Identification of Intellectual Disability Genes in Female Patients with a Skewed X-Inactivation Pattern

Hum Mutat. 2016 Aug;37(8):804-11. doi: 10.1002/humu.23012. Epub 2016 May 25.


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.

Keywords: escape genes; exome sequencing; intellectual disability; skewing of X-inactivation.

MeSH terms

  • Carrier Proteins / genetics
  • Cell Cycle Proteins / genetics
  • Chromosomal Proteins, Non-Histone / genetics
  • DEAD-box RNA Helicases / genetics
  • Exome
  • Female
  • Genetic Variation*
  • Humans
  • Intellectual Disability / genetics*
  • Membrane Proteins
  • Methyl-CpG-Binding Protein 2 / genetics
  • Nuclear Proteins / genetics
  • Sequence Analysis, DNA / methods*
  • X Chromosome Inactivation*


  • Carrier Proteins
  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • MECP2 protein, human
  • Membrane Proteins
  • Methyl-CpG-Binding Protein 2
  • NHS protein, human
  • Nuclear Proteins
  • WDR45 protein, human
  • structural maintenance of chromosome protein 1
  • DDX3X protein, human
  • DEAD-box RNA Helicases