title: Rare pseudoautosomal copy-number variations involving SHOX and/or its flanking regions in individuals with and without short stature.
abstract: Pseudoautosomal region 1 (PAR1) contains SHOX, in addition to seven highly conserved non-coding DNA elements (CNEs) with cis-regulatory activity. Microdeletions involving SHOX exons 1-6a and/or the CNEs result in idiopathic short stature (ISS) and Leri-Weill dyschondrosteosis (LWD). Here, we report six rare copy-number variations (CNVs) in PAR1 identified through copy-number analyzes of 245 ISS/LWD patients and 15 unaffected individuals. The six CNVs consisted of three microduplications encompassing SHOX and some of the CNEs, two microduplications in the SHOX 3'-region affecting one or four of the downstream CNEs, and a microdeletion involving SHOX exon 6b and its neighboring CNE. The amplified DNA fragments of two SHOX-containing duplications were detected at chromosomal regions adjacent to the original positions. The breakpoints of a SHOX-containing duplication resided within Alu repeats. A microduplication encompassing four downstream CNEs was identified in an unaffected father-daughter pair, whereas the other five CNVs were detected in ISS patients. These results suggest that microduplications involving SHOX cause ISS by disrupting the cis-regulatory machinery of this gene and that at least some of microduplications in PAR1 arise from Alu-mediated non-allelic homologous recombination. The pathogenicity of other rare PAR1-linked CNVs, such as CNE-containing microduplications and exon 6b-flanking microdeletions, merits further investigation.
authors.affiliation: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Fukami
authors.affiliation: Division of Endocrinology and Metabolism, National Center for Child Health and Development, Tokyo, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Naiki
authors.affiliation: Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Yokohama, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Muroya
authors.affiliation: Division of Endocrinology and Metabolism, Aichi Children's Health and Medical Center, Obu, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Hamajima
authors.affiliation: Department of Pediatrics, St. Marianna University School of Medicine, Kawasaki, Japan.
authors.forename: Shun
authors.initials: S
authors.lastname: Soneda
authors.affiliation: Division of Endocrinology and Metabolism, National Center for Child Health and Development, Tokyo, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Horikawa
authors.affiliation: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Jinno
authors.affiliation: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Momori
authors.initials: M
authors.lastname: Katsumi
authors.affiliation: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.|Department of Pediatrics, Hokkaido University School of Medicine, Sapporo, Japan.
authors.forename: Akie
authors.initials: A
authors.lastname: Nakamura
authors.affiliation: Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Yokohama, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Asakura
authors.affiliation: Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Yokohama, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Adachi
authors.affiliation: Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Ogata
authors.affiliation: Division of Pediatrics and Perinatology, Tottori University Faculty of Medicine, Tottori, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Kanzaki
mesh_terms: D024509:3' Flanking Region / Q000235:genetics; D024506:5' Flanking Region / Q000235:genetics; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D056915:DNA Copy Number Variations; D004392:Dwarfism / Q000235:genetics; D005260:Female; D020440:Gene Duplication; D005787:Gene Frequency; D006130:Growth Disorders / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D010009:Osteochondrodysplasias / Q000235:genetics; D017384:Sequence Deletion; D000074122:Short Stature Homeobox Protein; D055815:Young Adult
chemical_list: D018398:Homeodomain Proteins; C106071:SHOX protein, human; D000074122:Short Stature Homeobox Protein