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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
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.
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Submitted on : Thursday, July 18, 2019 - 10:30:12 AM
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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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