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

J Hum Genet. 2015 Sep;60(9):553-6. doi: 10.1038/jhg.2015.53. Epub 2015 Jun 4.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Flanking Region / genetics
  • 5' Flanking Region / genetics
  • Case-Control Studies
  • Child
  • Child, Preschool
  • DNA Copy Number Variations*
  • Dwarfism / genetics
  • Female
  • Gene Duplication
  • Gene Frequency
  • Growth Disorders / genetics*
  • Homeodomain Proteins / genetics*
  • Humans
  • Infant
  • Male
  • Middle Aged
  • Osteochondrodysplasias / genetics
  • Sequence Deletion
  • Short Stature Homeobox Protein
  • Young Adult


  • Homeodomain Proteins
  • SHOX protein, human
  • Short Stature Homeobox Protein

Supplementary concepts

  • Leri-Weil syndrome