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Familial transposition of great arteries caused by multiple mutations in laterality genes
  1. Alessandro De Luca1,*,
  2. Anna Sarkozy1,
  3. Federica Consoli1,
  4. Rosangela Ferese1,
  5. Valentina Guida1,
  6. Maria Lisa Dentici1,
  7. Rita Mingarelli1,
  8. Emanuele Bellacchio1,
  9. Giulia Tuo2,
  10. Giuseppe Limongelli3,
  11. Maria Cristina Digilio4,
  12. Bruno Marino5,
  13. Bruno Dallapiccola1
  1. 1 CSS-Mendel Institute, Rome, Italy;
  2. 2 Department of Pediatric Cardiology, G. Gaslini Hospital, Genova, Italy;
  3. 3 Department of Pediatric Cardiology, Monaldi Hospital, Napoli, Italy;
  4. 4 Department of Medical Genetics, Bambino Gesù Hospital, Rome, Italy;
  5. 5 Division of Pediatric Cardiology, Department of Pediatrics, La Sapienza University, Rome, Italy
  1. Correspondence to: Alessandro De Luca, Istituto CSS-Mendel, Viale Regina Margherita 261, Rome, 00128, Italy; a.deluca{at}


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.

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