Exome sequencing identifies three novel candidate genes implicated in intellectual disability.
Exome sequencing identifies three novel candidate genes implicated in intellectual disability.
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外部测序确定了涉及智力残疾的三个新型候选基因。
DOI：
10.1371/journal.pone.0112687
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Qamar R
中科院分区：
文献类型：
--
作者：
Agha Z;Iqbal Z;Azam M;Ayub H;Vissers LE;Gilissen C;Ali SH;Riaz M;Veltman JA;Pfundt R;van Bokhoven H;Qamar R
智力残疾（ID）是一个主要的健康问题，大多病因不明。最近，ID个体的外显子组测序确定了与疾病有关的新基因。因此，本研究的目的是确定遗传原因的ID在一个综合征和两个非综合征的巴基斯坦家庭。对3例ID先证者的外显子组进行全序列测定。发现了两个与常染色体隐性遗传ID相关的合理新基因的错义变异：赖氨酸（K）特异性甲基转移酶2B（KMT2B），锌指蛋白589（ZNF 589），以及具有常染色体显性遗传模式的从头突变的刺猬酰基转移酶（HHAT）。KMT2B隐性变异是隐性Kleefstra综合征样表型的首次报道。在先前未涉及疾病的基因中鉴定出两种隐性和一种显性类型ID的可能致病突变，强调了ID的巨大遗传异质性。这些结果也支持了大量ID基因聚集在有限数量的共同网络上的观点，即ZNF 589属于先前涉及ID的KRAB结构域锌指蛋白，HHAT被预测影响音刺猬，其涉及多种ID疾病，与综合征ID相关的KMT 2B符合Kleefstra综合征谱下的表观遗传模块。这些新的基因在三个不同的巴基斯坦ID家庭的关联突出了筛选这些基因在更多的家庭具有相似的表型，从不同的人群，以确认这些基因在ID的发病机制的参与的重要性。
Intellectual disability (ID) is a major health problem mostly with an unknown etiology. Recently exome sequencing of individuals with ID identified novel genes implicated in the disease. Therefore the purpose of the present study was to identify the genetic cause of ID in one syndromic and two non-syndromic Pakistani families. Whole exome of three ID probands was sequenced. Missense variations in two plausible novel genes implicated in autosomal recessive ID were identified: lysine (K)-specific methyltransferase 2B (KMT2B), zinc finger protein 589 (ZNF589), as well as hedgehog acyltransferase (HHAT) with a de novo mutation with autosomal dominant mode of inheritance. The KMT2B recessive variant is the first report of recessive Kleefstra syndrome-like phenotype. Identification of plausible causative mutations for two recessive and a dominant type of ID, in genes not previously implicated in disease, underscores the large genetic heterogeneity of ID. These results also support the viewpoint that large number of ID genes converge on limited number of common networks i.e. ZNF589 belongs to KRAB-domain zinc-finger proteins previously implicated in ID, HHAT is predicted to affect sonic hedgehog, which is involved in several disorders with ID, KMT2B associated with syndromic ID fits the epigenetic module underlying the Kleefstra syndromic spectrum. The association of these novel genes in three different Pakistani ID families highlights the importance of screening these genes in more families with similar phenotypes from different populations to confirm the involvement of these genes in pathogenesis of ID.
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影响因子：
30.8
作者：
Kyttälä, M;Tallila, J;Kestïla, M
通讯作者：
Kestïla, M
影响因子：
9.8
作者：
Lugtenberg, D;Yntema, HG;van Bokhoven, H
通讯作者：
van Bokhoven, H
影响因子：
2
作者：
Barbaro, Vanessa;Nardiello, Paola;Di Iorio, Enzo
通讯作者：
Di Iorio, Enzo
影响因子：
9.8
作者：
Kleefstra, Tjitske;Brunner, Han G.;van Bokhoven, Hans
通讯作者：
van Bokhoven, Hans
影响因子：
168.9
作者：
Rauch, Anita;Wieczorek, Dagmar;Strom, Tim M.
通讯作者：
Strom, Tim M.