Skewed X-Chromosome Inactivation Is a Common Feature of X-Linked Mental Retardation Disorders

• Published in: American journal of human genetics Vol. 71; no. 1; pp. 168 - 173
• Main Authors: Plenge, Robert M., Stevenson, Roger A., Lubs, Herbert A., Schwartz, Charles E., Willard, Huntington F.
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01.07.2002; University of Chicago Press; The American Society of Human Genetics
• Subjects: Biological and medical sciences; Case-Control Studies; Chromosome fragility (bloom syndrome, ataxia telangiectasia, fanconi anemia, x-linked mental retardation...); Dosage Compensation, Genetic; Female; Genetic Linkage; Heterozygote; Humans; Intellectual Disability - genetics; Male; Medical genetics; Medical sciences; Mutation; Pedigree; Receptors, Androgen - genetics; Human; Sex linked character; Pathophysiology; Pathogenesis; Exploration; Developmental disorder; Inactivation; Mental retardation; Genetic determinism; Genetic disease; Phenotype; Androgen receptor; Intellectual deficiency; Female; X-Chromosome; Carrier
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/341123

Some deleterious X-linked mutations may result in a growth disadvantage for those cells in which the mutation, when on the active X chromosome, affects cell proliferation or viability. To explore the relationship between skewed X-chromosome inactivation and X-linked mental retardation (XLMR) disorders, we used the androgen receptor X-inactivation assay to determine X-inactivation patterns in 155 female subjects from 24 families segregating 20 distinct XLMR disorders. Among XLMR carriers, ∼50% demonstrate markedly skewed X inactivation (i.e., patterns ⩾80:20), compared with only ∼10% of female control subjects ( P<.001). Thus, skewed X inactivation is a relatively common feature of XLMR disorders. Of the 20 distinct XLMR disorders, 4 demonstrate a strong association with skewed X inactivation, since all carriers of these mutations demonstrate X-inactivation patterns ⩾80:20. The XLMR mutations are present on the preferentially inactive X chromosome in all 20 informative female subjects from these families, indicating that skewing is due to selection against those cells in which the XLMR mutation is on the active X chromosome.