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Identification of USP9X as a leukemia susceptibility gene.

We recently reported that children with multiple birth defects have a
significantly higher risk of childhood cancer. We performed whole-genome
sequencing on a cohort of probands from this study with birth defects and
cancer and their parents. Structural variant analysis identified a novel 5
kb de novo heterozygous inframe deletion overlapping the catalytic domain
of USP9X in a female proband with multiple birth defects, developmental
delay, and B-cell acute lymphoblastic leukemia (球). Her phenotype was
consistent with female-restricted X-linked syndromic intellectual
developmental disorder-99 (MRXS99F). Genotype-phenotype analysis including
previously reported female probands (n = 42) demonstrated that MRXS99F
probands with B-ALL (n = 3) clustered with subjects with loss-of-function
(LoF) USP9X variants and multiple anomalies. The cumulative incidence of
B-ALL among these female probands (7.1%) was significantly higher than an
age- and sex-matched cohort (0.003%) from the Surveillance, Epidemiology,
and End Results database (磷 < .0001, log-rank test). There are no reports of LoF variants in males. Males with hypomorphic missense variants have neurodevelopmental disorders without birth defects or leukemia risk. In contrast, in sporadic B-ALL, somatic LoF USP9X mutations occur in both males and females, and expression levels are comparable in leukemia samples from both sexes (P = .54), with the highest expressors being female patients with extra copies of the X-chromosome. Overall, we describe USP9X as a novel female-specific leukemia predisposition gene associated with multiple congenital, neurodevelopmental anomalies, and B-ALL risk. In contrast, USP9X serves as a tumor suppressor in sporadic pediatric B-ALL in both sexes, with low expression associated with poorer survival in patients with high-risk B-ALL.

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