Exome and RNA-Seq analyses of an incomplete penetrance variant in USP9X in female-specific syndromic intellectual disability

Am J Med Genet A. 2022 Jun;188(6):1808-1814. doi: 10.1002/ajmg.a.62715. Epub 2022 Mar 7.

Abstract

Pathogenic variants in USP9X, on X chromosome, have been implicated in syndromic intellectual disability (ID) in both males and females with distinct craniofacial features. We report a truncating variant, c.885_889delAAAAG, p.(Lys296Serfs*4), in the USP9X gene with incomplete penetrance in two nontwin female siblings with phenotypic resemblance to female-specific syndromic ID (MIM 300969, also known as MRX99F). To investigate the possible genetic etiology of the reduced penetrance, X-inactivation, RNA-Seq, and full quad exome analyses were attempted, but failed to identify a promising candidate modifier. While the penetrance of pathogenic variants in USP9X in female appears to be high (95%) and the variants frequently occur de novo, incomplete penetrance should be considered.

Keywords: USP9X; incomplete penetrance; intellectual disability.

MeSH terms

  • Exome
  • Exome Sequencing
  • Female
  • Humans
  • Intellectual Disability* / diagnosis
  • Intellectual Disability* / genetics
  • Intellectual Disability* / pathology
  • Male
  • Penetrance
  • RNA-Seq
  • Ubiquitin Thiolesterase* / genetics

Substances

  • USP9X protein, human
  • Ubiquitin Thiolesterase