西亚试剂：Intellectual disability (ID), which affects 1–2% of the gen

Intellectual disability (ID), which affects 1–2% of the general population, is characterized by significant sub-average cognitive functioning, commonly defined by an IQ of lower than 70, and deficits in adaptive behavior, such as social and daily-living skills with an onset before 18 years of age. Most severe forms have a single genetic cause, and males are more often affected than females. Therefore, for many years, research has focused on the molecular elucidation of X-linked forms of ID which are thought to account for 10–12% of all males with ID.1 Until 2007, mutations in XLID genes known at that time had been detected in 42% of the Fragile X-negative families studied.2 Afterwards, a large-scale, comprehensive Sanger sequencing study was performed to identify the missing genes and mutations in a cohort of 208 families.3 This study was complemented by high-resolution array CGH profiling on the same set of families4 and by further genetic and functional evidence for some of the unique missense variants.5, 6, 7 However, in excess of 50% XLID families remained without plausible gene defects further indicating genetic heterogeneity of XLID. Since then, several novel XLID genes have been reported in the medical literature, including HUWE1 [MIM 300697],8SLC9A6 [MIM 300231],9PCDH19 [MIM 300460],10RAB39B [MIM 300774],11HDAC8 [MIM 300269],12HCFC1 [MIM 300019],13CCDC22 [MIM 300859],14, 15USP9X [MIM 300072],6PIGA [MIM 311770],16WDR45 [MIM 300526],17KDM6A [MIM 300128],18BCAP31 [MIM 300398],19ZC4H2 [MIM 300897],20KIAA2022 [MIM 300524]21 and MID2 [MIM 300204].22

In this study, we aimed to (i) identify the molecular causes of XLID in a large group of unresolved families, (ii) define the number of XLID genes that can be identified by performing targeted sequencing of all X chromosome-specific exons, (iii) gain knowledge about ID-related pathways and networks and (iv) estimate the proportion of families with XLID that can be solved using X-exome sequencing. For this, we initially focused on 248 families collected by the EUROMRX consortium and associated groups that remained unresolved by pre-screening for mutations in selected known XLID genes and by array CGH. In follow-up work we investigated an additional cohort of 157 similarly pre-screened families. We took advantage of next-generation sequencing (NGS) technology to substantially improve the coverage of X-chromosomal coding sequences compared with previous studies. We identified likely pathogenic variants in a range of previously established XLID genes as well as several novel and candidate XLID genes.

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