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Exome analysis of a family with pleiotropic congenital heart disease.

ABSTRACT: A number of single gene defects have been identified in patients with isolated or nonsyndromic congenital heart defects (CHDs). However, due to significant genetic heterogeneity, candidate gene approaches have had limited success in finding high-risk alleles in most cases. The purpose of this study was to use exome sequencing to identify high-risk gene variants in a family with highly penetrant pleiotropic CHD.DNA samples from 2 members of a family with diverse CHD were analyzed by exome sequencing. Variants were filtered to eliminate common variants and sequencing artifacts and then prioritized based on the predicted effect of the variant and on gene function. The remainder of the family was screened using polymerase chain reaction, high-resolution melting analysis, and DNA sequencing to evaluate variant segregation. After filtering, >2000 rare variants (including single nucleotide substitutions and indels) were shared by the 2 individuals. Of these, 46 were nonsynonymous, 3 were predicted to alter splicing, and 6 resulted in a frameshift. Prioritization reduced the number of variants potentially involved in CHD to 18. None of the variants completely segregated with CHD in the kindred. However, 1 variant, Myh6 Ala290Pro, was identified in all but 1 affected individual. This variant was previously identified in a patient with tricuspid atresia and large secundum atrial septal defect.It is likely that next-generation sequencing will become the method of choice for unraveling the complex genetics of CHD, but information gained by analysis of transmission through families will be crucial.

SUBMITTER: Arrington CB

PROVIDER: S-EPMC3329568 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Exome analysis of a family with pleiotropic congenital heart disease.

Arrington Cammon B CB Bleyl Steven B SB Matsunami Norisada N Bonnell Gabriel D GD Otterud Brith E M BE Nielsen Douglas C DC Stevens Jeffrey J Levy Shawn S Leppert Mark F MF Bowles Neil E NE

Circulation. Cardiovascular genetics 20120215 2

<h4>Background</h4>A number of single gene defects have been identified in patients with isolated or nonsyndromic congenital heart defects (CHDs). However, due to significant genetic heterogeneity, candidate gene approaches have had limited success in finding high-risk alleles in most cases. The purpose of this study was to use exome sequencing to identify high-risk gene variants in a family with highly penetrant pleiotropic CHD.<h4>Methods and results</h4>DNA samples from 2 members of a family ...[more]

PMID: 22337856

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Project description:RationaleCongenital heart disease (CHD) is the most common birth defect and an important cause of noninfectious deaths in infants and children. It has high prevalence globally, placing an enormous burden on society and families. Studies of individuals with hereditary or sporadic CHD have provided strong evidence for its genetic basis. The aim of this study was to identify causative gene variants in a Chinese family with congenital heart disease.Patient concerns and diagnosesThree generations of a CHD family were recruited. Proband III.9 was diagnosed with congenital heart disease at age 11 months, and the echocardiogram showed arterial ductus arteriosus, with a left-to-right shunt at the level of the arteries. Precedent III.10 was a twin of Proband III.9 who was diagnosed with congenital heart disease at age 11 months, in whom the echocardiogram revealed an arterial ductus arteriosus, an unenclosed patent ductus arteriosus, and a left to right shunt at the level of the arteries (second figure). III.8 was diagnosed with congenital heart disease at age 15, but echocardiography in this study showed no abnormalities. No cardiac abnormalities were detected in any of his parents, grandparents, or maternal grandparents. We performed whole-exome sequencing on CHD sufferers and their unexpressing family members to investigate the genetic causes of CHD in this family line. Exome sequencing identified 4 mutation sites in this family line. The variant c.3245A>G (p.His1082Arg) of the AMER1 gene was consistent with concomitant X-chromosome recessive inheritance, the variant c.238G>C (p.Val80Leu) of the KCNE1 gene was consistent with autosomal accessory inheritance, and the other 2 variants did not conform to the law of the mode of inheritance of the disease.OutcomesThe first identified variant, c.3245A>G (p.His1082Arg) of the AMER1 gene, with X-chromosome recessive inheritance, and the variant c.238G>C (p.Val80Leu) of the KCNE1 gene, which has been reported as autosomal dominant, may be the causative agent of CHD in this family line. These findings broaden the genetic scope of congenital heart disease and could help in the development of targeted drugs for the treatment of congenital heart disease.

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Exome analysis of a family with pleiotropic congenital heart disease.

Publications

Exome analysis of a family with pleiotropic congenital heart disease.

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