SHOX far‐downstream deletion in a patient with nonsyndromic short stature

Abstract Haploinsufficiency of SHOX represents one of the major genetic causes of nonsyndromic short stature. To date, eight DNA elements around SHOX exons have been proposed as putative enhancer regions. Although six copy‐number variations (CNVs) downstream to the known enhancer regions have recently been identified in patients with short stature, the pathogenicity of these CNVs remains uncertain. Here, we identified a paternally derived SHOX far‐downstream deletion in a boy. The deletion involved a ~100 kb genomic interval at a position >60 kb away from the known enhancer regions. The boy exhibited moderate short stature with nonspecific skeletal changes. The height of the father was within the normal range but lower than the mid‐parental height. The deletion of the boy and the six previously reported CNVs mostly overlapped; however, all CNVs had unique breakpoints. The deletion of our case encompassed a ~30 kb genomic interval that has previously been associated with a 4C‐seq peak, as well as several SHOX ‐regulatory SNPs/indels. These results indicate that the SHOX far‐downstream region contains a novel cis‐acting enhancer, whose deletion leads to nonsyndromic short stature of various degree. In addition, our data highlight genomic instability of SHOX ‐flanking regions that underlies diverse nonrecurrent CNVs.