GOSR2 was first reported in relation to autosomal recessive progressive myoclonus epilepsy in 2011 (Corbett et al., PMID: 21549339). A founder variant (c.430G>T, p.Gly144Trp) has been reported in the homozygous state in at least 28 individuals with progressive myoclonus epilepsy (PMIDs: 21549339, 23449775, 24458321, 30838261, 32105965). In addition, seven other variants (splicing, nonsense, in-frame deletion, start loss, missense) have been reported in five additional probands across five publications, and are included in this curation (PMIDs: 30363482, 29855340, 33639315, 34167170, and 37895210). Most individuals reported in the literature, especially with the founder variant, have ataxia, myoclonus, seizures, scoliosis, and elevated creatine kinase. In addition to these features, some individuals who are not homozygous for the founder variant in GOSR2 (either two non-founder variants or compound heterozygotes with a single founder variant) also present with muscular dystrophy and/or changes on muscle biopsy (PMIDs: 34167170, 29855340). There is no reported difference in disease mechanism for these cases. Because of this, and the large phenotypic overlap between these individuals and who are homozygous for the founder variant, we have lumped these cases into one curation for autosomal recessive progressive myoclonus epilepsy. The mechanism of pathogenicity appears to be loss of function (PMIDs: 21549339, 28982678). In summary, there is definitive evidence to support the relationship between GOSR2 and autosomal recessive progressive myoclonus epilepsy. 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 April 16, 2024 (SOP version 10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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