Identification of Intellectual Disability Genes in Female Patients with a Skewed X‐Inactivation Pattern |
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| Authors: | Nathalie Fieremans Hilde Van Esch Maureen Holvoet Gert Van Goethem Koenraad Devriendt Monica Rosello Sonia Mayo Francisco Martinez Shalini Jhangiani Donna M. Muzny Richard A. Gibbs James R. Lupski Joris R. Vermeesch Peter Marynen Guy Froyen |
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| Affiliation: | 1. Human Genome Laboratory, Department of Human Genetics, KU Leuven, Belgium;2. Human Genome Laboratory, VIB Center for the Biology of Disease, Leuven, Belgium;3. Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium;4. Het GielsBos, Gierle, Belgium and Department of Neurology, University Hospital of Antwerp (UZA), Antwerp, Belgium;5. Genetics Unit, Hospital Universitario y Politecnico La Fe, Valencia, Spain;6. Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas;7. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas;8. Department of Pediatrics, Baylor College of Medicine, Houston, Texas;9. Texas Children's Hospital, Houston, Texas |
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| 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. |
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| Keywords: | escape genes intellectual disability skewing of X‐inactivation exome sequencing |
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