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

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

Genetics in medicine, 2017-01, Vol.19 (1), p.13-19 [Periódico revisado por pares]

United States: Elsevier Inc

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Título:
Enrichment of mutations in chromatin regulators in people with Rett syndrome lacking mutations in MECP2
Autor: Sajan, Samin A. ; Jhangiani, Shalini N. ; Muzny, Donna M. ; Gibbs, Richard A. ; Lupski, James R. ; Glaze, Daniel G. ; Kaufmann, Walter E. ; Skinner, Steven A. ; Annese, Fran ; Friez, Michael J. ; Lane, Jane ; Percy, Alan K. ; Neul, Jeffrey L.
Assuntos: Adolescent ; Adult ; Child ; Child, Preschool ; Chromatin - genetics ; chromatin regulation ; CNV ; DNA Copy Number Variations - genetics ; exome sequencing ; Female ; Forkhead Transcription Factors - genetics ; glutamate signaling ; 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 ; Rett Syndrome - genetics ; Rett Syndrome - physiopathology ; Whole Exome Sequencing
É parte de: Genetics in medicine, 2017-01, Vol.19 (1), p.13-19
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SourceType-Scholarly Journals-1
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Current address: Department of Neurosciences, University of California San Diego, San Diego, California, USA
Descrição: 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.
Editor: United States: Elsevier Inc
Idioma: Inglês

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

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

United States: Elsevier Inc

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