GABRB3 – Developmental and Epileptic Encephalopathy 43

GABRB3 encodes the β3 subunit of the GABA
a receptor, which mediates inhibitory neurotransmission in the central nervous system. Pathogenic variants in GABRB3 are causally
linked to developmental and epileptic encephalopathy 43 (MONDO:0014921),
characterized by early-onset seizures and developmental impairment.

Genetic studies have identified heterozygous de novo and inherited GABRB3 variants in 23 unrelated patients, including three
probands from multiplex families, presenting with a spectrum of epileptic encephalopathies and absence seizures (PMID:28053010).
Variants span missense, truncating, splice-site, and frameshift changes, with recurrent hotspots such as p.Met80Val.

A recent long-term follow-up study describes a 16-year-old female with a de novo recurrent GABRB3 c.238A>G (p.Met80Val) variant.
She developed absence seizures at one year, exhibited persistent EEG abnormalities over a decade, and mild intellectual disability,
underscoring robust phenotype–genotype correlation (PMID:40542409).

Inheritance is autosomal dominant, driven predominantly by de novo events. Segregation in three multiplex families further
supports co-segregation of GABRB3 variants with disease. Variants are absent or extremely rare in population databases.

Functional assays across multiple studies demonstrate both loss-of-function (reduced GABA-induced currents) and gain-of-function
(increased GABA sensitivity, reduced zinc inhibition) effects. The p.Met80Val variant specifically shows a 2.6-fold increase in protein
expression, enhanced fluorescence intensity, and potentiated channel activity, indicating altered receptor gating and ion flux.

Pathogenic mechanisms converge on impaired GABAergic inhibition, with defective receptor assembly, trafficking, or gating leading to
cortical hyperexcitability. Experimental concordance between electrophysiological recordings in Xenopus oocytes, mammalian cells,
and structural modeling aligns with clinical severity.

Collectively, the genetic, segregation, and functional data satisfy ClinGen criteria for a Strong gene-disease association,
and a Strong genetic evidence tier, with Moderate functional support. This association informs diagnostic sequencing panels,
guides variant interpretation, and may influence therapeutic choices targeting GABA_A receptor modulation.

Key Take-home: Heterozygous GABRB3 variants cause autosomal dominant developmental and epileptic encephalopathy 43 through
diverse gain- and loss-of-function mechanisms; comprehensive genetic and functional characterization is essential for precise diagnosis
and management.

References

• Neurology • 2017 • Mutations in GABRB3: From febrile seizures to epileptic encephalopathies. PMID:28053010
• Italian journal of pediatrics • 2025 • Clinical and functional characterization of the GABRB3 p.Met80Val variant in early-onset epilepsy with long-term follow-up. PMID:40542409

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