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.

中文翻译：

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定位常染色体隐性智力障碍：结合微阵列和外显子组测序鉴定了192个近亲家族中的26个新候选基因。

全球约有1％的人受到智力残疾（ID）的影响，并且大多数人没有接受分子诊断。先前的研究表明遗传异质性水平很高，估计有超过2500个常染色体ID基因，其中大多数是常染色体隐性（AR）基因。在这里，我们结合了微阵列基因分型，血统纯合（HBD）作图，拷贝数变异（CNV）分析和全外显子组测序（WES），以鉴定192个非综合征的多重巴基斯坦和伊朗近亲家庭的疾病基因/突变ID。我们在72个不同基因的51％的家庭中确定了明确的或候选突变（或CNV），其中包括26个以前未报道过的ARID。新的ARID基因包括9个功能丧失的突变（ABI2，MAPK8，MPDZ，PIDD1，SLAIN1，TBC1D23，TRAPPC6B，UBA7和USP44）和错义突变包括与ID相关的BDNF或TET1变体的首次报道。鉴定出的基因还显示与其他神经精神疾病的从头基因集重叠。转录研究显示在产前大脑中有突出的表达。ID的AR突变的高产率表明，这种方法具有极好的临床潜力，并且应该为血缘常见的人群提供临床诊断信息，包括临床整个外显子组和基因组测序。与其他AR疾病一样，相关性也适用于近亲人群。转录研究显示在产前大脑中有突出的表达。ID的AR突变的高产率表明，这种方法具有极好的临床潜力，并且应该为血缘常见的人群提供临床诊断信息，包括临床整个外显子组和基因组测序。与其他AR疾病一样，相关性也适用于近亲人群。转录研究显示在产前大脑中有突出的表达。ID的AR突变的高产率表明，这种方法具有极好的临床潜力，并且应该为血缘常见的人群提供临床诊断信息，包括临床整个外显子组和基因组测序。与其他AR疾病一样，相关性也适用于近亲人群。