The diagnostic value of next generation sequencing in familial nonsyndromic congenital heart defects

To determine the diagnostic value of massive parallel sequencing of a panel of known cardiac genes in familial nonsyndromic congenital heart defects (CHD), targeted sequencing of the coding regions of 57 genes previously implicated in CHD was performed in 36 patients from 13 nonsyndromic CHD families with probable autosomal dominant inheritance. Following variant analysis and Sanger validation, we identified six potential disease causing variants in three genes (MYH6, NOTCH1, and TBX5), which may explain the defects in six families. Several problematic situations were encountered when performing genotype-phenotype correlations in the families to confirm the causality of these variants. In conclusion, by screening known CHD-associated genes in well-selected nonsyndromic CHD families and cautious variant interpretation, potential causative variants were identified in less than half of the families (6 out of 13; 46%). Variant interpretation remains a major challenge reflecting the complex genetic cause of CHD.