Rare pseudoautosomal copy-number variations involving SHOX and/or its flanking regions in individuals with and without short stature

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...

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Bibliographic Details
Published in:Journal of human genetics 2015-09, Vol.60 (9), p.553-556
Main Authors: Fukami, Maki, Naiki, Yasuhiro, Muroya, Koji, Hamajima, Takashi, Soneda, Shun, Horikawa, Reiko, Jinno, Tomoko, Katsumi, Momori, Nakamura, Akie, Asakura, Yumi, Adachi, Masanori, Ogata, Tsutomu, Kanzaki, Susumu
Format: Article
Language:English
Subjects:
3' Flanking Region - genetics
5' Flanking Region - genetics
Breakpoints
Case-Control Studies
Child
Child, Preschool
Deoxyribonucleic acid
DNA
DNA Copy Number Variations
Dwarfism - genetics
Exons
Female
Gene Duplication
Gene Frequency
Growth Disorders - genetics
Homeodomain Proteins - genetics
Homologous recombination
Humans
Infant
Male
Middle Aged
Osteochondrodysplasias - genetics
Pathogenicity
Sequence Deletion
Short Stature Homeobox Protein
Young Adult
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Summary: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.
ISSN:1434-5161
1435-232X
DOI:10.1038/jhg.2015.53