10, had unilateral syndactyly, and four patients, III16, IV3, IV6 and IV7, had bilateral finger syndactyly. All of their toes were unaffected. The proband and the other patients in this family had a c.917G > A (p.R306Q) mutation, which is located at position 917 of the second exon of the HOXD13 gene. This mutation results in a change in the amino acid at position 306, in which arginine is changed to glutamine. This mutation cosegregates in unaffected individuals and affected patients in this family. Moreover, 201 Mongolian genome databases and a thousand human genome databases were referenced to further confirm that the pathogenic genetic variant that causes syndactyly in this family is found in HOXD13.ConclusionThis study found that the mutation site of the pathogenic gene in this family was HOXD13, c.917G > A (p.R306Q). The phenotype of the family member III12 was normal, but this member was also a carrier of the pathogenic genetic variant. This indicates that the disease of this family has incomplete penetrance characteristics. Our results further enrich the expression profile of the HOXD13 gene.

Dataset Information

A mutation in the CACNA1C gene leads to early repolarization syndrome with incomplete penetrance: A Chinese family study.

Publications

A mutation in the CACNA1C gene leads to early repolarization syndrome with incomplete penetrance: A Chinese family study.

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