Background
The genetics of congenital heart disease (CHD) re
main inco
mpletely understood. Exo
me sequencing has been successfully used to identify disease-causing
mutations in fa
milial disorders in which candidate gene analyses and linkage
mapping have failed.
Methods
We studied a large family characterized by autosomal dominant isolated secundum atrial septal defect (ASD) (MIM No. 612794). Candidate gene resequencing and linkage analysis were uninformative.
Results
Whole-exome sequencing of 2 affected family members identified 44 rare shared variants, including a nonsynonymous mutation (c.532A>T, p.M178L, ) in alpha-cardiac actin (m>ACTC1m>). This mutation was absent from 1834 internal controls as well as from the 1000 Genomes and the Exome Sequencing Project (ESP) databases, but predictions regarding its effect on protein function were divergent. However, p.M178L was the only rare mutation segregating with disease in our family.
Conclusions
Our results provide further evidence supporting a causative role for m>ACTC1m> mutations in ASD. Massively parallel sequencing of the exome allows for the detection of novel rare variants causing CHD without the limitations of a candidate gene approach. When mutation prediction algorithms are not helpful, studies of familial disease can help distinguish rare pathologic mutations from benign variants. Consideration of the family history can lead to genetic insights into CHD.