Mapping autosomal recessive intellectual disability: combined microarray and exome sequencing identifies 26 novel candidate genes in 192 consanguineous families
Mapping autosomal recessive intellectual disability: combined microarray and exome sequencing identifies 26 novel candidate genes in 192 consanguineous families
复制标题
DOI：
10.1038/mp.2017.60
复制
发表时间：
2018-04-01
影响因子：
11
通讯作者：
Vincent, J. B.
中科院分区：
文献类型：
--
作者：
Harripaul, R.;Vasli, N.;Vincent, J. B.
全球约有1%的人口受到智力残疾（ID）的影响，大多数人没有得到分子诊断。以往的研究表明，高水平的遗传异质性，估计超过2500常染色体ID基因，其中大多数是常染色体隐性（AR）。在这里，我们结合微阵列基因分型，纯合性血统（HBD）映射，拷贝数变异（CNV）分析，全外显子组测序（WES），以确定疾病基因/突变在192个多重巴基斯坦和伊朗的非综合征ID的血缘家庭。我们确定了明确的或候选突变（或CNV）在51%的家庭在72个不同的基因，包括26个以前没有报告的ARID。新的ARID基因包括9个功能丧失突变（ABI 2，MAPK 8，MPDZ，PIDD 1，SLAIN 1，TBC 1D 23，TRAPPC 6 B，UBA 7和USP 44），错义突变包括与ID相关的BDNF或TET 1变异的首次报道。转录研究表明，在产前大脑中的显着表达。ID的AR突变率很高，表明这种方法具有出色的临床潜力，应该为血缘关系常见的人群提供临床诊断信息，包括临床全外显子组和基因组测序。与其他AR疾病一样，相关性也将适用于远交人群。
Approximately 1% of the global population is affected by intellectual disability (ID), and the majority receive no molecular diagnosis. Previous studies have indicated high levels of genetic heterogeneity, with estimates of more than 2500 autosomal ID genes, the majority of which are autosomal recessive (AR). Here, we combined microarray genotyping, homozygosity-by-descent (HBD) mapping, copy number variation (CNV) analysis, and whole exome sequencing (WES) to identify disease genes/mutations in 192 multiplex Pakistani and Iranian consanguineous families with non-syndromic ID. We identified definite or candidate mutations (or CNVs) in 51% of families in 72 different genes, including 26 not previously reported for ARID. The new ARID genes include nine with loss-of-function mutations (ABI2, MAPK8, MPDZ, PIDD1, SLAIN1, TBC1D23, TRAPPC6B, UBA7 and USP44), and missense mutations include the first reports of variants in BDNF or TET1 associated with ID. The genes identified also showed overlap with de novo gene sets for other neuropsychiatric disorders. Transcriptional studies showed prominent expression in the prenatal brain. The high yield of AR mutations for ID indicated that this approach has excellent clinical potential and should inform clinical diagnostics, including clinical whole exome and genome sequencing, for populations in which consanguinity is common. As with other AR disorders, the relevance will also apply to outbred populations.