|Title||Enrichment of mutations in chromatin regulators in people with Rett syndrome lacking mutations in MECP2.|
|Publication Type||Journal Article|
|Year of Publication||2016|
|Authors||Sajan, SA, Jhangiani, SN, Muzny, DM, Gibbs, RA, Lupski, JR, Glaze, DG, Kaufmann, WE, Skinner, SA, Annese, F, Friez, MJ, Lane, J, Percy, AK, Neul, JL|
|Date Published||2016 May 12|
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 advance online publication 12 May 2016Genetics in Medicine (2016); doi:10.1038/gim.2016.42.
|Alternate Journal||Genet. Med.|
|PubMed Central ID||PMC5107176|
|Grant List||U54 HD061222 / HD / NICHD NIH HHS / United States |
U54 HG006542 / HG / NHGRI NIH HHS / United States