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

Int J Mol Sci. 2019 Jul 24;20(15):3621. doi: 10.3390/ijms20153621.


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.

Keywords: GABAa receptors genes; NGS; STXBP1; atypical RTT.

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Exome Sequencing
  • Female
  • Forkhead Transcription Factors / genetics
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Intellectual Disability / genetics*
  • Intellectual Disability / physiopathology
  • Methyl-CpG-Binding Protein 2 / genetics*
  • Munc18 Proteins / genetics*
  • Mutation
  • Nerve Tissue Proteins / genetics
  • Phenotype
  • Protein Serine-Threonine Kinases / genetics
  • Receptors, GABA / genetics
  • Receptors, GABA-A / genetics
  • Rett Syndrome / genetics*
  • Rett Syndrome / physiopathology
  • Young Adult


  • FOXG1 protein, human
  • Forkhead Transcription Factors
  • GABRB2 protein, human
  • MECP2 protein, human
  • Methyl-CpG-Binding Protein 2
  • Munc18 Proteins
  • Nerve Tissue Proteins
  • Receptors, GABA
  • Receptors, GABA-A
  • STXBP1 protein, human
  • Protein Serine-Threonine Kinases
  • CDKL5 protein, human