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Pathogenic Variants in STXBP1 and in Genes for GABAa Receptor Subunities Cause Atypical Rett/Rett-like Phenotypes.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2019 Jul 24; Vol. 20 (15). Date of Electronic Publication: 2019 Jul 24. - Publication Year :
- 2019
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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.
- Subjects :
- Adolescent
Adult
Child
Female
Forkhead Transcription Factors genetics
High-Throughput Nucleotide Sequencing
Humans
Intellectual Disability physiopathology
Mutation
Nerve Tissue Proteins genetics
Phenotype
Protein Serine-Threonine Kinases genetics
Receptors, GABA genetics
Receptors, GABA-A genetics
Rett Syndrome physiopathology
Exome Sequencing
Young Adult
Intellectual Disability genetics
Methyl-CpG-Binding Protein 2 genetics
Munc18 Proteins genetics
Rett Syndrome genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 20
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 31344879
- Full Text :
- https://doi.org/10.3390/ijms20153621