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, 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
Abstract
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.
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References
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Source: PubMed