GABRB1 – Developmental and Epileptic Encephalopathy 45

Developmental and epileptic encephalopathy 45 (DEE45) is an autosomal dominant neurodevelopmental disorder caused by heterozygous pathogenic variants in GABRB1, encoding the β1 subunit of the GABA
type A receptor. Patients typically present in early infancy with hypotonia, focal and migratory seizures refractory to multiple antiseizure medications, and evolve into a Lennox–Gastaut–like syndrome with spasms and atypical absence status. Progressive acquired microcephaly, profound intellectual disability, tetraparesis, ataxia, and dysmetria are consistent features, reflecting broad central nervous system involvement ([PMID:37518907]; [PMID:38633326]; [PMID:38024579]).

Genetic evidence includes three unrelated de novo variants identified in affected individuals: c.841A>G (p.Thr281Ala) ([PMID:37518907]), c.686C>T (p.Ala229Val) ([PMID:38633326]), and c.858_859delinsTT (p.286_287delinsIleSer) ([PMID:38024579]). All variants cluster within transmembrane helices of the β1 subunit, supporting a shared mechanism. No additional familial segregation has been reported.

The variant spectrum in DEE45 comprises two missense changes and one in‐frame indel, each arising de novo. No recurrent or founder alleles have been described. Population databases lack these alleles, consistent with high penetrance and selection against.

Functional studies in the Chinese patient’s fibroblasts demonstrated significantly increased mutant GABRB1 expression at mRNA and protein levels, suggesting a dominant‐gain‐of‐function or mistrafficking mechanism ([PMID:38024579]). Electrophysiological characterization remains pending, but the localization in transmembrane domains parallels pathogenic mechanisms in related GABA_A receptor subunit disorders.

No studies have disputed GABRB1 as the cause of DEE45, and all reported variants are absent from controls and predicted deleterious by multiple in silico tools. The consistent clinical phenotypes across age ranges and concordant experimental findings strengthen the association.

Collectively, genetic and functional data support a Moderate level of evidence for GABRB1 in DEE45, with clear diagnostic utility for early genetic testing and counselling. Key Take-home: GABRB1 de novo transmembrane variants should be considered in infants with early‐onset refractory seizures and profound developmental impairment.

References

• Epileptic disorders • 2023 • GABRB1-related early onset developmental and epileptic encephalopathy: Clinical trajectory and novel de novo mutation. PMID:37518907
• Frontiers in pediatrics • 2024 • Case Report: A developmental and epileptic encephalopathy 45 due to de novo variant of GABRB1. PMID:38633326
• Intractable & rare diseases research • 2023 • Identification of novel and de novo GABRB1 mutation in Chinese patient with developmental and epileptic encephalopathy 45. PMID:38024579

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