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

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, Xinactivation, 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.

Identification of USP9X as a leukemia susceptibility gene

“…Molecularly, this cohort was reported with nonsense, frameshift, missense variants, and intragenic and inframe germline deletions in USP9X ( Figure 2 A). 4 , 5 , 27 , 28 , 29 , 30 , 31 , 32 , 33 The clinical importance of exon 33 (deleted in the GOBACK proband) is implicated by the overlap of this exon with 2 pathogenic missense variants p.D1685N and p.L1693W, previously reported in 3 female patients: Jolly et al females 26, 27, and Jolly et al. female 8 with this disorder 4 , 5 ( Figure 2 A).…”