Genetics and genomics of congenital heart disease and associated neurodevelopmental abnormalities

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 DESCRIPTION (provided by applicant): Congenital heart disease (CHD) is the most common survivable birth defect, affecting 0.7% of all liveborn infants worldwide. Management of CHD has made great strides, so that there are now more living adults with CHD than children, but many patients with complex CHD have long-term morbidity frequently manifesting as neurodevelopmental abnormalities (NDA). The causative mechanisms of CHD have been poorly understood although genetic factors are strongly believed to play a role. Dramatic advances in genomic technologies now allow systematic identification of specific genes and pathways that have very large effects on disease pathogenesis. As part of the PCGC, we have performed whole-exome sequencing on 1,300 parent-offspring trios selected from over 9,000 patients recruited into the PCGC study. The salient findings are that de novo mutations occurring in genes that are highly expressed in the heart account for at least 8% of the CHD cases studied, and disproportionately occur in patients with CHD classified as left ventricular outflow obstruction, and in patients with CHD and NDA. Among the genes with de-novo mutations in CHD there is a marked enrichment of mutations, particularly damaging mutations, in genes involved in chromatin modification, and these mutations are strongly biased toward CHD cases with NDA. Moreover, and very unexpectedly, we find highly significant overlap of genes with damaging mutations in CHD and in autism. We propose that genes involved in chromatin regulation are dosage sensitive for both heart and neurodevelopment, and that mutations in these genes can result in both CHD and NDA. By sequencing all genes in the chromatin modification set in 10,000 PCGC cases using rapid, inexpensive targeted sequencing via MIPS (molecular inversion probe sequencing) we will identify genes in this pathway that contribute to CHD and determine their specific relationship to NDA. Since the last funding cycle has enabled us to show that CHD has high locus heterogeneity, we will also continue to use cost-effective exome sequencing to identify additional genes in which de-novo mutations confer large effects on disease risk. In order to determine the spectrum of NDA resulting from chromatin modifier mutations, we will identify patients from the existing PCGC cohort with and without mutation in this gene set and perform neurodevelopmental testing. Finally, we will prospectively recruit patients under one year of age, test for chromatin modifier mutations, and follow their neurodevelopmental outcome. In summary, we expect these studies to identify an easily testable set of genes that can be evaluated rapidly and inexpensively to identify CHD patients at increased risk for ND abnormalities.