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

Abstract

BACKGROUND: Congenital 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. METHODS: To 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. RESULTS: The 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. CONCLUSIONS: Our results confirm a significant role for cilia genes in recessive forms of CHD and suggest important functions of cilia genes in cardiac septation.