Molecular and clinical characterization of 25 individuals with exonic deletions of NRXN1 and comprehensive review of the literature
Molecular and clinical characterization of 25 individuals with exonic deletions of NRXN1 and comprehensive review of the literature
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DOI：
10.1002/ajmg.b.32148
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发表时间：
2013-06-01
影响因子：
2.8
通讯作者：
Schoumans, Jacqueline
中科院分区：
文献类型：
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作者：
Bena, Frederique;Bruno, Damien L.;Schoumans, Jacqueline
这项研究旨在通过对迄今为止描述的最大的NRXN1外显子缺失患者队列的分析，以及通过全面回顾发表在同行评议文献中的所有疾病队列中的所有可比拷贝数变异(总共30篇单独的论文)，来阐明观察到的与NRXN1(Neureox1)单倍体不足相关的可变表型表达。对25例先前未描述的NRXN1外显子缺失患者的临床细节的评估显示，反复出现的表型特征包括中到重度智能障碍(91%)、严重语言延迟(81%)、自闭症谱系障碍(65%)、癫痫发作(43%)和低眼压(38%)。这些与以前报道的NRXN1缺失相关表型在光谱和频率方面都有相当大的重叠。然而，我们没有发现涉及Neuresin-1异构体的缺失与头部大小增加之间存在关联的证据，就像最近发表的涉及NRXN1 C末端缺失的四例病例那样。我们在20%的病例中发现了额外的罕见拷贝数变异。这项研究支持NRXN1杂合外显子缺失在神经发育障碍中的致病作用。在最近的神经发育障碍的双基因模型中，发现的额外的稀有拷贝数变异可能作为可能的表型修饰因子。(C)2013年威利期刊公司。
This study aimed to elucidate the observed variable phenotypic expressivity associated with NRXN1 (Neurexin 1) haploinsufficiency by analyses of the largest cohort of patients with NRXN1 exonic deletions described to date and by comprehensively reviewing all comparable copy number variants in all disease cohorts that have been published in the peer reviewed literature (30 separate papers in all). Assessment of the clinical details in 25 previously undescribed individuals with NRXN1 exonic deletions demonstrated recurrent phenotypic features consisting of moderate to severe intellectual disability (91%), severe language delay (81%), autism spectrum disorder (65%), seizures (43%), and hypotonia (38%). These showed considerable overlap with previously reported NRXN1-deletion associated phenotypes in terms of both spectrum and frequency. However, we did not find evidence for an association between deletions involving the -isoform of neurexin-1 and increased head size, as was recently published in four cases with a deletion involving the C-terminus of NRXN1. We identified additional rare copy number variants in 20% of cases. This study supports a pathogenic role for heterozygous exonic deletions of NRXN1 in neurodevelopmental disorders. The additional rare copy number variants identified may act as possible phenotypic modifiers as suggested in a recent digenic model of neurodevelopmental disorders. (c) 2013 Wiley Periodicals, Inc.