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dc.contributor.authorReijnders, Margot RF
dc.contributor.authorZachariadis, Vasilios
dc.contributor.authorLatour, Brooke
dc.contributor.authorJolly, Lachlan
dc.contributor.authorMancini, Grazia M
dc.contributor.authorPfundt, Rolph
dc.contributor.authorWu, Ka Man
dc.contributor.authorvan Ravenswaaij-Arts, Conny MA
dc.contributor.authorVeenstra-Knol, Hermine E
dc.contributor.authorAnderlid, Britt-Marie M
dc.contributor.authorWood, Stephen A
dc.contributor.authorCheung, Sau Wai
dc.contributor.authorBarnicoat, Angela
dc.contributor.authorProbst, Frank
dc.contributor.authorMagoulas, Pilar
dc.contributor.authorBrooks, Alice S
dc.contributor.authorMalmgren, Helena
dc.contributor.authorHarila-Saari, Arja
dc.contributor.authorMarcelis, Carlo M
dc.contributor.authorVreeburg, Maaike
dc.contributor.authorHobson, Emma
dc.contributor.authorSutton, V Reid
dc.contributor.authorStark, Zornitza
dc.contributor.authorVogt, Julie
dc.contributor.authorCooper, Nicola
dc.contributor.authorLim, Jiin Ying
dc.contributor.authorPrice, Sue
dc.contributor.authorLai, Angeline Hwei Meeng
dc.contributor.authorDomingo, Deepti
dc.contributor.authorReversade, Bruno
dc.contributor.authorGecz, Jozef
dc.contributor.authorGilissen, Christian
dc.contributor.authorBrunner, Han G
dc.contributor.authorKini, Usha
dc.contributor.authorRoepman, Ronald
dc.contributor.authorNordgren, Ann
dc.contributor.authorKleefstra, Tjitske
dc.date.accessioned2019-03-12T00:28:01Z
dc.date.available2019-03-12T00:28:01Z
dc.date.issued2016
dc.identifier.issn0002-9297
dc.identifier.doi10.1016/j.ajhg.2015.12.015
dc.identifier.urihttp://hdl.handle.net/10072/123978
dc.description.abstractMutations 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.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherElsevier
dc.relation.ispartofpagefrom373
dc.relation.ispartofpageto381
dc.relation.ispartofissue2
dc.relation.ispartofjournalAmerican Journal of Human Genetics
dc.relation.ispartofvolume98
dc.subject.fieldofresearchBiological sciences
dc.subject.fieldofresearchGenetics not elsewhere classified
dc.subject.fieldofresearchBiomedical and clinical sciences
dc.subject.fieldofresearchcode31
dc.subject.fieldofresearchcode310599
dc.subject.fieldofresearchcode32
dc.titleDe Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific Recognizable Syndrome with Developmental Delay and Congenital Malformations
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
dc.description.versionAccepted Manuscript (AM)
gro.rights.copyright© 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.
gro.hasfulltextFull Text
gro.griffith.authorWood, Stephen A.


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