WWOX was first reported in relation to autosomal recessive developmental and epileptic encephalopathy (DEE; MONDO:0100062) in 2014 (Abdel-Salam et al., PMID: 24456803). Patients often present with seizures and other phenotypes including: global developmental delay, intellectual disability, microcephaly, and hypotonia. Of note, an assertion has also been made for a relationship between WWOX and spinocerebellar ataxia (OMIM:614322). At the time of curation, there were few cases of individuals with variants in WWOX and spinocerebellar ataxia available in the literature. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism and inheritance pattern, and little difference in phenotypic variability between DEE and spinocerebellar ataxia in patients with WWOX variants. Given the evidence available at this time, the group feels that spinocerebellar ataxia fits best as part of a broader spectrum of disease, rather than a distinct gene-disease relationship. Therefore, we have lumped these cases into one curation for autosomal recessive DEE (MONDO:0100062).
Eleven variants (missense, nonsense, frameshift, splice-site, deletions) reported in nine probands in four publications are included in this curation (PMIDs: 24456803, 24369382, 25411445, 30853297). Of note, some cases in Mignot et al. (2015, PMID: 25411445) include copy number variants that cannot yet be scored in the GCI. For that reason, they are detailed here in the evidence summary. We have scored the compound heterozygous multi-exon deletions in exons 1-5 and 6-8 reported in patient 1 at 1 point each. Patient 2 was reported to have a deletion spanning exon 6, along with a p.Trp335* nonsense variant (ClinVar: 180249), both scored at 1 point. This additional evidence therefore adds 4 points to the genetic evidence category. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The gene-disease relationship is also supported by an animal model (PMIDs: 24369382). In summary, there is a definitive relationship between WWOX and autosomal recessive DEE (MONDO:0100062). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on August 3, 2021 (SOP Version 8).
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