Whole exome sequencing reveals a monogenic cause in 57% of individuals with laterality disorders and associated congenital cardiac defects

Background: Heterotaxy refers to any congenital disruption in the left-right (L-R) laterality arrangement of visceral organs and is highly associated with complex congenital cardiac malformations. The molecular basis of heterotaxy is broad and heterogenous, with over 25 genes implicated in its pathogenesis thus far.

Objective: We sought to elucidate the molecular basis of heterotaxy syndrome associated with complex congenital heart defects in a cohort of 28 unrelated families of Arab-Muslim descent, using next generation sequencing techniques.

Methods: Detailed clinical and morphologic phenotyping followed by Whole Exome Sequencing (WES) were pursued for each of the probands and their parents (when available). Sanger sequencing was used for segregation analysis of disease-causing mutations in the families.

Results: 71% had right atrial isomerism, 18% had atrial situs inversus and 11% had left atrial isomerism. Using WES, a molecular diagnosis was reached for 16 probands (57%). Homozygous pathogenic variants in genes associated with heterotaxy and/or primary ciliary dyskinesia were detected in: CFAP53 (CCDC11), CFAP298, CFAP300, LRRC6, GDF1, DNAAF1, DNAH5, CCDC39, CCDC40 and TTC25. Additionally, we detected a homozygous disease causing mutation in DAND5, as a novel recessive monogenic cause for heterotaxy. Three additional probands were found to harbor variants of uncertain significance, including biallelic variants in DNAH7, CFAP46, CCDC185, PKHD1L1, CER1 and CELSR1.

Conclusions: Our findings contribute to the current knowledge regarding monogenic causes of heterotaxy and its associated congenital heart defects and underscore the role of next generation sequencing techniques in the diagnostic workup of such patients, and especially among consanguineous families