Variants in GABRD were first reported in individuals with seizures in 2004 (PMID: 15115768). In 2022, variants in GABRD were also reported in individuals with phenotypes other than seizures, including developmental delays, autism spectrum disorder, and intellectual disability (PMID:34633442). Of note, some of these individuals had seizures, while others did not. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found a difference in phenotypic variability between these cases and therefore have chosen to split this evidence into multiple disease entities: epilepsy (MONDO:0005027) (for those individuals presenting solely with seizures) and complex neurodevelopmental disorder (MONDO:0100038) (for those individuals with neurodevelopmental phenotypes alone, or with neurodevelopmental disorders in addition to epilepsy). The split curation for complex neurodevelopmental disorder has been evaluated separately.
Three missense variants reported in three probands in three publications are included in this curation (PMIDs: 29924869, 33391346, 15115768). To date, many individuals with epilepsy have been reported with the p.Arg220His variant: at least 16 in case-control studies (PMIDs: 29785705, 16023832) and at least two case reports (PMIDs: 16023832, 29785705). Individuals with the p.Arg220His variant were not awarded points as a part of this curation, as there is currently conflicting evidence of pathogenicity according in small case-control studies (PMIDs: 29785705, 16023832), and there is a high allele frequency of 1.74x10-2 in gnomAD v2.1.1 with 55 homozygotes. It is possible that this variant is a risk allele and therefore does not support a relationship with Mendelian disease. Additionally, the p.Thr401Met variant reported in Lee et al. (2018, PMID:29924869) was not scored due to high allele frequency in gnomAD v.2.1.1, with 554 homozygotes.
In summary, there is limited evidence to support the gene-disease relationship between GABRD and epilepsy (MONDO:0005027). Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Epilepsy GCEP on the meeting date July 18, 2023 (SOP Version 9).
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