PT  - JOURNAL ARTICLE
AU  - Alessandro De Luca
AU  - Anna Sarkozy
AU  - Federica Consoli
AU  - Rosangela Ferese
AU  - Valentina Guida
AU  - Maria Lisa Dentici
AU  - Rita Mingarelli
AU  - Emanuele Bellacchio
AU  - Giulia Tuo
AU  - Giuseppe Limongelli
AU  - Maria Cristina Digilio
AU  - Bruno Marino
AU  - Bruno Dallapiccola
TI  - Familial transposition of the great arteries caused by multiple mutations in laterality genes
AID  - 10.1136/hrt.2009.181685
DP  - 2010 May 01
TA  - Heart
PG  - 673--677
VI  - 96
IP  - 9
4099  - http://heart.bmj.com/content/96/9/673.short
4100  - http://heart.bmj.com/content/96/9/673.full
SO  - Heart2010 May 01; 96
AB  - 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.