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The phenotypic spectrum of WWOX-related disorders: 20 additional cases of WOREE syndrome and review of the literature

Juliette Piard 1 Lara Hawkes 2 Mathieu Milh 3, 4 Laurent Villard 4 Renato Borgatti 5 Romina Romaniello 5 Mélanie Fradin 6 Yline Capri 7 Delphine Heron 8 Marie-Christine Nougues 9 Caroline Nava 10 Oana Tarta Arsene 11 Debbie Shears 2 John Taylor 2 Alistair Pagnamenta 12 Jenny C. Taylor 12 Yoshimi Sogawa 13 Diana Johnson 14 Helen Firth 14 Pradeep Vasudevan 15 Gabriela Jones 15 Marie-Ange Nguyen-Morel 16 Tiffany Busa 17, 4 Agathe Roubertie 18 Myrthe van den Born 19 Elise Brischoux-Boucher 1 Michel Koenig 20 Cyril Mignot 21 Usha Kini 2 Christophe Philippe 22, 23
1 UFC - Université de Franche-Comté
2 Oxford University Hospitals NHS Trust
3 Service de pédiatrie et neurologie pédiatrique
4 MMG - Marseille medical genetics - Centre de génétique médicale de Marseille
5 IRCCS Eugenio Medea
6 IGDR - Institut de Génétique et Développement de Rennes
7 Hôpital Robert Debré Paris
8 Centre de Génétique (Hôpital de la Pitié-Salpétrière, Paris)
9 Service de Neuropédiatrie [CHU Trousseau]
10 ICM - Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute
11 UMPCD - University of Medicine and Pharmacy “Carol Davila” Bucharest
12 Oxford NIHR Biomedical Research Centre
13 Children's Hospital of Pittsburgh of UPMC [Etats-Unis]
14 Department of Clinical Genetics
15 University Hospitals of Leicester
16 CHU de Grenoble-Alpes
17 Département de génétique médicale [Hôpital de la Timone - APHM]
18 INM - Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs
19 Erasmus MC - Erasmus University Medical Center [Rotterdam]
20 LGMR - Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques
21 Centre de référence "Déficiences Intellectuelles de Causes Rares" - Paris
22 Plateau technique de Biologie [CHU de Dijon]
23 Equipe GAD (LNC - U1231)
LNC - Lipides - Nutrition - Cancer [Dijon - U1231]
Abstract : PurposeGermline WWOX pathogenic variants have been associated with disorder of sex differentiation (DSD), spinocerebellar ataxia (SCA), and WWOX-related epileptic encephalopathy (WOREE syndrome). We review clinical and molecular data on WWOX-related disorders, further describing WOREE syndrome and phenotype/genotype correlations.MethodsWe report clinical and molecular findings in 20 additional patients from 18 unrelated families with WOREE syndrome and biallelic pathogenic variants in the WWOX gene. Different molecular screening approaches were used (quantitative polymerase chain reaction/multiplex ligation-dependent probe amplification [qPCR/MLPA], array comparative genomic hybridization [array-CGH], Sanger sequencing, epilepsy gene panel, exome sequencing).ResultsTwo copy-number variations (CNVs) or two single-nucleotide variations (SNVs) were found respectively in four and nine families, with compound heterozygosity for one SNV and one CNV in five families. Eight novel missense pathogenic variants have been described. By aggregating our patients with all cases reported in the literature, 37 patients from 27 families with WOREE syndrome are known. This review suggests WOREE syndrome is a very severe epileptic encephalopathy characterized by absence of language development and acquisition of walking, early-onset drug-resistant seizures, ophthalmological involvement, and a high likelihood of premature death. The most severe clinical presentation seems to be associated with null genotypes.ConclusionGermline pathogenic variants in WWOX are clearly associated with a severe early-onset epileptic encephalopathy. We report here the largest cohort of individuals with WOREE syndrome. We report here 20 additional patients with biallelic pathogenic variants in the WWOX gene associated with severe early-onset encephalopathy. After a literature review, we define the main linical features of the WWOX-related disorders and discuss genotype–phenotype correlations.
Keywords : epilepsy encephalopathy WWOX
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Juliette Piard, Lara Hawkes, Mathieu Milh, Laurent Villard, Renato Borgatti, et al.. The phenotypic spectrum of WWOX-related disorders: 20 additional cases of WOREE syndrome and review of the literature. Genetics in Medicine, Nature Publishing Group, 2019, 21 (6), pp.1308-1318. ⟨10.1038/s41436-018-0339-3⟩. ⟨hal-01932796⟩

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