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  • De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific Recognizable Syndrome with Developmental Delay and Congenital Malformations

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    Author(s)
    Reijnders, Margot RF
    Zachariadis, Vasilios
    Latour, Brooke
    Jolly, Lachlan
    Mancini, Grazia M
    Pfundt, Rolph
    Wu, Ka Man
    van Ravenswaaij-Arts, Conny MA
    Veenstra-Knol, Hermine E
    Anderlid, Britt-Marie M
    Wood, Stephen A
    Cheung, Sau Wai
    Barnicoat, Angela
    Probst, Frank
    Magoulas, Pilar
    Brooks, Alice S
    Malmgren, Helena
    Harila-Saari, Arja
    Marcelis, Carlo M
    Vreeburg, Maaike
    Hobson, Emma
    Sutton, V Reid
    Stark, Zornitza
    Vogt, Julie
    Cooper, Nicola
    Lim, Jiin Ying
    Price, Sue
    Lai, Angeline Hwei Meeng
    Domingo, Deepti
    Reversade, Bruno
    Gecz, Jozef
    Gilissen, Christian
    Brunner, Han G
    Kini, Usha
    Roepman, Ronald
    Nordgren, Ann
    Kleefstra, Tjitske
    Griffith University Author(s)
    Wood, Stephen A.
    Year published
    2016
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    Abstract
    Mutations in more than a hundred genes have been reported to cause X-linked recessive intellectual disability (ID) mainly in males. In contrast, the number of identified X-linked genes in which de novo mutations specifically cause ID in females is limited. Here, we report 17 females with de novo loss-of-function mutations in USP9X, encoding a highly conserved deubiquitinating enzyme. The females in our study have a specific phenotype that includes ID/developmental delay (DD), characteristic facial features, short stature, and distinct congenital malformations comprising choanal atresia, anal abnormalities, post-axial ...
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    Mutations in more than a hundred genes have been reported to cause X-linked recessive intellectual disability (ID) mainly in males. In contrast, the number of identified X-linked genes in which de novo mutations specifically cause ID in females is limited. Here, we report 17 females with de novo loss-of-function mutations in USP9X, encoding a highly conserved deubiquitinating enzyme. The females in our study have a specific phenotype that includes ID/developmental delay (DD), characteristic facial features, short stature, and distinct congenital malformations comprising choanal atresia, anal abnormalities, post-axial polydactyly, heart defects, hypomastia, cleft palate/bifid uvula, progressive scoliosis, and structural brain abnormalities. Four females from our cohort were identified by targeted genetic testing because their phenotype was suggestive for USP9X mutations. In several females, pigment changes along Blaschko lines and body asymmetry were observed, which is probably related to differential (escape from) X-inactivation between tissues. Expression studies on both mRNA and protein level in affected-female-derived fibroblasts showed significant reduction of USP9X level, confirming the loss-of-function effect of the identified mutations. Given that some features of affected females are also reported in known ciliopathy syndromes, we examined the role of USP9X in the primary cilium and found that endogenous USP9X localizes along the length of the ciliary axoneme, indicating that its loss of function could indeed disrupt cilium-regulated processes. Absence of dysregulated ciliary parameters in affected female-derived fibroblasts, however, points toward spatiotemporal specificity of ciliary USP9X (dys-)function.
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    Journal Title
    American Journal of Human Genetics
    Volume
    98
    Issue
    2
    DOI
    https://doi.org/10.1016/j.ajhg.2015.12.015
    Copyright Statement
    © 2016 American Society of Human Genetics. This is the author-manuscript version of this paper. Reproduced in accordance with the copyright policy of the publisher. Please refer to the journal's website for access to the definitive, published version.
    Subject
    Biological sciences
    Genetics not elsewhere classified
    Biomedical and clinical sciences
    Publication URI
    http://hdl.handle.net/10072/123978
    Collection
    • Journal articles

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