Enrichment of mutations in chromatin regulators in people with Rett syndrome lacking mutations in MECP2

被引:52
|
作者
Sajan, Samin A. [1 ,2 ,10 ]
Jhangiani, Shalini N. [3 ]
Muzny, Donna M. [3 ]
Gibbs, Richard A. [3 ,4 ]
Lupski, James R. [3 ,4 ,5 ,6 ]
Glaze, Daniel G. [1 ]
Kaufmann, Walter E. [7 ]
Skinner, Steven A. [8 ]
Annese, Fran [8 ]
Friez, Michael J. [8 ]
Lane, Jane [9 ]
Percy, Alan K. [9 ]
Neul, Jeffrey L. [1 ,2 ,4 ,10 ]
机构
[1] Baylor Coll Med, Dept Pediat, Sect Child Neurol & Dev Neurosci, Houston, TX 77030 USA
[2] Texas Childrens Hosp, Jan & Dan Duncan Neurol Res Inst, Houston, TX 77030 USA
[3] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA
[4] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA
[5] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA
[6] Texas Childrens Hosp, Houston, TX 77030 USA
[7] Boston Childrens Hosp, Dept Neurol, Boston, MA USA
[8] Greenwood Genet Ctr, Greenwood, SC 29646 USA
[9] Univ Alabama Birmingham, Dept Pediat, Birmingham, AL USA
[10] Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA
基金
美国国家卫生研究院;
关键词
chromatin regulation; CNV; exome sequencing; glutamate signaling; Rett syndrome; INTELLECTUAL DISABILITY; AUTISM; EPILEPSY; GENE; MICRODUPLICATION; DISORDERS; IMPLICATE; FEATURES; VARIANT;
D O I
10.1038/gim.2016.42
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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.
引用
收藏
页码:13 / 19
页数:7
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