Article ; Online: Identification of USP9X as a leukemia susceptibility gene.
2023 Volume 7, Issue 16, Page(s) 4563–4575
Abstract: 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 ... ...
| Abstract | 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 (B-ALL). 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 (P < .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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| MeSH term(s) | Female ; Humans ; Male ; Intellectual Disability/genetics ; Leukemia ; Loss of Function Mutation ; Mutation, Missense ; Phenotype ; Ubiquitin Thiolesterase/genetics ; Ubiquitin Thiolesterase/metabolism |
| Chemical Substances | Ubiquitin Thiolesterase (EC 3.4.19.12) ; USP9X protein, human |
| Language | English |
| Publishing date | 2023-06-07 |
| Publishing country | United States |
| Document type | Case Reports ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. |
| ZDB-ID | 2915908-8 |
| ISSN | 2473-9537 ; 2473-9529 |
| ISSN (online) | 2473-9537 |
| ISSN | 2473-9529 |
| DOI | 10.1182/bloodadvances.2023009814 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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