Skewed X inactivation in Lesch-Nyhan disease carrier females

J Hum Genet. 2017 Dec;62(12):1079-1083. doi: 10.1038/jhg.2017.88. Epub 2017 Sep 14.

Abstract

X chromosome inactivation (XCI) ratios of normal females can range from a highly skewed ratio of 0:100 to a 50:50 ratio. In several X-linked disorders, female carriers present skewed X inactivation. Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency is an X-linked disorder. Males are affected and present with the complete Lesch-Nyhan disease (LND) or with a partial phenotype (Lesch-Nyhan variant, LNV). Female carriers are usually asymptomatic. The aim of the present study was to analyze the XCI pattern of HPRT-deficiency carrier females. As a group, 75% of HPRT-deficiency carrier females presented skewed XCI. Moreover, skewed XCI is significantly more frequent in LND carriers (83%) than in LNV (0-50%, depending on the phenotype severity). The ratios of the preferentially inactivated allele of carrier females were significantly higher than the ratios of the preferentially inactivated allele of noncarrier females (89.4±15, n=52 vs 65.2±12, n=52; P<0.0001). For carrier diagnosis, the presence of skewed XCI presents a sensitivity of 75% with a specificity of 85%. In LND families, the presence of skewed XCI is more sensitive for carrier diagnosis than in LNV families; however, we believe that this test is not accurate for carrier diagnostic purposes.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Female
  • Heterozygote
  • Humans
  • Hypoxanthine Phosphoribosyltransferase / genetics*
  • Lesch-Nyhan Syndrome / genetics*
  • Middle Aged
  • Phenotype
  • X Chromosome Inactivation / genetics*

Substances

  • Hypoxanthine Phosphoribosyltransferase