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

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.

Automated summary

This study reports a truncating variant in the USP9X gene in two non-twin female siblings. Despite the high penetrance of pathogenic variants in the USP9X gene in females, this truncating variant showed incomplete penetrance in the two patients. Genetic regulation studies related to female-specific ID syndrome failed to identify a clear cause.