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

Samin A. Sajan, Shalini N. Jhangiani, Donna M. Muzny, Richard A. Gibbs, James R. Lupski, Daniel G. Glaze, Walter E. Kaufmann, Steven A. Skinner, Fran Annese, Michael J. Friez, Jane Lane, Alan K. Percy, Jeffrey L. Neul

    Research output: Contribution to journalArticlepeer-review

    40 Scopus citations


    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.

    Original languageEnglish (US)
    Pages (from-to)13-19
    Number of pages7
    JournalGenetics in Medicine
    Issue number1
    StatePublished - Jan 1 2017


    • CNV
    • Rett syndrome
    • chromatin regulation
    • exome sequencing
    • glutamate signaling

    ASJC Scopus subject areas

    • Genetics(clinical)


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