Submission Details

SEMA6B was first reported in relation to autosomal dominant (AD) progressive myoclonus epilepsy in 2020 (Hamanaka et al., PMID: 32169168). Phenotypic features in individuals with heterozygous SEMA6B variants include seizures (generalized tonic-clonic, myoclonic, absence, and atonic), cognitive impairment, regression, ataxia, tremor, myoclonus, hyperreflexia, hypertonicity, and microcephaly (Altintas et al., PMID: 39419291). Onset of seizures is typically in infancy or childhood; however, adult onset has been reported in a few individuals (Chen et al., PMID: 36873942, Castellotti et al., PMID: 36719163). Developmental delays have been frequently noted as a primary initial finding. Brain MRI findings are normal in the majority of affected individuals, but cerebellar atrophy and corpus callosum abnormalities have been reported (Cordovado et al., PMID: 35604360, Chen et al., PMID: 36873942).

At least 35 affected individuals with over 20 unique heterozygous variants have been reported in the literature (Hamanaka et al., PMID: 32169168, Cordovado et al., PMID: 35604360, Chen et al., PMID: 36873942, Castelloti et al., PMID: 36719163, Duan et al., PMID: 35573939, Xiaozhen et al., PMID: 34017830, Herzog et al., PMID: 34092044, Altintas et al., PMID: 39419291). Variants have been reported to be dominantly de novo (when segregation information is available). There has been at least 1 reported case of affected siblings with a missense variant where parental analysis was not performed (Chen et al., PMID: 36873942). Reported variants include nonsense, frameshift and missense variants; missense variants have demonstrated variable severity (Cordovado et al., PMID: 35604360, Chen et al., PMID: 36873942, Xiaozhen et al., PMID: 34017830).

The vast majority of reported variants are protein truncating variants found in the last exon of the gene (exon 17) that are either predicted or proven (Hamanaka et al., PMID: 32169168, Xiaozhen et al., PMID: 34017830) to escape nonsense mediated decay (NMD). It is hypothesized that variants escaping NMD produce a truncated protein and cause disease via a gain of function or dominant negative mechanism. One variant predicted to result in haploinsufficiency (a nonsense variant in exon 11) has been reported (Cordovado et al., PMID: 35604360). This individual was mildly affected and parental testing was not performed; therefore, this variant was not scored. Additionally, Torene et al. demonstrated that SEMA6B is a gene where de novo variants in NMD escape regions are enriched (Torene et al., PMID: 38091987).