Skewed X-inactivation and Females with Intellectual Disability

Abstract

The existence of X-inactivation (XI) in females has been employed since the 1990s as means of explaining the variability of phenotype in females harboring an X-linked disorder. Random XI could explain the presence of the X-linked phenotype while skewed XI would result in a normal phenotype due to “protective” inactivation of the X chromosome carrying the mutation associated with the X-linked disorder. In fact, some have proposed using the presence of skewed XI in a mother of two males with X-linked intellectual disability (XLID) to suggest the family had an increased risk of an X-linked condition versus an autosomal recessive one (Plenge et al., Am J Hum Genet 71: 168–73, 2002). In this issue, Fieremans et al. (Hum Mutat 37: 804–811, 2016) have taken a different approach. They utilized the presence of skewed XI in a female patient with an intellectual disability as a means of identifying a causative mutation in an X-linked gene. Why would a female with ID have skewed XI? This would be counter intuitive to geneticists studying XLID. However, the authors’ results validate their hypothesis. Granted, Fieremans et al. had to analyze a cohort of 223 families with ID in order to identify 6 patients (2.7%) whose ID could definitively be linked to a mutation in a gene on the X chromosome. But as they point out, this yield is not much different from that obtained by others using whole exome sequencing (WES). However, if one only considered the 19 female patients who exhibited skewed XI, the yield is close to 30% (6/19), implying skewed XI would be valuable information to have as one sorts through data generated by WES. More importantly, the data raises the intriguing question: Why would an X-linked mutation in a gene be favored over the normal allele? Answering this question will provide valuable insight in the genetics of the X chromosome.