Familial transposition of the great arteries caused by multiple mutations in laterality genes.
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.
De Luca
Alessandro
A
Mendel Laboratory, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo, Italy. a.deluca@css-mendel.it
Sarkozy
Anna
A
Consoli
Federica
F
Ferese
Rosangela
R
Guida
Valentina
V
Dentici
Maria Lisa
ML
Mingarelli
Rita
R
Bellacchio
Emanuele
E
Tuo
Giulia
G
Limongelli
Giuseppe
G
Digilio
Maria Cristina
MC
Marino
Bruno
B
Dallapiccola
Bruno
B
D019943:Amino Acid Substitution / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D014188:Transposition of Great Vessels / Q000235:genetics*