GABRA1 was first reported in relation to autosomal dominant (AD) epilepsy in 2014 (Epi4K Consortium et al. PMID: 23934111). GABRA1-related epilepsy is characterized by seizures and highly variable degrees of intellectual disability and movement disorders such as dystonia. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found evidence for two different molecular mechanisms for heterozygous variants: loss of function and gain of function as measured by GABA-evoked current amplitudes. While all individuals present with epilepsy, individuals with gain of function variants have been associated with more severe clinical outcomes, while individuals with loss of function variants are associated with a broader spectrum of clinical outcomes (PMID: 37606373). Due to the considerable overlap in phenotypes, the following disease entities have been lumped into the disease term “epilepsy” (http://purl.obolibrary.org/obo/MONDO_0005027): developmental and epileptic encephalopathy (OMIM:615744) and epilepsy, juvenile myoclonic or absence (OMIM:611136). As with most splitting or lumping determinations, this may change over time as more variants are characterized mechanistically and phenotypically.
Thirty-two missense variants that have been reported in 32 probands in 10 publications (PMIDs: 23934111, 24623842, 26918889, 27521439, 28864462, 31618474, 32047208, 34399161, 34673242, 37606373) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is also supported by animal models, expression studies, and in-vitro functional assays (PMIDs: 25954001, 27521439, 37606373).
In summary, there is definitive evidence supporting the relationship between GABRA1 and autosomal dominant (AD) epilepsy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This gene-disease pair was originally evaluated by the Epilepsy GCEP on 05/21/2019 using the disease term developmental and epileptic encephalopathy (DEE). It was reevaluated on 9/3/2024 to reassess the disease term (SOP Version 10). As a result of this reevaluation, the disease term was changed in order to reflect the spectrum of phenotypes observed with heterozygous variants in GABRA1, but the classification did not change.
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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