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EFTUD2 haploinsufficiency leads to syndromic oesophageal atresia

Christopher T. Gordon 1 Florence Petit 2 Myriam Oufadem 1 Charles Decaestecker 2 Anne-Sophie Jourdain 3 Joris Andrieux 4 Valérie Malan 5 Jean-Luc Alessandri 6, 7, 8 Geneviève Baujat 5 Clarisse Baumann 9 Odile Boute-Benejean 3 Roseline Caumes 10 Bruno Delobel 11 Klaus Dieterich 12 Dominique Gaillard 13 Marie Gonzales 14 Didier Lacombe 15 Fabienne Escande 3 Sylvie Manouvrier-Hanu 16 Sandrine Marlin 17 Michèle Mathieu-Dramard 18 Sarju G. Mehta Ingrid Simonic 19 Arnold Munnich 5, 1 Michel Vekemans 5, 1 Nicole Porchet 3 Loïc de Pontual 10, 20 Sabine Sarnacki 21 Tania Attié-Bitach 22, 1 Stanislas Lyonnet 22, 1 Muriel Holder-Espinasse 23 Jeanne Amiel 5, 1, 22
1 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
2 Service de Génétique Médicale [Lille]
3 CHRU Lille - Centre Hospitalier Régional Universitaire [Lille]
4 Laboratoire de Génétique Médicale
5 Inserm U781 - Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement
6 Service de Réanimation Néonatale et Pédiatrique
7 CHU La Réunion - Centre Hospitalier Universitaire de La Réunion
8 GRI - Groupe de Recherche en Immunopathologies et maladies infectueuses
9 Service de génétique clinique
10 Inserm U393 - Handicaps génétiques de l'enfant
11 Centre de Génétique Chromosomique
12 Service de Génétique Clinique
13 Service de Génétique
14 Service de Génétique et d'Embryologie Médicales
15 MRGM - Maladies Rares - Génétique et Métabolisme
16 Laboratoire de Génétique Clinique
17 CHU Trousseau [APHP]
18 Service de génétique médicale
19 Addenbrooke's Hospital
20 Hôpital Jean Verdier [AP-HP]
21 CHU Necker - Enfants Malades [AP-HP]
22 Service de Génétique Médicale [CHU Necker]
23 Service de génétique clinique
Abstract : BACKGROUND: Oesophageal atresia (OA) and mandibulofacial dysostosis (MFD) are two congenital malformations for which the molecular bases of syndromic forms are being identified at a rapid rate. In particular, the EFTUD2 gene encoding a protein of the spliceosome complex has been found mutated in patients with MFD and microcephaly (MIM610536). Until now, no syndrome featuring both MFD and OA has been clearly delineated. RESULTS: We report on 10 cases presenting with MFD, eight of whom had OA, either due to de novo 17q21.31 deletions encompassing EFTUD2 and neighbouring genes or de novo heterozygous EFTUD2 loss-of-function mutations. No EFTUD2 deletions or mutations were found in a series of patients with isolated OA or isolated oculoauriculovertebral spectrum (OAVS). CONCLUSIONS: These data exclude a contiguous gene syndrome for the association of MFD and OA, broaden the spectrum of clinical features ascribed to EFTUD2 haploinsufficiency, define a novel syndromic OA entity, and emphasise the necessity of mRNA maturation through the spliceosome complex for global growth and within specific regions of the embryo during development. Importantly, the majority of patients reported here with EFTUD2 lesions were previously diagnosed with Feingold or CHARGE syndromes or presented with OAVS plus OA, highlighting the variability of expression and the wide range of differential diagnoses.
Keywords : Adolescent Child Preschool Chromosome Deletion Chromosomes Human Pair 17 Comparative Genomic Hybridization Esophageal Atresia Facies Female Haploinsufficiency Humans Infant Male Peptide Elongation Factors Phenotype Ribonucleoprotein U5 Small Nuclear Syndrome
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https://hal.univ-reunion.fr/hal-01274605
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Submitted on : Tuesday, February 16, 2016 - 8:42:18 AM
Last modification on : Tuesday, September 1, 2020 - 3:06:37 AM

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Christopher T. Gordon, Florence Petit, Myriam Oufadem, Charles Decaestecker, Anne-Sophie Jourdain, et al.. EFTUD2 haploinsufficiency leads to syndromic oesophageal atresia. Journal of Medical Genetics, 2012, 49 (12), pp.737--746. ⟨10.1136/jmedgenet-2012-101173⟩. ⟨hal-01274605⟩

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