Enrichment of mutations in chromatin regulators in people with Rett syndrome lacking mutations in MECP2.
Genet Med
; 19(1): 13-19, 2017 01.
Article
em En
| MEDLINE
| ID: mdl-27171548
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Síndrome de Rett
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Proteínas Serina-Treonina Quinases
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Proteína 2 de Ligação a Metil-CpG
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Fatores de Transcrição Forkhead
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Proteínas do Tecido Nervoso
Limite:
Adolescent
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Adult
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Child
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Child, preschool
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Female
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Humans
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Infant
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Male
Idioma:
En
Revista:
Genet Med
Assunto da revista:
GENETICA MEDICA
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Estados Unidos