title: Two females with mutations in USP9X highlight the variable expressivity of the intellectual disability syndrome.
abstract: The genetic causes of intellectual disability (ID) are heterogeneous and include both chromosomal and monogenic etiologies. The X-chromosome is known to contain many ID-related genes and males show a marked predominance for intellectual disability. Here we report two females with syndromic intellectual disability. The first individual was relatively mild in her presentation with mild-moderate intellectual disability, hydronephrosis and altered pigmentation along the lines of Blaschko without additional congenital anomalies. A second female presented shortly after birth with dysmorphic facial features, post-axial polydactyly and, on follow-up assessment, demonstrated moderate intellectual disability. Chromosomal studies for Individual 1 identified an X-chromosome deletion due to a de novo pericentric inversion; the inversion breakpoint was associated with deletion of the 5'UTR of the USP9X, a gene which has been implicated in a syndromic intellectual disability affecting females. The second individual had a de novo frameshift mutation detected by whole-exome sequencing that was predicted to be deleterious, NM_001039590.2 (USP9X): c.4104_4105del (p.(Arg1368Serfs*2)). Haploinsufficiency of USP9X in females has been associated with ID and congenital malformations that include heart defects, scoliosis, dental abnormalities, anal atresia, polydactyly, Dandy Walker malformation and hypoplastic corpus callosum. The extent of the congenital malformations observed in Individual 1 was less striking than Individual 2 and other individuals previously reported in the literature, and suggests that USP9X mutations in females can have a wider spectrum of presentation than previously appreciated.
authors.affiliation: Department of Medical Genetics, Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, AB, Canada.
authors.forename: P Y B
authors.initials: PYB
authors.lastname: Au
authors.affiliation: Department of Pathology, University of British Columbia Women and Children's Hospital, Vancouver, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Huang
authors.affiliation: Genetic Services of Western Australia, Department of Health, Government of Western Australia, Subiaco, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Broley
authors.affiliation: Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Gallagher
authors.affiliation: Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Creede
authors.affiliation: Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Lahey
authors.affiliation: Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Ordorica
authors.affiliation: Diagnostic Genomics, PathWest, Department of Health, Government of Western Australia, WA, Australia.
authors.forename: K
authors.initials: K
authors.lastname: Mina
authors.affiliation: Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Canada; Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada.
authors.forename: K M
authors.initials: KM
authors.lastname: Boycott
authors.affiliation: Genetic Services of Western Australia, Department of Health, Government of Western Australia, Subiaco, Australia; School of Paediatrics and Child Health, The University of Western Australia, Crawley, Australia; Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Australia; Office of Population Health Genomics, Public Health Division, Department of Health, Government of Western Australia, East Perth, Australia; Telethon Kids Institute, University of Western Australia, Subiaco, Australia; Western Australian Register of Developmental Anomalies, Subiaco, Australia; School of Spatial Sciences, Curtin University, Bentley, Australia.
authors.forename: G
authors.initials: G
authors.lastname: Baynam
authors.affiliation: Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Canada; Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada. Electronic address: ddyment@cheo.on.ca.
authors.forename: D A
authors.initials: DA
authors.lastname: Dyment
mesh_terms: D020121:5' Untranslated Regions; D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics*; D000328:Adult; D002675:Child, Preschool; D002872:Chromosome Deletion; D041321:Chromosomes, Human, X / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation; D057895:Haploinsufficiency; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D010641:Phenotype; D013577:Syndrome; D043222:Ubiquitin Thiolesterase / Q000235:genetics*
chemical_list: D020121:5' Untranslated Regions; C506234:USP9X protein, human; D043222:Ubiquitin Thiolesterase
keywords: Intellectual disability; Lines of Blaschko; USP9X