A Heterozygous Variant in the GABBR2 Gene in a Girl With Clinical Classic Rett Syndrome.

backgroundRett syndrome (RTT) is a neurodevelopmental disorder mainly affecting females and may start with seemingly normal early development but leads to developmental stagnation, regression, and characteristic neurological symptoms. While most cases involve MECP2 variants, other genes have been implicated in RTT and RTT-like phenotypes, but the underlying molecular mechanisms remain incompletely understood.

methodsWe describe a girl fulfilling the clinical diagnostic criteria for classic RTT in whom standard genetic testing, including MECP2 and CDKL5, was normal. Trio-based whole-exome sequencing was used to identify an alternative genetic cause that was confirmed using Sanger sequencing.

resultsA heterozygous de novo variant in GABBR2 (NM_005458.7:c.1699G>A; p.Ala567Thr) was identified as the only clinically relevant genetic finding. The patient fulfilled the clinical diagnostic criteria for classic RTT and exhibited developmental stagnation, progressive impairment of purposeful hand use, characteristic stereotypic movements, autonomic dysfunction, and behavioral disturbances.

conclusionThis patient expands the phenotypic spectrum associated with GABBR2 variants and, together with previously reported cases, provides further evidence that GABBR2-related disease may present with a clinical RTT phenotype. These findings support a role for GABBR2-mediated GABAergic signaling in the pathophysiology of RTT and highlight the importance of considering GABBR2 in the genetic evaluation of MECP2-negative patients with a clinical RTT phenotype.