GABBR2 was first reported in relation to autosomal dominant complex neurodevelopmental disorder (CND) in 2014 by EuroEPINOMICS-RES Consortium (PMID: 25262651), reporting individuals with seizures, severe intellectual disability, developmental delay, speech delay and autistic features. The current literature displays a broad range of phenotypes for patients with variants in GABBR2. Some probands with heterozygous variants have been reported with drooling, hypotonia, and scoliosis in addition to seizures (PMID: 29100083). Other probands have been reported with neurodevelopmental disorder with poor language and loss of hand skills (Atypical RTT) (PMID: 28856709, 29369404) with or without seizures (PMID: 26740508, 28856709, 29369404). Given the broad neurodevelopmental phenotypes present in these individuals, we have chosen to curate this gene-disease relationship under the disease term complex neurodevelopmental disorder (CND) (MONDO:0100038).
Five missense variants reported in nine probands across five publications were included in this curation (PMIDs: 25262651, 29100083, 26740508); several of these variants were supported by functional evidence (PMID: 28856709, 29369404). Of note, one individual with a mosaic heterozygous missense variant in GABBR2 was scored, due to the presence of functional data demonstrating an impact on the protein (PMID: 25262651, 28856709, 29369404).
In summary, there is moderate evidence to support the relationship between GABBR2 and autosomal dominant complex neurodevelopmental disorder. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on November 19, 2024 (SOP version 11).
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