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

Margot R.F. Reijnders, Vasilios Zachariadis, Brooke Latour, Lachlan Jolly, Grazia M. Mancini, Rolph Pfundt, Ka Man Wu, Conny M.A. Van Ravenswaaij-Arts, Hermine E. Veenstra-Knol, Britt Marie M. Anderlid, Stephen A. Wood, Sau Wai Cheung, Angela Barnicoat, Frank Probst, Pilar Magoulas, Alice S. Brooks, Helena Malmgren, Arja Harila-Saari, Carlo M. Marcelis, Maaike VreeburgEmma Hobson, V. Reid Sutton, Zornitza Stark, Julie Vogt, Nicola Cooper, Jiin Ying Lim, Sue Price, Angeline Hwei Meeng Lai, Deepti Domingo, Bruno Reversade, Jozef Gecz, Christian Gilissen, Han G. Brunner, Usha Kini, Ronald Roepman, Ann Nordgren, Tjitske Kleefstra

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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 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.

Original languageEnglish
Pages (from-to)373-381
Number of pages9
JournalAmerican Journal of Human Genetics
Volume98
Issue number2
DOIs
Publication statusPublished - 4 Feb 2016

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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