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 MECP2 pathogenic variant in 95% of cases, from atypical girls, 40–73% carrying MECP2 variants, and rarely CDKL5 and FOXG1 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 STXBP1 gene in four atypical RTT and two RTT-like girls. De novo pathogenic variants—one in GABRB2 and, for first time, one in GABRG2—were disclosed in classic and atypical RTT patients. Interestingly, the GABRG2 variant occurred at low rate percentage in blood and buccal swabs, reinforcing the relevance of mosaicism in neurological disorders. We confirm the role of STXBP1 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 MECP2 defective in vitro and in vivo models.
Highlights
Rett syndrome (RTT) is a neurodevelopmental disorder, with an incidence of approximately 1 in 10,000 live births, most frequently affecting girls during early childhood [1]
The Next Generation Sequencing (NGS) experiments identified eight patients carrying a pathogenic variant in genes alternative to the customarily tested genes in RTT syndrome
Six patients (No 1–6) exhibited a pathogenic variant in the STXBP1 gene (OMIM 602926), one patient (No 7) showed a pathogenic variant in GABRG2 (OMIM 137164), while another one (No 8) had a pathogenic variant in GABRB2 (OMIM 600232)
Summary
Rett syndrome (RTT) is a neurodevelopmental disorder, with an incidence of approximately 1 in 10,000 live births, most frequently affecting girls during early childhood [1]. Up to 95% of classical RTT cases are accounted for by mutations in the Methyl CpG-binding protein 2 gene (MECP2) [2], mapping at Xq28 and encoding a multifunctional protein whose expression impacts many fundamental biological processes [3]. The MeCP2 protein acts as epigenetic “reader” [4] which by binding with methylated DNA, interacting with corepressors and recruiting histone deacetylases to methylated genes, leads to their silencing [5], but it can dampen transcriptional noise genome-wide, altering global chromatine structure [6]. MeCP2 is a transcriptional activator through its interaction with the c-AMP responsive element-binding protein 1 (CREB1), has a role in alternative splicing in a DNA methylation-dependent manner and in microRNA processing and may influence global translation through modulation of the AKT/mTOR pathway [7,8,9]. Perturbations in the genes acting in GABAergic circuits [10] could result in neuron hyperexcitability, which in turn is potentially responsible for epilepsy reported in 60–80% of RTT patients [11]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
