XLID-Causing Mutations and Associated Genes Challenged in Light of Data From Large-Scale Human Exome Sequencing
XLID-Causing Mutations and Associated Genes Challenged in Light of Data From Large-Scale Human Exome Sequencing
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DOI：
10.1016/j.ajhg.2013.06.013
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发表时间：
2013-08-08
影响因子：
9.8
通讯作者：
Mandel, Jean-Louis
中科院分区：
文献类型：
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作者：
Piton, Amelie;Redin, Claire;Mandel, Jean-Louis
由于在智力残疾（ID）中观察到的不平衡的性别比（1.3-1.4比1）和显示X连锁分离的大ID影响的家庭的鉴定，X连锁ID（XLID）的遗传学一直受到关注。目前已报道了100多个基因中的突变导致单基因XLID，其中大多数通常包括在XLID诊断基因组中。然而，真正的突变和罕见的非致病性变异之间的界限往往仍然难以捉摸。为了避免假阳性结果，需要对大量的对照X染色体进行测序，这在过去是不可能的。这些信息现在可以获得，这要归功于大规模的测序项目，如国家心脏，肺和血液（NHLBI）外显子组测序项目，该项目提供了来自普通人群的10，563条X染色体的变异信息。我们使用这个NHLBI队列系统地重新评估了106个基因的含义，这些基因被认为与单基因型XLID有关。我们特别质疑其中10种（AGTR 2、MAGT 1、ZNF 674、SRPX 2、ATP 6AP 2、ARHGEF 6、NXF 5、ZCCHC 12、ZNF 41和ZNF 81）在XLID中的意义，在这些突变中，在该队列中观察到的截短变体或先前发表的突变频率相对较高。我们还强调了其他15个基因（CCDC 22，CLIC 2，CNKSR 2，FRMPD 4，HCFC 1，IGBP 1，KIAA 2022，KLF 8，MAOA，NAA 10，NLGN 3，RPL 10，SHROOM 4，ZDHHC 15和ZNF 261），这些基因的复制研究是必要的。我们建议，使用来自大规模人类外显子组测序的数据对报告的突变（和基因）进行类似的重新评估将与广泛的其他遗传疾病相关。
Because of the unbalanced sex ratio (1.3-1.4 to 1) observed in intellectual disability (ID) and the identification of large ID-affected families showing X-linked segregation, much attention has been focused on the genetics of X-linked ID (XLID). Mutations causing monogenic XLID have now been reported in over 100 genes, most of which are commonly included in XLID diagnostic gene panels. Nonetheless, the boundary between true mutations and rare non-disease-causing variants often remains elusive. The sequencing of a large number of control X chromosomes, required for avoiding false-positive results, was not systematically possible in the past. Such information is now available thanks to large-scale sequencing projects such as the National Heart, Lung, and Blood (NHLBI) Exome Sequencing Project, which provides variation information on 10,563 X chromosomes from the general population. We used this NHLBI cohort to systematically reassess the implication of 106 genes proposed to be involved in monogenic forms of XLID. We particularly question the implication in XLID of ten of them (AGTR2, MAGT1, ZNF674, SRPX2, ATP6AP2, ARHGEF6, NXF5, ZCCHC12, ZNF41, and ZNF81), in which truncating variants or previously published mutations are observed at a relatively high frequency within this cohort. We also highlight 15 other genes (CCDC22, CLIC2, CNKSR2, FRMPD4, HCFC1, IGBP1, KIAA2022, KLF8, MAOA, NAA10, NLGN3, RPL10, SHROOM4, ZDHHC15, and ZNF261) for which replication studies are warranted. We propose that similar reassessment of reported mutations (and genes) with the use of data from large-scale human exome sequencing would be relevant for a wide range of other genetic diseases.