Analysis of Premature Termination Codons Predicted to Escape Nonsense Mediated Decay Identifies Novel Genes, Pathways, and Networks Contributing to an Oligogenic Etiology of Congenital Heart Disease

Background A large fraction of clinically relevant pathogenic genomic variation consists of premature termination codons ( PTC). While PTCs can trigger nonsense mediated mRNA decay ( NMDtrig ) causing loss of function ( LOF ), those near the end of transcripts can escape NMD ( NMDesc ), allowing expression of truncated proteins. As NMDesc PTCs are not well studied, and can lead to possible gain of function ( GOF ) effects, we investigated the impact of NMDtrig/NMDesc PTCs on human congenital heart disease ( CHD ). Results Whole exome sequencing data from ∼3,000 CHD patients and ∼5,000 control subjects were analyzed for PTCs using known rules for classifying variants as NMDtrig/NMDesc. CHD patients had an increased burden of PTCs in gene-sets related to both heart and brain developmental processes. NMDesc PTCs were enriched in the MAPK pathway, known to harbor GOF variants that cause Noonan syndrome. Also identified were Hedgehog and ERBB signaling, pathways with prominent roles in heart development but not previously reported in nonsyndromic CHD. NMD analysis of PTCs at the transcript level identified 11 genes (9 novel) associated with CHD. Enrichment of digenic combinations between these 11 genes and digenic and higher order combinations of PTCs within heart developmental genes suggest a role for oligogenicity. Conclusions We observed NMDesc PTCs play a role in CHD pathogenesis, and this role may be disproportionately specific to heart development. Our analysis uncovered new genes and pathways, identifying MAPK, Hedgehog, and ERBB signaling as pathways contributing to nonsyndromic CHD. The additional observation of digenic and higher order combinations of PTCs suggests an oligogenic framework to the genetic architecture of human CHD.