CELSR1 Risk Alleles in Familial Bicuspid Aortic Valve and Hypoplastic Left Heart Syndrome

Background: Whole-genome sequencing in families enables deciphering of congenital heart disease causes. A shared genetic basis for familial bicuspid aortic valve (BAV) and hypoplastic left heart syndrome (HLHS) was postulated. Methods: Whole-genome sequencing was performed in affected members of 6 multiplex BAV families, an HLHS cohort of 197 probands and 546 relatives, and 813 controls. Data were filtered for rare, predicted-damaging variants that cosegregated with familial BAV and disrupted genes associated with congenital heart disease in humans and mice. Candidate genes were further prioritized by rare variant burden testing in HLHS cases versus controls. Modifier variants in HLHS proband-parent trios were sought to account for the severe developmental phenotype. Results: In 5 BAV families, missense variants in 6 ontologically diverse genes for structural (SPTBN1 ,PAXIP1 , andFBLN1 ) and signaling (CELSR1 ,PLXND1 , andNOS3 ) proteins fulfilled filtering metrics.CELSR1 , encoding cadherin epidermal growth factor laminin G seven-pass G-type receptor, was identified as a candidate gene in 2 families and was the only gene demonstrating rare variant enrichment in HLHS probands (P =0.003575). HLHS-associatedCELSR1 variants included 16 missense, one splice site, and 3 noncoding variants predicted to disrupt canonical transcription factor binding sites, most of which were inherited from a parent without congenital heart disease. Filtering whole-genome sequencing data for rare, predicted-damaging variants inherited from the other parent revealed 2 cases ofCELSR1 compound heterozygosity, one case ofCELSR1 -CELSR3 synergistic heterozygosity, and 4 cases ofCELSR1 -MYO15A digenic heterozygosity.Conclusions: CELSR1 is a susceptibility gene for familial BAV and HLHS, further implicating planar cell polarity pathway perturbation in congenital heart disease.