Oto-facial syndrome and esophageal atresia, intellectual disability and zygomatic anomalies - expanding the phenotypes associated with EFTUD2 mutations.

Claudia Voigt (1) , André Mégarbané (2) , Kornelia Neveling (3) , Johanna Christina Czeschik (1) , Beate Albrecht (1) , Bert Callewaert (4) , Florian von Deimling (5) , Andreas Hehr (6) , Marie Falkenberg Smeland (7) , Rainer König (8) , Alma Kuechler (1) , Carlo Marcelis (3) , Maria Puiu (9) , Willie Reardon (10) , Hilde Monica Frostad Riise Stensland (7) , Bernd Schweiger (11) , Marloes Steehouwer (3) , Christopher Teller (12) , Marcel Martin (13) , Sven Rahmann (13, 14) , Ute Hehr (6) , Han Brunner (3) , Hermann-Josef Lüdecke (1) , Dagmar Wieczorek (1)

1 Institute of Human Genetics - Institut für Humangenetik [Essen]
2 GMGF - Génétique Médicale et Génomique Fonctionnelle
3 Department of Human Genetics
4 Department of Pediatrics and Genetics
5 Medizinische Genetik
6 Zentrum für Humangenetik
7 Department of Medical Genetics
8 Humangenetik
9 Genetica medicala
10 National Centre for Medical Genetics
11 Institut für Diagnostische und Interventionelle Radiologie und Neuroradiologie
12 Institut für Humangenetik [Ulm]
13 Bioinformatics, Computer Science XI
14 Abteilung Genominformatik

BACKGROUND: Mutations in EFTUD2 were proven to cause a very distinct mandibulofacial dysostosis type Guion-Almeida (MFDGA, OMIM #610536). Recently, gross deletions and mutations in EFTUD2 were determined to cause syndromic esophageal atresia (EA), as well. We set forth to find further conditions caused by mutations in the EFTUD2 gene (OMIM *603892). METHODS AND RESULTS: We performed exome sequencing in two familial cases with clinical features overlapping with MFDGA and EA, but which were previously assumed to represent distinct entities, a syndrome with esophageal atresia, hypoplasia of zygomatic complex, microcephaly, cup-shaped ears, congenital heart defect, and intellectual disability in a mother and her two children [AJMG 143A(11):1135-1142, 2007] and a supposedly autosomal recessive oto-facial syndrome with midline malformations in two sisters [AJMG 132(4):398-401, 2005]. While the analysis of our exome data was in progress, a recent publication made EFTUD2 mutations highly likely in these families. This hypothesis could be confirmed with exome as well as with Sanger sequencing. Also, in three further sporadic patients, clinically overlapping to these two families, de novo mutations within EFTUD2 were identified by Sanger sequencing. Our clinical and molecular workup of the patients discloses a broad phenotypic spectrum, and describes for the first time an instance of germline mosaicism for an EFTUD2 mutation. CONCLUSIONS: The clinical features of the eight patients described here further broaden the phenotypic spectrum caused by EFTUD2 mutations or deletions. We here show, that it not only includes mandibulofacial dysostosis type Guion-Almeida, which should be reclassified as an acrofacial dysostosis because of thumb anomalies (present in 12/35 or 34% of patients) and syndromic esophageal atresia [JMG 49(12). 737-746, 2012], but also the two new syndromes, namely oto-facial syndrome with midline malformations published by Mégarbané et al. [AJMG 132(4): 398-401, 2005] and the syndrome published by Wieczorek et al. [AJMG 143A(11): 1135-1142, 2007] The finding of mild phenotypic features in the mother of one family that could have been overlooked and the possibility of germline mosaicism in apparently healthy parents in the other family should be taken into account when counseling such families.

Mots clés: EFTUD2; Mandibulofacial dysostosis type Guion-Almeida (MFDGA); Esophageal atresia (EA); Oto-facial syndrome with midline malformation; Acrofacial dysostosis type Guion-Almeida (AFDGA)

Domaines: Génétique

Claudia Voigt, André Mégarbané, Kornelia Neveling, Johanna Christina Czeschik, Beate Albrecht, et al.. Oto-facial syndrome and esophageal atresia, intellectual disability and zygomatic anomalies - expanding the phenotypes associated with EFTUD2 mutations.. Orphanet Journal of Rare Diseases, 2013, 8 (1), pp.110. ⟨10.1186/1750-1172-8-110⟩. ⟨inserm-00849063⟩