SEMA6B

Inheritance Pattern: AD

Disease ID:MONDO:0001071

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0030034

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0030034

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0030034

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0020074

Submitter: ClinGen

*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). ​ This gene-disease relationship is also supported by a zebrafish model. Mosaic crispants with exon 17 frameshift variants demonstrate neurological impairment and clonus-like behavior when exposed to 5 mM pentylenetetrazole. However, as the clonus-like behavior was induced and the crispants did not present with spontaneous seizures, this evidence was not scored as per Epilepsy GCEP guidance (Hamanaka et al., PMID: 32169168). In summary, there is definitive evidence supporting the relationship between *SEMA6B* and autosomal dominant progressive myoclonus epilepsy which has been replicated over time. This classification was approved by the ClinGen Epilepsy GCEP on the meeting date January 21, 2025 (SOP Version 11).

Inheritance Pattern: AD

Disease ID:MONDO:0030034

Submitter: Labcorp Genetics (formerly Invitae)