title: Identification of Intellectual Disability Genes in Female Patients with a Skewed X-Inactivation Pattern.
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.
authors.affiliation: Human Genome Laboratory, Department of Human Genetics, KU Leuven, Belgium.|Human Genome Laboratory, VIB Center for the Biology of Disease, Leuven, Belgium.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Fieremans
authors.affiliation: Center for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Hilde
authors.initials: H
authors.lastname: Van Esch
authors.affiliation: Center for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Maureen
authors.initials: M
authors.lastname: Holvoet
authors.affiliation: Het GielsBos, Gierle, Belgium and Department of Neurology, University Hospital of Antwerp (UZA), Antwerp, Belgium.
authors.forename: Gert
authors.initials: G
authors.lastname: Van Goethem
authors.affiliation: Center for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Koenraad
authors.initials: K
authors.lastname: Devriendt
authors.affiliation: Genetics Unit, Hospital Universitario y Politecnico La Fe, Valencia, Spain.
authors.forename: Monica
authors.initials: M
authors.lastname: Rosello
authors.affiliation: Genetics Unit, Hospital Universitario y Politecnico La Fe, Valencia, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Mayo
authors.affiliation: Genetics Unit, Hospital Universitario y Politecnico La Fe, Valencia, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Martinez
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Shalini
authors.initials: S
authors.lastname: Jhangiani
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.|Department of Pediatrics, Baylor College of Medicine, Houston, Texas.|Texas Children's Hospital, Houston, Texas.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.affiliation: Center for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
authors.forename: Joris R
authors.initials: JR
authors.lastname: Vermeesch
authors.affiliation: Human Genome Laboratory, Department of Human Genetics, KU Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Marynen
authors.affiliation: Human Genome Laboratory, Department of Human Genetics, KU Leuven, Belgium.
authors.forename: Guy
authors.initials: G
authors.lastname: Froyen
mesh_terms: D002352:Carrier Proteins / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D053487:DEAD-box RNA Helicases / Q000235:genetics; D059472:Exome; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008565:Membrane Proteins; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods*; D049951:X Chromosome Inactivation; D000098550:Structural Maintenance of Chromosome Protein 1
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; C497392:MECP2 protein, human; D008565:Membrane Proteins; D051783:Methyl-CpG-Binding Protein 2; C488621:NHS protein, human; D009687:Nuclear Proteins; C578284:WDR45 protein, human; D000098550:Structural Maintenance of Chromosome Protein 1; C119332:DDX3X protein, human; D053487:DEAD-box RNA Helicases
keywords: escape genes; exome sequencing; intellectual disability; skewing of X-inactivation