Abstract 16103: Congenital Heart Defects Result From Accumulated Disturbance of Pathways that Regulate Heart Development

Introduction: Congenital heart defects (CHDs) are the most common birth defect and although studies of the developing vertebrate heart have provided a framework of regulatory control the underlying cause of the majority of CHDs remains unknown. Hypothesis: CHDs result from an accumulation of modest genetic changes which collectively perturb networks involved in regulating cardiac development. Methods: We analyzed sequence variants in cardiac networks by comparing high resolution exome data from 4 infants with Hypoplastic Left Heart Syndrome (HLHS), 4 patients with Neurodevelopmental Disorders (ND) but no heart involvement, 10 normally developing individuals to the reference sequence: hg19 dbSNPs 144. Analysis was restricted to exonic regions with confidence standards set to call quality of at least 20. We excluded variants that occurred with a frequency > 0.5% in standard reference populations: 1000 Genome project; ExAC; European American NHLBI ESP exomes. We retained variants that were homozygous, compou...