Chromosomal microarray testing identifies a 4p terminal region associated with seizures in Wolf-Hirschhorn syndrome.
Chromosomal microarray testing identifies a 4p terminal region associated with seizures in Wolf-Hirschhorn syndrome.
复制标题
染色体微阵列测试确定了与沃尔夫·希尔希霍恩综合征癫痫发作相关的4p末端区域。
DOI：
10.1136/jmedgenet-2015-103626
复制
发表时间：
2016-04
影响因子：
4
通讯作者：
Battaglia A
中科院分区：
文献类型：
--
作者：
Ho KS;South ST;Lortz A;Hensel CH;Sdano MR;Vanzo RJ;Martin MM;Peiffer A;Lambert CG;Calhoun A;Carey JC;Battaglia A
Wolf-Hirschhorn综合征（WHS）是一种涉及4p16.3区域可变大小缺失的连续基因缺失综合征。癫痫发作经常，但并不总是与WHS相关。我们假设缺失区域的大小和位置可能与癫痫发作的表现有关。利用染色体微阵列分析，我们精细地绘制了48例WHS患者拷贝数变异（CNVs）的断点。癫痫表型数据通过家长报告的全面问卷调查收集，并辅以现有的医疗记录。我们观察到间质4p缺失的存在与癫痫表型的缺乏之间存在显著的相关性（Fisher精确检验p=3.59e-6）。在我们的队列中，有5例间质缺失，远端断点至少在4p末端近端751kbp处。其中4例患者从未有过明显的癫痫发作，第5例患者在1.5岁时有过一次发热性癫痫发作。在我们的队列中，所有其他缺失包括末端751 kbp区域的个体报告有典型的WHS癫痫发作。文献中的其他例子证实了这些观察结果，并进一步将候选癫痫易感性区域细化为197 kbp大小的区域，从4号染色体末端开始368 kbp。我们在4p染色体上发现了一个小的末端区域，它代表了癫痫易感性区域。在WHS的情况下，该区域的删除足以引起癫痫发作。
Wolf–Hirschhorn syndrome (WHS) is a contiguous gene deletion syndrome involving variable size deletions of the 4p16.3 region. Seizures are frequently, but not always, associated with WHS. We hypothesised that the size and location of the deleted region may correlate with seizure presentation. Using chromosomal microarray analysis, we finely mapped the breakpoints of copy number variants (CNVs) in 48 individuals with WHS. Seizure phenotype data were collected through parent-reported answers to a comprehensive questionnaire and supplemented with available medical records. We observed a significant correlation between the presence of an interstitial 4p deletion and lack of a seizure phenotype (Fisher's exact test p=3.59e-6). In our cohort, there were five individuals with interstitial deletions with a distal breakpoint at least 751 kbp proximal to the 4p terminus. Four of these individuals have never had an observable seizure, and the fifth individual had a single febrile seizure at the age of 1.5 years. All other individuals in our cohort whose deletions encompass the terminal 751 kbp region report having seizures typical of WHS. Additional examples from the literature corroborate these observations and further refine the candidate seizure susceptibility region to a region 197 kbp in size, starting 368 kbp from the terminus of chromosome 4. We identify a small terminal region of chromosome 4p that represents a seizure susceptibility region. Deletion of this region in the context of WHS is sufficient for seizure occurrence.