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

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), genome 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.

The Genetic Landscape of Epilepsy of Infancy with Migrating Focal Seizures

“…We present the first case of EIMFS (Patient 93) associated with biallelic compound heterozygous variants of WWOX in the context of profound ID, microcephaly, and scoliosis. Reported WWOX encephalopathy cases have had DEEs with infantile spasms and Lennox–Gastaut syndrome; our patient also developed epileptic spasms.…”

Early onset epileptic encephalopathy caused by novel compound heterozygous mutation of WWOX gene

“…There has been an average of 3 to 4 articles about WOREE every year since 2014. In 2019, Juliette Piard et al reported a series of 20 cases of WOREE (Piard et al, 2019; Table S1). From Table S1, we found that there were more female patients than male ones (boys: girls = 22:38), and the ratio of male to female patients in the Juliette's 20 case series was 8:12.…”

“…Since 2014, more than 17 articles have reported the clinical data of WWOX-related epileptic encephalopathy (WOREE ; Table S1; Abdel-Salam et al, 2014;Ben-Salem, Al-Shamsi, John, Ali, & Al-Gazali, 2015;Davids et al, 2019;Ehaideb, Al-Bu Ali, Al-Obaid, Aljassim, & Alfadhel, 2018;Elsaadany, El-Said, Ali, Kamel, & Ben-Omran, 2016;Gribaa et al, 2007;Johannsen et al, 2018;Mallaret et al, 2014;Mignot et al, 2015;Piard et al, 2019;Serin, Simsek, Isik, & Gokben, 2018;Shaukat, Hertecant, El-Hattab, Ali, & Suleiman, 2018;Tabarki et al, 2015;Tarta-Arsene, Barca, Craiu, & Iliescu, 2017;Valduga et al, 2015;Weisz-Hubshman et al, 2019;Yang, Zhang, Song, Yi, & Li, 2019). Here we summarized the clinical features and genetic data of a Chinese infant, and analyzed the characteristics of genotype and clinical phenotype of this kind of disease by reviewing the relevant literatures.…”

Novel compound heterozygous mutations in the WWOX gene cause early infantile epileptic encephalopathy

“…Piard J et al reported the largest cohort of individuals with WOREE syndrome (WWOX‐related epilepticencephalopathy syndrome) which include 20 additional patients from 18 unrelated families. They explained that germline pathogenic variants in WWOX are clearly associated with a severe early‐onset epileptic encephalopathy (Piard and Hawkes, 2019).…”