Enrichment of mutations in chromatin regulators in people with Rett syndrome lacking mutations in MECP2

Genet Med. 2017 Jan;19(1):13-19. doi: 10.1038/gim.2016.42. Epub 2016 May 12.

Abstract

Purpose: Rett syndrome (RTT) is a neurodevelopmental disorder caused primarily by de novo mutations in MECP2 and sometimes in CDKL5 and FOXG1. However, some RTT patients lack mutations in these genes.

Methods: Twenty-two RTT patients without apparent MECP2, CDKL5, and FOXG1 mutations were subjected to both whole-exome sequencing and single-nucleotide polymorphism array-based copy-number variant (CNV) analyses.

Results: Three patients had MECP2 mutations initially missed by clinical testing. Of the remaining 19, 17 (89.5%) had 29 other likely pathogenic intragenic mutations and/or CNVs (10 patients had 2 or more). Interestingly, 13 patients had mutations in a gene/region previously reported in other neurodevelopmental disorders (NDDs), thereby providing a potential diagnostic yield of 68.4%. These mutations were significantly enriched in chromatin regulators (corrected P = 0.0068) and moderately enriched in postsynaptic cell membrane molecules (corrected P = 0.076), implicating glutamate receptor signaling.

Conclusion: The genetic etiology of RTT without MECP2, CDKL5, and FOXG1 mutations is heterogeneous, overlaps with other NDDs, and complicated by a high mutation burden. Dysregulation of chromatin structure and abnormal excitatory synaptic signaling may form two common pathological bases of RTT.Genet Med 19 1, 13-19.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • Chromatin / genetics
  • DNA Copy Number Variations / genetics
  • Female
  • Forkhead Transcription Factors / genetics*
  • Humans
  • Infant
  • Male
  • Methyl-CpG-Binding Protein 2 / genetics*
  • Mutation
  • Nerve Tissue Proteins / genetics*
  • Polymorphism, Single Nucleotide / genetics
  • Protein-Serine-Threonine Kinases / genetics*
  • Rett Syndrome / genetics*
  • Rett Syndrome / physiopathology
  • Whole Exome Sequencing

Substances

  • Chromatin
  • FOXG1 protein, human
  • Forkhead Transcription Factors
  • MECP2 protein, human
  • Methyl-CpG-Binding Protein 2
  • Nerve Tissue Proteins
  • Protein-Serine-Threonine Kinases
  • CDKL5 protein, human