title: Oto-facial syndrome and esophageal atresia, intellectual disability and zygomatic anomalies - expanding the phenotypes associated with EFTUD2 mutations.
abstract: 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).
  
  
  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.
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Voigt
authors.forename: André
authors.initials: A
authors.lastname: Mégarbané
authors.forename: Kornelia
authors.initials: K
authors.lastname: Neveling
authors.forename: Johanna Christina
authors.initials: JC
authors.lastname: Czeschik
authors.forename: Beate
authors.initials: B
authors.lastname: Albrecht
authors.forename: Bert
authors.initials: B
authors.lastname: Callewaert
authors.forename: Florian
authors.initials: F
authors.lastname: von Deimling
authors.forename: Andreas
authors.initials: A
authors.lastname: Hehr
authors.forename: Marie
authors.initials: M
authors.lastname: Falkenberg Smeland
authors.forename: Rainer
authors.initials: R
authors.lastname: König
authors.forename: Alma
authors.initials: A
authors.lastname: Kuechler
authors.forename: Carlo
authors.initials: C
authors.lastname: Marcelis
authors.forename: Maria
authors.initials: M
authors.lastname: Puiu
authors.forename: Willie
authors.initials: W
authors.lastname: Reardon
authors.forename: Hilde Monica Frostad
authors.initials: HM
authors.lastname: Riise Stensland
authors.forename: Bernd
authors.initials: B
authors.lastname: Schweiger
authors.forename: Marloes
authors.initials: M
authors.lastname: Steehouwer
authors.forename: Christopher
authors.initials: C
authors.lastname: Teller
authors.forename: Marcel
authors.initials: M
authors.lastname: Martin
authors.forename: Sven
authors.initials: S
authors.lastname: Rahmann
authors.forename: Ute
authors.initials: U
authors.lastname: Hehr
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Lüdecke
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wieczorek
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004933:Esophageal Atresia / Q000235:genetics / Q000473:pathology*; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics / Q000473:pathology*; D008297:Male; D008342:Mandibulofacial Dysostosis / Q000235:genetics / Q000473:pathology*; D009154:Mutation; D010445:Peptide Elongation Factors / Q000235:genetics*; D010641:Phenotype; D017415:Ribonucleoprotein, U5 Small Nuclear; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: C581608:EFTUD2 protein, human; D010445:Peptide Elongation Factors; D017415:Ribonucleoprotein, U5 Small Nuclear