Journal
GENETICS IN MEDICINE
Volume 19, Issue 1, Pages 13-19Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/gim.2016.42
Keywords
chromatin regulation; CNV; exome sequencing; glutamate signaling; Rett syndrome
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Funding
- US National Institutes of Health [U54HG006542, U54HD061222]
- International Rett Syndrome Foundation
- Rett Syndrome Research Trust
- Cynthia and Anthony Petrello Scholar fund at the Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital
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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.
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