Systematic molecular analyses of SHOX in Japanese patients with idiopathic short stature and Leri–Weill dyschondrosteosis

Abstract

The etiology of idiopathic short stature (ISS) and Leri-Weill dyschondrosteosis (LWD) in European patients is known to include SHOX mutations and copy-number variations (CNVs) involving SHOX and/or the highly evolutionarily conserved non-coding DNA elements (CNEs) flanking the gene. However, the frequency and types of SHOX abnormalities in non-European patients and the clinical importance of mutations in the CNEs remains to be clarified. Here, we performed systematic molecular analyses of SHOX for 328 Japanese patients with ISS or LWD. SHOX abnormalities accounted for 3.8% of ISS and 50% of LWD cases. CNVs around SHOX were identified in 16 cases, although the ~47 kb deletion frequently reported in European patients was absent in our cases. Probably damaging mutations and benign/silent substitutions were detected in four cases, respectively. Although CNE-linked substitutions were detected in 15 cases, most of them affected poorly conserved nucleotides and were shared by unaffected individuals. These results suggest that the frequency and mutation spectrum of SHOX abnormalities are comparable between Asian and European patients, with the exception of a European-specific downstream deletion. Furthermore, this study highlights the clinical importance and genetic heterogeneity of the SHOX-flanking CNVs, and indicates a limited clinical significance of point mutations in the CNEs.

Next generation sequencing-based mutation screening of 86 patients with idiopathic short stature

“…All patients presented with short stature of lower than −2.0 SD of the Japanese population. The lack of SHOX abnormalities in these patients was confirmed in our previous study [16]. Of the 39 patients whose parental heights were available, seven had at least one parent with short stature.…”

Recurrent Copy Number Variants Associated with Syndromic Short Stature of Unknown Cause

“…It is assumed that the heterozygous loss of the SHOX gene is responsible for Leri-Weill dyschondrosteosis (OMIM 127300), whereas homozygous loss leads to Langer mesomelic dysplasia (OMIM 249700), both being characterized by disproportionate short stature [29, 30]. Defects on the SHOX gene have also been identified in idiopathic short stature [31, 32]. Patients with identified Xp22.33 rearrangements usually had some additional features of disproportionate short stature that mask the suspicion of heterozygous loss of the SHOX gene.…”

Identification of a novel heterozygous mutation of the Aggrecan gene in a family with idiopathic short stature and multiple intervertebral disc herniation

“…1 Recently, mutations in the SHOX gene or the NPR2 gene have been found to account for a minor portion of patients with ISS; however, the genetic background of ISS remains largely unexplored. 2,3 Aggrecan, encoded by the ACAN gene, is a major proteoglycan component of the extracellular matrix of the growth plates and the articular cartilage. Aggrecan provides the hydrated gel structure, which is important for the load-bearing properties of joints, and also plays a key role in chondrocyte and bone morphogenesis.…”