Rare homozygous cilia gene variants identified in consanguineous congenital heart disease patients

BACKGROUNDCongenital heart defects (CHD) appear in almost one percent of live births. Asian countries have the highest birth prevalence of CHD in the world. Recessive genotypes may represent a significant CHD risk factor in Asian populations, because Asian populations have a high degree of consanguineous marriages, which increases the risk of CHD. Genetic analysis of consanguineous families may represent a relatively unexplored source for investigating CHD etiology. METHODSTo obtain insight into the contribution of recessive genotypes in CHD we analysed a cohort of forty-nine Pakistani CHD probands, originating from consanguineous unions. The majority (82%) of patients malformations were septal defects. We identified protein altering, rare homozygous variants (RHVs) in the patients coding genome by whole exome sequencing. RESULTSThe patients had a median of seven damaging RHVs each, and our analysis revealed a total of 758 RHVs in 693 different genes. By prioritizing these genes based on variant severity, loss-of-function intolerance and specific expression in the developing heart, we identified a set of 23 candidate disease genes. These candidate genes were significantly enriched for genes known to cause heart defects in recessive mouse models (P<2.4e-06). In addition, we found a significant enrichment of cilia genes in both the initial set of 693 genes (P<5.4e-04) and the 23 candidate disease genes (P<5.2e-04). Functional investigation of ADCY6 in cell- and zebrafish-models verified its role in heart development. CONCLUSIONSOur results confirm a significant role for cilia genes in recessive forms of CHD and suggest important functions of cilia genes in cardiac septation.