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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."xsd:string
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http://purl.uniprot.org/citations/27171548http://purl.uniprot.org/core/author"Gibbs R.A."xsd:string
http://purl.uniprot.org/citations/27171548http://purl.uniprot.org/core/author"Muzny D.M."xsd:string
http://purl.uniprot.org/citations/27171548http://purl.uniprot.org/core/author"Lupski J.R."xsd:string
http://purl.uniprot.org/citations/27171548http://purl.uniprot.org/core/author"Jhangiani S.N."xsd:string
http://purl.uniprot.org/citations/27171548http://purl.uniprot.org/core/author"Kaufmann W.E."xsd:string
http://purl.uniprot.org/citations/27171548http://purl.uniprot.org/core/author"Friez M.J."xsd:string
http://purl.uniprot.org/citations/27171548http://purl.uniprot.org/core/author"Skinner S.A."xsd:string
http://purl.uniprot.org/citations/27171548http://purl.uniprot.org/core/author"Lane J."xsd:string
http://purl.uniprot.org/citations/27171548http://purl.uniprot.org/core/author"Sajan S.A."xsd:string
http://purl.uniprot.org/citations/27171548http://purl.uniprot.org/core/author"Percy A.K."xsd:string
http://purl.uniprot.org/citations/27171548http://purl.uniprot.org/core/author"Neul J.L."xsd:string
http://purl.uniprot.org/citations/27171548http://purl.uniprot.org/core/author"Glaze D.G."xsd:string
http://purl.uniprot.org/citations/27171548http://purl.uniprot.org/core/author"Annese F."xsd:string
http://purl.uniprot.org/citations/27171548http://purl.uniprot.org/core/date"2017"xsd:gYear
http://purl.uniprot.org/citations/27171548http://purl.uniprot.org/core/name"Genet Med"xsd:string
http://purl.uniprot.org/citations/27171548http://purl.uniprot.org/core/pages"13-19"xsd:string
http://purl.uniprot.org/citations/27171548http://purl.uniprot.org/core/title"Enrichment of mutations in chromatin regulators in people with Rett syndrome lacking mutations in MECP2."xsd:string
http://purl.uniprot.org/citations/27171548http://purl.uniprot.org/core/volume"19"xsd:string
http://purl.uniprot.org/citations/27171548http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/27171548
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http://purl.uniprot.org/uniprot/#_O76039-mappedCitation-27171548http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/27171548
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