Pathogenic Variants in STXBP1 and in Genes for GABAa Receptor Subunities Cause Atypical Rett/Rett-like Phenotypes

Abstract

Rett syndrome (RTT) is a neurodevelopmental disorder, affecting 1 in 10,000 girls. Intellectual disability, loss of speech and hand skills with stereotypies, seizures and ataxia are recurrent features. Stringent diagnostic criteria distinguish classical Rett, caused by a <i>MECP2</i> pathogenic variant in 95% of cases, from atypical girls, 40-73% carrying <i>MECP2</i> variants, and rarely <i>CDKL5</i> and <i>FOXG1</i> alterations. A large fraction of atypical and RTT-like patients remain without genetic cause. Next Generation Sequencing (NGS) targeted to multigene panels/Whole Exome Sequencing (WES) in 137 girls suspected for RTT led to the identification of a de novo variant in <i>STXBP1</i> gene in four atypical RTT and two RTT-like girls. De novo pathogenic variants-one in <i>GABRB2</i> and, for first time, one in <i>GABRG2</i>-were disclosed in classic and atypical RTT patients. Interestingly, the <i>GABRG2</i> variant occurred at low rate percentage in blood and buccal swabs, reinforcing the relevance of mosaicism in neurological disorders. We confirm the role of <i>STXBP1</i> in atypical RTT/RTT-like patients if early psychomotor delay and epilepsy before 2 years of age are observed, indicating its inclusion in the RTT diagnostic panel. Lastly, we report pathogenic variants in Gamma-aminobutyric acid-A (GABAa) receptors as a cause of atypical/classic RTT phenotype, in accordance with the deregulation of GABAergic pathway observed in <i>MECP2</i> defective <i>in vitro</i> and <i>in vivo</i> models.