GABBR2 – Neurodevelopmental Disorder with Poor Language and Loss of Hand Skills

In a single pediatric case, an 11-year-old girl with a de novo GABBR2 missense variant presented with global developmental delay (HP:0001263), generalized hypotonia (HP:0001290), motor stereotypy (HP:0000733), infantile spasms (HP:0012469) and loss of acquired hand skills. Exome sequencing identified NM_005458.8:c.2077G>T (p.Gly693Trp) as a de novo event, implicating GABBR2 in the neurodevelopmental disorder with poor language and loss of hand skills (PMID:35414446).

Functional characterization across cell culture and Xenopus tropicalis models demonstrated that pathogenic GABBR2 variants reduce GABA_B receptor activity and recapitulate neurodevelopmental phenotypes, with rescue upon agonist exposure supporting a loss-of-function mechanism (PMID:28856709). Together, these data suggest haploinsufficiency of GABBR2 as the molecular basis for this disorder. Key take-home: Screening for GABBR2 variants should be considered in patients with early infantile epileptic encephalopathy and Rett-like features to inform diagnosis and potential targeted therapy.

References

• Brain & development • 2022 • Paroxysmal limb dystonias associated with GABBR2 pathogenic variant: A case-based literature review. PMID:35414446
• Annals of neurology • 2017 • GABBR2 mutations determine phenotype in rett syndrome and epileptic encephalopathy. PMID:28856709

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