title: Xp11.2 microduplications including IQSEC2, TSPYL2 and KDM5C genes in patients with neurodevelopmental disorders.
abstract: Copy number variations are a common cause of intellectual disability (ID). Determining the contribution of copy number variants (CNVs), particularly gains, to disease remains challenging. Here, we report four males with ID with sub-microscopic duplications at Xp11.2 and review the few cases with overlapping duplications reported to date. We established the extent of the duplicated regions in each case encompassing a minimum of three known disease genes TSPYL2, KDM5C and IQSEC2 with one case also duplicating the known disease gene HUWE1. Patients with a duplication encompassing TSPYL2, KDM5C and IQSEC2 without gains of nearby SMC1A and HUWE1 genes have not been reported thus far. All cases presented with ID and significant deficits of speech development. Some patients also manifested behavioral disturbances such as hyperactivity and attention-deficit/hyperactivity disorder. Lymphoblastic cell lines from patients show markedly elevated levels of TSPYL2, KDM5C and SMC1A, transcripts consistent with the extent of their CNVs. The duplicated region in our patients contains several genes known to escape X-inactivation, including KDM5C, IQSEC2 and SMC1A. In silico analysis of expression data in selected gene expression omnibus series indicates that dosage of these genes, especially IQSEC2, is similar in males and females despite the fact they escape from X-inactivation in females. Taken together, the data suggest that gains in Xp11.22 including IQSEC2 cause ID and are associated with hyperactivity and attention-deficit/hyperactivity disorder, and are likely to be dosage-sensitive in males.
authors.affiliation: Department of Paediatrics, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia, Australia.|Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Ching
authors.initials: C
authors.lastname: Moey
authors.affiliation: Department of Paediatrics, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia, Australia.|Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Hinze
authors.affiliation: Clinical Genetics unit, Birmingham Women's Hospital, Birmingham, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Brueton
authors.affiliation: Clinical Genetics unit, Birmingham Women's Hospital, Birmingham, UK.
authors.forename: Jenny
authors.initials: J
authors.lastname: Morton
authors.affiliation: West Midlands Regional Genetics Laboratories, Birmingham, UK.
authors.forename: Dominic J
authors.initials: DJ
authors.lastname: McMullan
authors.affiliation: Hunter Genetics, Newcastle, New South Wales, Australia.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Kamien
authors.affiliation: South Australian Clinical Genetics Service, Adelaide, South Australia, Australia.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Barnett
authors.affiliation: Department of Translational Medicine, Federico II University, Napoli, Italy.|Telethon Institute of Genetics and Medicine, Napoli, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Brunetti-Pierri
authors.affiliation: SA Pathology, Adelaide, South Australia, Australia.
authors.forename: Jillian
authors.initials: J
authors.lastname: Nicholl
authors.affiliation: Department of Paediatrics, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia, Australia.|Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Jozef
authors.identifier: http://orcid.org/0000-0002-7884-6861
authors.initials: J
authors.lastname: Gecz
authors.affiliation: Department of Paediatrics, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia, Australia.|Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Shoubridge
mesh_terms: D000293:Adolescent; D001519:Behavior; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D058674:Chromosome Duplication; D041321:Chromosomes, Human, X / Q000235:genetics*; D004268:DNA-Binding Proteins; D005260:Female; D005786:Gene Expression Regulation; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D056466:Histone Demethylases / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D065886:Neurodevelopmental Disorders / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D055815:Young Adult; D000098550:Structural Maintenance of Chromosome Protein 1
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; C550083:IQSEC2 protein, human; D009687:Nuclear Proteins; D012333:RNA, Messenger; C432963:TSPYL2 protein, human; D000098550:Structural Maintenance of Chromosome Protein 1; D056466:Histone Demethylases; C086877:KDM5C protein, human