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, whereas it can be found in individuals with lateralisation defects, heterotaxy and asplenia syndrome (right isomerism).
Objective To analyse genes previously associated with heterotaxy in order to assess mutations in familial TGA unassociated with other features of laterality defects.
Methods Probands of seven families with isolated TGA and a family history of concordant or discordant congenital heart disease 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 three sequence variations in two out of seven TGA probands. A FOXH1 (Pro21Ser) missense variant was found in a proband who was also heterozogous for an amino acid substitution (Gly17Cys) in the 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 harbour a splice site variant (IVS2-1G→C) in the NODAL gene.
Conclusions The present study provides evidence that some cases of familial TGA are caused by mutations in laterality genes and therefore are part of the same disease spectrum of heterotaxy syndrome, and argues for an oligogenic or complex mode of inheritance in these pedigrees.
- Congenital heart disease
- molecular genetics
- transportation of the great arteries
- transposition of great vessels
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Funding This research was supported by the Italian Ministry of Health grant RF2009 and RC2009, and Italy–USA Program on Rare Diseases (Istituto Superiore di Sanità).
Competing interests None.
Patient consent Obtained.
Ethics approval This study was conducted with the approval of the Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo.
Provenance and peer review Not commissioned; externally peer reviewed.