Abstract 14506: Re-Evaluating Clinically Relevant Genes in Conotruncal Cardiac Defects by Burden Analyses of Rare and Ultra-Rare Protein-Altering Variants

Abstract

Conotruncal cardiac defects (CTD) is a group of congenital heart diseases (CHD) involving malformation of outflow tract, with an estimated prevalence of 11.6 per 10,000 births. Currently, a robust consensus on causative genes for nonsyndromic CTD remains to be elucidated. To prioritize clinically relevant genes in whole exome sequencing (WES), we performed gene burden analysis on rare (gnomAD exome allele frequency < 0.01%) protein-altering variants in a cohort of nonsyndromic CTD (n = 245) comparing with ethnicity and location matched controls (n = 853); and expanded to a combined analysis of damaging ultra-rare (CADD ≥ 20 and absent in gnomAD exome) variants involving four CTD cohorts (n = 1451; 391 Chinese and 1060 Europeans) and ethnicity matched gnomAD exome singletons as controls. Gene burden analysis on variants identified within a high-confidence list of 132 CHD genes showed significant (Bonferroni corrected p-value < 0.05) excess of rare protein-altering variants in two well-established genes ( GATA6 , NOTCH1 ) and four potentially relevant genes for CTD ( ANKRD11 , DOCK6 , NPHP4 , STRA6 ). Furthermore, burden analysis of ultra-rare variants in the combined cohorts identified three genes robustly (Bonferroni corrected p-value < 0.05) associated with CTD ( FLT4 , NOTCH1 , TBX1 ). Predominantly more FLT4 loss-of-function variants were reported in Europeans than in Chinese, while GATA6 was the only gene with robust burden in Chinese but was not identified in Europeans, suggesting potential differences in the genetic landscape of CTD disease etiology among different ethnicities. Our results provided evidence of aggregate variant excess for nonsyndromic CTD in case-control comparisons and shortlisted significant genes with potential clinical relevance for further systematic curation, to guide appropriate genetic diagnosis for CTD with the application of WES.