Title: Identification of Intellectual Disability Genes in Female Patients with A Skewed X Inactivation Pattern
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 # ×
Issue Date: Aug-2016
Publisher: John Wiley & Sons, Inc.
Series Title: Human Mutation vol:37 issue:8 pages:804-811
Article number: 10.1002/humu.23012
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 due to the hemizygous state of their X chromosome. Carrier females are generally unaffected due to 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 analysed 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 6 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 3 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. This article is protected by copyright. All rights reserved.
ISSN: 1059-7794
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Human Genome Laboratory
Department of Human Genetics - miscellaneous
Studiegebied Gezondheidszorg VIVES-Zuid
× corresponding author
# (joint) last author

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