Common deletion variants causing protocadherin-α deficiency contribute to the complex genetics of BAV and left-sided congenital heart disease

Abstract

Summary Bicuspid aortic valve (BAV) with ~1%–2% prevalence is the most common congenital heart defect (CHD). It frequently results in valve disease and aorta dilation and is a major cause of adult cardiac surgery. BAV is genetically linked to rare left-heart obstructions (left ventricular outflow tract obstructions [LVOTOs]), including hypoplastic left heart syndrome (HLHS) and coarctation of the aorta (CoA). Mouse and human studies indicate LVOTO is genetically heterogeneous with a complex genetic etiology. Homozygous mutation in the Pcdha protocadherin gene cluster in mice can cause BAV, and also HLHS and other LVOTO phenotypes when accompanied by a second mutation. Here we show two common deletion copy number variants (delCNVs) within the PCDHA gene cluster are associated with LVOTO. Analysis of 1,218 white individuals with LVOTO versus 463 disease-free local control individuals yielded odds ratios (ORs) at 1.47 (95% confidence interval [CI], 1.13–1.92; p = 4.2 × 10 −3 ) for LVOTO, 1.47 (95% CI, 1.10–1.97; p = 0.01) for BAV, 6.13 (95% CI, 2.75–13.7; p = 9.7 × 10 −6 ) for CoA, and 1.49 (95% CI, 1.07–2.08; p = 0.019) for HLHS. Increased OR was observed for all LVOTO phenotypes in homozygous or compound heterozygous PCDHA delCNV genotype comparison versus wild type. Analysis of an independent white cohort (381 affected individuals, 1,352 control individuals) replicated the PCDHA delCNV association with LVOTO. Generalizability of these findings is suggested by similar observations in Black and Chinese individuals with LVOTO. Analysis of Pcdha mutant mice showed reduced PCDHA expression at regions of cell-cell contact in aortic smooth muscle and cushion mesenchyme, suggesting potential mechanisms for BAV pathogenesis and aortopathy. Together, these findings indicate common variants causing PCDHA deficiency play a significant role in the genetic etiology of common and rare LVOTO-CHD.

Polygenic risk scores of endo-phenotypes identify the effect of genetic background in congenital heart disease

“…Rare mutations in NOTCH1 have been known to cause bicuspid aortic valve, a common type of isolated CHD. 13 , 67 , 68 The GWAS summary statistics show that this variant has a p-value of 1.90 × 10 −3 and a beta value of −8.89 × 10 −4 , indicating that it has a protective effect. This SNV has a relatively high minor allele frequency of 0.133.…”

Novel Insights into the Etiology, Genetics, and Embryology of Hypoplastic Left Heart Syndrome

“…Interestingly, analysis of each mutation separately showed the Sap130 mutation likely drives the hypoplastic LV phenotype, while the Pcdha9 mutation may contribute to the aorta/aortic valve defect phenotypes. 30 Thus, the Pcdha9 mutation can give rise to BAV, 30,33 a phenotype that also can be seen in the Ohia HLHS mutant mice harboring mutations in both Sap130 and Pcdha9. These observations suggest HLHS is a phenotype constructed in a modular or combinatorial fashion.…”

“…The total number of patients analyzed with the different phenotypes are indicated. From Teekakirikul et al 33…”

Endocardial Regulation of Cardiac Development

“…BAV has also been found in over 25% of E14.5 mice mutant for the protocadherin-coding gene Pcdha9 . SiRNA knockdown of Pcdh9 causes upregulation of EndoMT-associated genes including Tgfb1 , Tgfb2 , Snail1 , Notch1 and Postn , indicating that protocadherin deficiency can perturb EndoMT and potentially contribute to aortic valve defects [ 141 ].…”