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

Orphanet Journal of Rare Diseases

Dagmar Wieczorek⁶  Hermann-Josef Lüdecke⁶  Han G Brunner^1,14  Ute Hehr⁹  Sven Rahmann²  Marcel Martin⁵  Christopher Teller³  Marloes Steehouwer^1,14  Bernd Schweiger^1,10  Hilde Monica Frostad Riise Stensland^1,12  Willie Reardon⁴  Maria Puiu⁸  Carlo Marcelis^1,14  Alma Kuechler⁶  Rainer König¹  Marie Falkenberg Smeland^1,12  Andreas Hehr⁹  Florian von Deimling^1,11  Bert Callewaert⁷  Beate Albrecht⁶  Johanna Christina Czeschik⁶  Kornelia Neveling^1,14  André Mégarbané^1,13  Claudia Voigt⁶ 

[1]Humangenetik, Universitätsklinikum Frankfurt, Frankfurt, Germany

[2]Abteilung Genominformatik, Institut für Humangenetik, Universität Duisburg-Essen, Essen, Germany

[3]Institut für Humangenetik, Institut für Humangenetik, Universitätsklinikum Ulm, Ulm, Germany

[4]National Centre for Medical Genetics, Our Lady’s Hospital for Sick Children, Crumlin, Dublin, Ireland

[5]Bioinformatics, Computer Science XI, TU Dortmund, Dortmund, Germany

[6]Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany

[7]Department of Pediatrics and Genetics, Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium

[8]Genetica medicala, Universitatea de Medicina si Farmacie, Timisoara, Romania

[9]Zentrum für Humangenetik, Universitätsklinikum Regensburg, Regensburg, Germany

[10]Institut für Diagnostische und Interventionelle Radiologie und Neuroradiologie, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany

[11]Sozialpädiatrisches Zentrum Coburg, Coburg, Germany

[12]Department of Medical Genetics, Division of Child and Adolescent Health, University Hospital of North Norway, Tromsø, Norway

[13]Unité de Génétique Médicale et laboratoire associé INSERM à l'Unité UMR_S 910, PôleTechnologie Santé, Université Saint-Joseph, Beirut 545, Lebanon

[14]Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands

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

Others  :  863641
DOI  :  10.1186/1750-1172-8-110

 received in 2013-04-10, accepted in 2013-07-05,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Voigt et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Ng SB, Buckingham KJ, Lee C, Bigham AW, Tabor HK, Dent KM, Huff CD, Shannon PT, Jabs EW, Nickerson DA, et al.: Exome sequencing identifies the cause of a mendelian disorder. Nat Genet 2010, 42(1):30-35.
• [2]Lines MA, Huang L, Schwartzentruber J, Douglas SL, Lynch DC, Beaulieu C, Guion-Almeida ML, Zechi-Ceide RM, Gener B, Gillessen-Kaesbach G, et al.: Haploinsufficiency of a spliceosomal GTPase encoded by EFTUD2 causes mandibulofacial dysostosis with microcephaly. Am J Hum Genet 2012, 90(2):369-377.
• [3]Guion-Almeida ML, Zechi-Ceide RM, Vendramini S, Tabith Júnior A: A new syndrome with growth and mental retardation, mandibulofacial dysostosis, microcephaly, and cleft palate. Clin Dysmorphol 2006, 15(3):171-174.
• [4]Wieczorek D, Gener B, González MJ, Seland S, Fischer S, Hehr U, Kuechler A, Hoefsloot LH, de Leeuw N, Gillessen-Kaesbach G, et al.: Microcephaly, microtia, preauricular tags, choanal atresia and developmental delay in three unrelated patients: a mandibulofacial dysostosis distinct from Treacher Collins syndrome. Am J Med Genet A 2009, 149A(5):837-843.
• [5]Bernier FP, Caluseriu O, Ng S, Schwartzentruber J, Buckingham KJ, Innes AM, Jabs EW, Innis JW, Schuette JL, Gorski JL, et al.: Haploinsufficiency of SF3B4, a component of the pre-mRNA spliceosomal complex, causes Nager syndrome. Am J Hum Genet 2012, 90(5):925-933.
• [6]Luquetti DV, Hing AV, Rieder MJ, Nickerson DA, Turner EH, Smith J, Park S, Cunningham ML: “Mandibulofacial dysostosis with microcephaly” caused by EFTUD2 mutations: expanding the phenotype. Am J Med Genet A 2013, 161A(1):108-113.
• [7]Wieczorek D: Human facial dysostoses. Clin Genet 2013, 83(6):499-510.
• [8]Gordon CT, Petit F, Oufadem M, Decaestecker C, Jourdain AS, Andrieux J, Malan V, Alessandri JL, Baujat G, Baumann C, et al.: EFTUD2 haploinsufficiency leads to syndromic oesophageal atresia. J Med Genet 2012, 49(12):737-746.
• [9]Wieczorek D, Shaw-Smith C, Kohlhase J, Schmitt W, Buiting K, Coffey A, Howard E, Hehr U, Gillessen-Kaesbach G: Esophageal atresia, hypoplasia of zygomatic complex, microcephaly, cup-shaped ears, congenital heart defect, and mental retardation–new MCA/MR syndrome in two affected sibs and a mildly affected mother? Am J Med Genet A 2007, 143A(11):1135-1142.
• [10]Mégarbané A, Chouery E, Rassi S, Delague V: A new autosomal recessive oto-facial syndrome with midline malformations. Am J Med Genet A 2005, 132(4):398-401.
• [11]Czeschik JC, Voigt C, Alanay Y, Albrecht B, Avci S, Fitzpatrick D, Goudie DR, Hehr U, Hoogeboom AJ, Kayserili H: Clinical and mutation data in 12 patients with the clinical diagnosis of Nager syndrome. Hum Genet 2013, 132(8):885-898. Epub 2013 Apr 9
• [12]Hoischen A, van Bon BW, Gilissen C, Arts P, van Lier B, Steehouwer M, de Vries P, de Reuver R, Wieskamp N, Mortier G, et al.: De novo mutations of SETBP1 cause Schinzel-Giedion syndrome. Nat Genet 2010, 42(6):483-485.
• [13]Fabrizio P, Laggerbauer B, Lauber J, Lane WS, Lührmann R: An evolutionarily conserved U5 snRNP-specific protein is a GTP-binding factor closely related to the ribosomal translocase EF-2. EMBO J 1997, 16(13):4092-4106.
• [14]Häcker I, Sander B, Golas MM, Wolf E, Karagöz E, Kastner B, Stark H, Fabrizio P, Lührmann R: Localization of Prp8, Brr2, Snu114 and U4/U6 proteins in the yeast tri-snRNP by electron microscopy. Nat Struct Mol Biol 2008, 15(11):1206-1212.
• [15]Need AC, Shashi V, Hitomi Y, Schoch K, Shianna KV, McDonald MT, Meisler MH, Goldstein DB: Clinical application of exome sequencing in undiagnosed genetic conditions. J Med Genet 2012, 49(6):353-361.