Blue et al. (2023) Rare variants in CAPN2 increase risk for isolated hypoplastic left heart syndrome
We show that the genetic basis of isolated hypoplastic left heart syndrome (iHLHS) is not explained by single, large effect alleles in genes previously reported to underlie iHLHS or congenital heart disease. Instead, we find that rare coding changes in CAPN2 are enriched among those affected by iHLHS. Functional validation in a vertebrate animal model confirms that these associated variants are hypomorphic and can recapitulate the phenotype in Xenopus laevis. This is important because HLHS accounts for 25% of deaths from congenital heart defects, we show that iHLHS is not a typical Mendelian condition as previously described, and we identify a novel pathway involved in HLHS pathogenesis. Contributing consortia: University of Washington Center for Mendelian Genomics