Abstract 1789: Genomic Analyses Identify New Loci and Genes in Isolated, Sporadic Congenital Heart Disease
Congenital heart disease (CHD) commonly occurs as a sporadic, isolated malformation of unknown cause. To assess whether copy number variants (CNVs) contribute to this frequent presentation we surveyed the genome of 114 tetralogy of Fallot (TOF) and 25 hypoplastic left heart syndrome (HLHS) patients and their unaffected parents using the Affymetrix 6.0 array. We identified 11 de novo CNVs in the TOF cohort and three de novo CNVs in the HLHS cohort that were absent or extremely rare (frequency <0.1%) in 3,401 controls also genotyped on the 6.0 array. Four rare, inherited CNVs that were either very large (>2 Mb) or shared by both TOF and HLHS patients were also identified. An additional 398 TOF patients and a cohort of 700 patients representing 15 different forms of CHD were then screened for additional CNVs at these loci by MLPA. From all patients studied, recurrent CNVs were identified at chromosome 1q21.1 (six patients; four duplications and two deletions), 1q32.1 (duplications in two patients), 3p25.1 (duplications affecting RAF1 in eight patients), 7p21.3 (three patients), 9q34.3 (partial deletions of NOTCH1 in three patients), 10q21.3 (duplications affecting CTNNA3 in three patients), 15q26.3 (duplications affecting MEF2A in two patients) and 20q13.33 (two patients). Expression of novel candidate genes, altered by CNVs, was determined in human right ventricular outflow tract and left ventricle prioritizing future investigation. High-throughput massively parallel sequencing was used to map the duplications that result in premature truncation of RAF1 in seven patients. In conclusion, our genome-wide screen identified multiple loci affected by rare CNVs demonstrating the genetic heterogeneity of isolated CHD and implicating mutations within these loci as etiologic in TOF, HLHS and other forms of CHD. Our data predicts that at least 10% (4.5–15.5, 95% CI) of sporadic, non-syndromic TOF and HLHS reflects de novo CNVs.