Identification of Intellectual Disability Genes in Female Patients with a Skewed X‐Inactivation Pattern. Issue 8 (25th May 2016)

• Record Type: Journal Article
• Authors: Fieremans, Nathalie; Van Esch, Hilde; Holvoet, Maureen; Van Goethem, Gert; Devriendt, Koenraad; Rosello, Monica; Mayo, Sonia; Martinez, Francisco; Jhangiani, Shalini; Muzny, Donna M.; Gibbs, Richard A.; Lupski, James R.; Vermeesch, Joris R.; Marynen, Peter; Froyen, Guy
• Is Part Of: Human mutation. Volume 37:Issue 8(2016)
• Page Start: 804
• Page End: 811
• Publication Date: 2016-05-25
• Subjects: escape genes -- intellectual disability -- skewing of X‐inactivation -- exome sequencing; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.23012
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract : X‐linked Intellectual disability (XLID) studies have previously focused on males only as carrier females are generally unaffected due to skewing of X inactivation. Exome sequencing of 19 female patients with ID and extreme skewing (>90%) however, revealed causal XLID variants in 6 females. Interestingly, variants in genes escaping X‐inactivation may cause both XLID and skewing. Hence, extreme skewing is a good indicator for the presence of X‐linked variants in female patients. ABSTRACT: Intellectual disability (ID) is a heterogeneous disorder with an unknown molecular etiology in many cases. Previously, X‐linked ID (XLID) studies focused on males because of the hemizygous state of their X chromosome. Carrier females are generally unaffected because of the presence of a second normal allele, or inactivation of the mutant X chromosome in most of their cells (skewing). However, in female ID patients, we hypothesized that the presence of skewing of X‐inactivation would be an indicator for an X chromosomal ID cause. We analyzed the X‐inactivation patterns of 288 females with ID, and found that 22 (7.6%) had extreme skewing (>90%), which is significantly higher than observed in the general population (3.6%; P = 0.029). Whole‐exome sequencing of 19 females with extreme skewing revealed causal variants in six females in the XLID genes DDX3X, NHS, WDR45, MECP2, and SMC1A . Interestingly, variants in genes escaping X‐inactivation presumably cause both XLID and skewing of X‐inactivation in three of these patients. Moreover, variants likely accounting for skewing only were detected in MED12, HDAC8, and TAF9B . All tested candidate causative variants were de novo events. Hence, extreme skewing is a good indicator for the presence of X‐linked variants in female patients.