A recurrent copy number variation of the NEB triplicate region: only revealed by the targeted nemaline myopathy CGH array
A recurrent copy number variation of the NEB triplicate region: only revealed by the targeted nemaline myopathy CGH array
复制标题
DOI：
10.1038/ejhg.2015.166
复制
发表时间：
2016-04-01
影响因子：
5.2
通讯作者：
Pelin, Katarina
中科院分区：
文献类型：
--
作者：
Kiiski, Kirsi;Lehtokari, Vilma-Lotta;Pelin, Katarina
最近，新的大变异已被确定在nebulin基因（NEB）引起线虫性肌病（NM）。NM构成了先天性肌病中的一组异质性疾病，NEB中的致病变体是复发性遗传形式NM的主要原因。NEB由183个外显子组成，它包括同源序列，如32-kb的三重区（TRI），其中8个外显子重复三次（外显子82-89，90-97，98-105）。在人类中，NEB TRI的正常拷贝数为6（每个等位基因中有3个拷贝）。最近，我们描述了一种定制的NM-CGH微阵列，旨在检测已知NM基因中的拷贝数变异（CNVs）。该阵列现已更新，包括所有目前已知的10个NM基因。NM-CGH阵列在检测CNV方面具有上级优势，特别是NEB TRI，其不包括在外显子组捕获试剂盒中。迄今为止，我们使用NM-CGH微阵列研究了来自196个NM家族的266个样本，并在13%（26/196）的家族和10%（6/60）的对照中发现了新的复发性NEB TRI变异。对断点的分析揭示了相邻的重复元件，已知其易发生重排，如CNV。对照CNV样品仅与正常的六个拷贝偏离一个拷贝，而NM样品包括多达四个额外拷贝的CNV。基于这项研究，NEB似乎容忍一个TRI拷贝的偏差，而增加两个或更多个拷贝可能是致病的。
Recently, new large variants have been identified in the nebulin gene (NEB) causing nemaline myopathy (NM). NM constitutes a heterogeneous group of disorders among the congenital myopathies, and disease-causing variants in NEB are a main cause of the recessively inherited form of NM. NEB consists of 183 exons and it includes homologous sequences such as a 32-kb triplicate region (TRI), where eight exons are repeated three times (exons 82-89, 90-97, 98-105). In human, the normal copy number of NEB TRI is six (three copies in each allele). Recently, we described a custom NM-CGH microarray designed to detect copy number variations (CNVs) in the known NM genes. The array has now been updated to include all the currently known 10 NM genes. The NM-CGH array is superior in detecting CNVs, especially of the NEB TRI, that is not included in the exome capture kits. To date, we have studied 266 samples from 196 NM families using the NM-CGH microarray, and identified a novel recurrent NEB TRI variation in 13% (26/196) of the families and in 10% of the controls (6/60). An analysis of the breakpoints revealed adjacent repeat elements, which are known to predispose for rearrangements such as CNVs. The control CNV samples deviate only one copy from the normal six copies, whereas the NM samples include CNVs of up to four additional copies. Based on this study, NEB seems to tolerate deviations of one TRI copy, whereas addition of two or more copies might be pathogenic.