Genetic Analysis of Heterotaxy in a Consanguineous Cohort

Heterotaxy (HTX) is a group of clinical conditions with a shared pathology of dislocation of one or more organs along the left-right axis. The etiology of HTX is tremendously heterogeneous spanning environmental factors, chromosomal aberrations, mono/oligogenic variants, and complex inheritance. However, in the vast majority of cases, the etiology of HTX remains elusive. Here, we sought to describe the yield of genetic analysis and spectrum of variants in HTX in our highly consanguineous population. Twenty-four affected individuals, from 19 unrelated families, were consecutively recruited. Genetic analysis, with exome sequencing, genome sequencing, or multigene panel, detected 9 unique variants, 7 of which were novel, in 8 genes known to be implicated in autosomal recessive form of HTX (C1orf127, CCDC39, CIROP, DNAAF3, DNAH5, DNAH9, MMP21, and MNS1) providing a yield of 42.1%. Of note, 7 of the 9 variants were homozygous, while 2 were inherited in compound heterozygosity, including a heterozygous CNV deletion. A search for candidate genes in negative cases did not reveal a plausible variant. Our work demonstrates a relatively high yield of genetic testing in HTX in a consanguineous population with an enrichment of homozygous variants. The significant genetic heterogeneity observed herewith underscores the complex developmental mechanisms implicated in the pathogenesis of HTX and supports adopting a genome-wide analysis in the diagnostic evaluation of HTX.