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 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.