Mutations in epilepsy and intellectual disability genes in patients with features of Rett syndrome

Am J Med Genet A. 2015 Sep;167A(9):2017-25. doi: 10.1002/ajmg.a.37132. Epub 2015 Apr 25.


Rett syndrome and neurodevelopmental disorders with features overlapping this syndrome frequently remain unexplained in patients without clinically identified MECP2 mutations. We recruited a cohort of 11 patients with features of Rett syndrome and negative initial clinical testing for mutations in MECP2. We analyzed their phenotypes to determine whether patients met formal criteria for Rett syndrome, reviewed repeat clinical genetic testing, and performed exome sequencing of the probands. Using 2010 diagnostic criteria, three patients had classical Rett syndrome, including two for whom repeat MECP2 gene testing had identified mutations. In a patient with neonatal onset epilepsy with atypical Rett syndrome, we identified a frameshift deletion in STXBP1. Among seven patients with features of Rett syndrome not fulfilling formal diagnostic criteria, four had suspected pathogenic mutations, one each in MECP2, FOXG1, SCN8A, and IQSEC2. MECP2 mutations are highly correlated with classical Rett syndrome. Genes associated with atypical Rett syndrome, epilepsy, or intellectual disability should be considered in patients with features overlapping with Rett syndrome and negative MECP2 testing. While most of the identified mutations were apparently de novo, the SCN8A variant was inherited from an unaffected parent mosaic for the mutation, which is important to note for counseling regarding recurrence risks.

Keywords: CDKL5; FOXG1; MECP2; Rett syndrome; SCN8A; STXBP1; deletions; genetic; mutations; whole exome sequencing.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • Epilepsy / genetics*
  • Exome / genetics
  • Forkhead Transcription Factors / genetics
  • Frameshift Mutation / genetics*
  • Genetic Testing / methods
  • Guanine Nucleotide Exchange Factors / genetics
  • Humans
  • Intellectual Disability / genetics*
  • Methyl-CpG-Binding Protein 2 / genetics
  • Munc18 Proteins / genetics
  • NAV1.6 Voltage-Gated Sodium Channel / genetics
  • Nerve Tissue Proteins / genetics
  • Phenotype
  • Rett Syndrome / genetics*
  • Young Adult


  • FOXG1 protein, human
  • Forkhead Transcription Factors
  • Guanine Nucleotide Exchange Factors
  • IQSEC2 protein, human
  • Methyl-CpG-Binding Protein 2
  • Munc18 Proteins
  • NAV1.6 Voltage-Gated Sodium Channel
  • Nerve Tissue Proteins
  • SCN8A protein, human
  • STXBP1 protein, human

Supplementary concepts

  • Rett Syndrome, Atypical