Genetics of Congenitally Corrected Transposition of the Great Arteries: next generation sequencing shows a mutation load effect for 156 genes involved in cardiac patterning

Congenital heart disease (CHD) is a major public health issue. It is considered as a major cause of infant mortality today. We focused on a complex and rare CHD, the congenitally corrected transposition of the great arteries (CCTGA). The aim of this study was to identify the genes that control the alignment of cardiac chambers that are abnormal in CCTGA to further understand the mechanism of this CHD. We analyzed a cohort of 43 CCTGA cases (41 sporadic cases and 2 familial cases) of isolated CCTGA by next generation sequencing analysis (whole-genome sequencing and whole-exome sequencing). Under the hypothesis of Mendelian model including de novo genomic alterations, no major gene effect involved in the disease could be identified. Under the hypothesis of a complex model of inheritance, we highlighted a group of 156 cardiac mutated genes in our patients, in which we found a significant enrichment of rare variants in patients compared to controls in a replication cohort. The highly heterogeneous combinations of susceptibility rare variants, mostly inherited from the healthy mother and father respectively, are correlated with the CCTGA phenotype, any given deleterious variant combination within the CCTGA gene set being specific to the affected individual. Taken together, the cases could be explained by a mutation load of segregated alleles at loci mostly involved in heart tube looping, outflow tract morphogenesis and establishment of left-right asymmetry. Our data suggest that CHD are not Mendelian traits, but rather of polygenic origin. In the majority of cases, both parents harbour a set of susceptibility alleles for the CHD that are inherited by the offspring in a combination that confers the risk of CCTGA.