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, compound heterozygous or haploinsufficient in at least 1 out of 4 cases, but excluded variants that occurred in ≥ 7 of the 10 controls. We used Ingenuity Variant Analysis to retain only variants with a high probability of being deleterious. The final step removed variants not part of 5 cardiac networks derived from Ingenuity Pathways Analysis: WNT, Cardiogenesis in Vertebrates, NOTCH, SHH and Cardiomyocyte Differentiation via BMP receptors.
Results: The number of variants was similar between the HLHS patients and the ND patients until the final filtering step. The number of genes from the cardiac networks with probable deleterious changes was 158 of 653 (24%) in the HLHS group which was enriched compared to the cardiac networks in the ND group (63/653, 9.7%, p < .0001) or a random set of 600 genes which had 29 variants (4.8%, p < .0001). When we retained all variants including those assessed as benign, we saw no difference in the number of variants in the cardiac network genes among the HLHS patients, the ND patients or the controls.
Conclusions: Thus even with this small sample, there was a significant increase in potentially disruptive variants in networks that regulate heart development in patients with HLHS.
Author Disclosures: D.C. Bittel: Research Grant; Modest; Kansas City Area Life Sciences Institute, Katherine Barry Ross Fund. N. Kibiryeva: None. J. Marshall: None. T.M. Swanson: None. M. Artman: None. J.E. O’Brien: None.
- © 2016 by American Heart Association, Inc.