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Genet Med. 2019 Jun;21(6):1308-1318. doi: 10.1038/s41436-018-0339-3. Epub 2018 Oct 25.

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

Author information

1
Centre de Génétique Humaine, Université de Franche-Comté, CHU Besançon, Besançon, France.
2
Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
3
Aix Marseille Univ, Inserm, MMG, Marseille, France.
4
Pediatric Neurology, La Timone Children's Hospital, AP-HM, Marseille, France.
5
Medical Genetics, La Timone Children's Hospital, AP-HM, Marseille, France.
6
Neuropsychiatry and Neurorehabilitation Unit, Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Italy.
7
Service de Génétique, CLAD Ouest, CHU Rennes, Rennes, France.
8
Département de Génétique, Hôpital Robert Debré, APHP Paris, Paris, France.
9
APHP, Département de Génétique, Centre de Référence Déficiences Intellectuelles de Causes Rares, Groupe Hospitalier Pitié Salpêtrière et GHUEP Hôpital Trousseau, Sorbonne Université, GRC "Déficience Intellectuelle et Autisme", Paris, France.
10
Neuropédiatrie et Unité d'électrophysiologie clinique, Centre de Référence des Maladies Neuromusculaires de l'EST parisien et DHU I2B, Hôpital d'Enfants Armand Trousseau, Paris, France.
11
Département de Génétique, Sorbonne Universités, Institut du Cerveau et de la Moelle épinière, ICM, Inserm U1127, CNRS UMR 7225, APHP, Hôpital de la Pitié Salpêtrière, Paris, France.
12
Pediatric Neurology Clinic, "Alexandru Obregia" Clinical Psychiatry Hospital, "Carol Davila" University of Medicine, Bucharest, Romania.
13
Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Oxford, UK.
14
NIHR Oxford Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
15
Division of Pediatric Neurology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA.
16
Department of Clinical Genetics, Sheffield Children's NHS Trust, Sheffield, United Kingdom.
17
Department of Clinical Genetics, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
18
Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
19
Clinical Genetics Department, University Hospitals Leicester NHS Trust, Leicester, UK.
20
Service de Neurologie pédiatrique, Hopital Couple Enfant, CHU Grenoble Alpes, Grenoble, France.
21
Département de Neuropédiatrie, Centre Hospitalier Universitaire de Montpellier, INSERM U 1051, Institut des Neurosciences de Montpellier, Montpellier, France.
22
Department for Clinical Genetics, Erasmus MC, Rotterdam, Netherlands.
23
EA7402 Institut Universitaire de Recherche Clinique, and Laboratoire de Génétique Moléculaire, CHU and Université de Montpellier, Montpellier, France.
24
Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK. usha.kini@ouh.nhs.uk.
25
Laboratoire de génétique, Innovations en diagnostic génomique des maladies rares, Plateau Technique de Biologie, CHU Dijon, Dijon, France.
26
INSERM 1231, LNC UMR1231 GAD, Burgundy University, Dijon, France.

Abstract

PURPOSE:

Germline 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.

METHODS:

We 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), genome sequencing.

RESULTS:

Two 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.

CONCLUSION:

Germline 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.

KEYWORDS:

WWOX; encephalopathy; epilepsy

PMID:
30356099
DOI:
10.1038/s41436-018-0339-3

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