Background: The pathogenesis of transposition of the great arteries (TGA) is still largely unknown. In general, TGA is not associated with the more common genetic disorders nor with extracardiac anomalies, while it can be found in individuals with lateralization defects, heterotaxy and asplenia syndrome (right isomerism).
Objective: Analyze genes previously associated to heterotaxy in order to assess mutations in familial TGA unassociated with other features of laterality defects.
Methods: Probands of 7 families with isolated TGA and family history of concordant or discordant CHDs were screened for mutations in the ZIC3, ACVR2B, LEFTYA, CFC1, NODAL, FOXH1, GDF1, CRELD1, GATA4 and NKX2.5 genes.
Results: Mutation analysis allowed the identification of 3 sequence variations in 2 out of 7 TGA probands. A FOXH1 (Pro21Ser) missense variant was found in a proband who was also heterozogous for an amino acid substitution (Gly17Cys) in ZIC3 gene. This ZIC3 variant was also found in another family member with a second sequence variation (Val150Ile) in the NKX2.5 gene homeodomain who was affected by multiple ventricular septal defects. A second proband was found to harbor a splice site variant (IVS2-1G>C) in NODAL gene.
Conclusions: The present study provides evidence that some cases of familial TGA are caused by mutations in laterality genes and thereby are part of the same disease spectrum of heterotaxy syndrome, and argues for an oligogenic or complex mode of inheritance in these pedigrees.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.