SCN1B was first reported in relation to autosomal dominant generalized epilepsy with febrile seizures plus (GEFS+) in 1998 (Wallace et al., PMID: 9697698). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in inheritance pattern and phenotypic variability. Therefore the following disease entities have been split into multiple disease entities: autosomal dominant GEFS+, autosomal recessive developmental and epileptic encephalopathy (DEE), and autosomal dominant atrial fibrillation or Brugada syndrome. Autosomal recessive DEE has been curated separately by the Epilepsy Gene Curation Expert Panel. This curation focuses only on autosomal dominant GEFS+ and does not include cases with isolated autosomal dominant atrial fibrillation/Brugada syndrome.
Eleven variants, including missense, nonsense, and start loss variants, in 15 probands from 11 publications have been included in this curation (PMIDs: 9697698, 14504340, 17020904, 28726809, 30660056, 31729702, 31980526, 35704740, 35886038, 19522081, 12011299). A well-described founder variant (p.Cys121Trp) has also been reported (PMIDs: 9697698, 17020904, 20628201). Variants in this gene were shown to segregate with disease in many additional family members. However, incomplete penetrance (calculated as ~60% in PMID: 9697698) and clinical heterogeneity have been reported. Therefore, there is some uncertainty around whether heterozygous variants in SCN1B might better be described as risk factors as opposed to a typical Mendelian disease of reasonable penetrance. The exact mechanism of disease is currently unknown.
This gene-disease relationship is also supported by animal models and biochemical experiments revealing gene function (PMIDs: 20628201, 23090990). In summary, there is definitive evidence supporting the relationship between SCN1B and GEFS+. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Of note, this gene-disease pair was originally evaluated by the ClinGen Epilepsy Gene Curation Expert Panel on January 4, 2022. It was reevaluated on December 13, 2022. As a result of this reevaluation, the classification changed from Moderate to Definitive with the addition of new case data (PMIDs: 35704740, 35886038, 19522081, 12011299) and a new mouse model (PMID: 20628201) (SOP Version 9).
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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