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

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

Author information

  • 1Section of Child Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
  • 2Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA.
  • 3Current address: Department of Neurosciences, University of California San Diego, San Diego, California, USA.
  • 4Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
  • 5Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
  • 6Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas, USA.
  • 7Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA.
  • 8Greenwood Genetic Center, Greenwood, South Carolina, USA.
  • 9Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA.



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.


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.


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.


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.

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