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 epilepsy has been evaluated separately.
Eight variants (missense, in-frame indel) reported in eight probands in two publications are included in this curation (PMIDs: 34633442, 25156961). Of note, each of these variants is de novo. There are other individuals published in the literature with variants in this gene, but with phenotypes that are either not at the individual level or not specific/detailed enough to determine whether they should be included in this curation or in the separate epilepsy curation (PMIDs: 28600779, 31785789). This gene-disease relationship is also supported by case-level functional evidence from electrophysiological studies in Xenopus laevis oocytes (PMIDs: 25156961, 34633442).
In summary, there is moderate evidence to support the gene-disease relationship between GABRD and complex neurodevelopmental disorder (MONDO:0100038). While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Epilepsy GCEP on the meeting date July 18, 2023 (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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