RT Journal Article
SR Electronic
T1 Familial transposition of the great arteries caused by multiple mutations in laterality genes
JF Heart
JO Heart
FD BMJ Publishing Group Ltd and British Cardiovascular Society
SP 673
OP 677
DO 10.1136/hrt.2009.181685
VO 96
IS 9
A1 Alessandro De Luca
A1 Anna Sarkozy
A1 Federica Consoli
A1 Rosangela Ferese
A1 Valentina Guida
A1 Maria Lisa Dentici
A1 Rita Mingarelli
A1 Emanuele Bellacchio
A1 Giulia Tuo
A1 Giuseppe Limongelli
A1 Maria Cristina Digilio
A1 Bruno Marino
A1 Bruno Dallapiccola
YR 2010
UL http://heart.bmj.com/content/96/9/673.abstract
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.