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

Juliette C 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 T. 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 CHU Pitié-Salpêtrière [AP-HP]
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 Leicester
16 CHU de Grenoble-Alpes
17 Département de génétique médicale [Hôpital de la Timone - APHM]
18 INM - Institut des Neurosciences de Montpellier
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 [CHU Pitié-Salpétrière]
22 Plateau technique de Biologie [CHU de Dijon]
23 Equipe GAD (LNC - U1231)

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: WWOX; encephalopathy; epilepsy

Domains: Life Sciences [q-bio]; Genetics; Life Sciences [q-bio]; Genetics; Human genetics

Juliette C 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, 2019, 21 (6), pp.1308-1318. ⟨10.1038/s41436-018-0339-3⟩. ⟨hal-01932796⟩