1. Oto-facial syndrome and esophageal atresia, intellectual disability and zygomatic anomalies - expanding the phenotypes associated with EFTUD2 mutations
- Author
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Voigt, C., Megarbane, A., Neveling, K., Czeschik, J.C., Albrecht, B., Callewaert, B., Deimling, F. von, Hehr, A., Smeland, M. Falkenberg, Konig, R., Kuechler, A., Marcelis, C., Puiu, M., Reardon, W., Stensland, H.M. Riise, Schweiger, B., Steehouwer, M., Teller, C., Martin, M., Rahmann, S., Hehr, U., Brunner, H.G., Ludecke, H.J., Wieczorek, D., BMC, Ed., Institute of Human Genetics - Institut für Humangenetik [Essen], Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen)-Universitat Duisberg-Essen, Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Human Genetics, Radboud University Medical Center [Nijmegen], Department of Pediatrics and Genetics, Ghent University Hospital-Center for Medical Genetics, Medizinische Genetik, Sozialpädiatrisches Zentrum Coburg, Zentrum für Humangenetik, Universitätsklinikum Regensburg, Department of Medical Genetics, Division of Child and Adolescent Health-University Hospital of North Norway [Tromsø] (UNN), Humangenetik, Universitätsklinikum Frankfurt, Genetica medicala, Victor Babeş University of Medicine and Pharmacy (UMFT), National Centre for Medical Genetics, Our Lady's Children's Hospital, Crumlin OLCHC, Institut für Diagnostische und Interventionelle Radiologie und Neuroradiologie, Universitätsklinikum Essen, Institut für Humangenetik [Ulm], Universitätsklinikum Ulm - University Hospital of Ulm, Bioinformatics, Computer Science XI, Technische Universität Dortmund [Dortmund] (TU), Abteilung Genominformatik, Universität Duisburg-Essen [Essen]-Institut für Humangenetik, This work was supported by the German Ministry of Education and Research for the CRANIRARE to DW and the FACE consortium to DW and H-JL (BMBF 01GM1211B and 01GM1109B). BC is a postdoctoral research fellow of the fund for scientific research-flanders., and Universität Duisburg-Essen = University of Duisburg-Essen [Essen]-Institut für Humangenetik
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Adult ,Male ,Adolescent ,Medizin ,Oto-facial syndrome with midline malformation ,[SDV.GEN] Life Sciences [q-bio]/Genetics ,HAPLOINSUFFICIENCY ,EFTUD2 ,Genomic disorders and inherited multi-system disorders [IGMD 3] ,Young Adult ,Oto-facial syndrome with midline malformation, Acrofacial dysostosis type Guion-Almeida (AFDGA) ,SNRNP ,Intellectual Disability ,Humans ,Genetics(clinical) ,Pharmacology (medical) ,Mandibulofacial dysostosis type Guion-Almeida (MFDGA) ,Child ,Esophageal Atresia ,Genetic Association Studies ,Ribonucleoprotein, U5 Small Nuclear ,Medicine(all) ,Acrofacial dysostosis type Guion-Almeida (AFDGA) ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,COMPLEX ,Esophageal atresia (EA) ,Research ,Biology and Life Sciences ,Sequence Analysis, DNA ,NAGER SYNDROME ,Peptide Elongation Factors ,Phenotype ,Child, Preschool ,Mutation ,Female ,MANDIBULOFACIAL DYSOSTOSIS ,Genetics and epigenetic pathways of disease Genomic disorders and inherited multi-system disorders [NCMLS 6] ,MENTAL-RETARDATION ,Mandibulofacial Dysostosis - Abstract
Contains fulltext : 185259.pdf (Publisher’s version ) (Open Access) 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 Megarbane 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.
- Published
- 2013
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