Abstract
ABSTRACT
Background
Rett 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.
Methods
We 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.
Results
A 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.
Conclusion
This 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.