ESPE Abstracts

Background: SHOX, located on the pseudoautosomal region 1 (PAR1), encodes a transcriptional factor implicated in human skeletal growth. Alterations in SHOX or its regulatory elements are observed in ~70% of patients with Leri–Weill dyschondrosteosis (LWD), in ~90% with Langer mesomelic dysplasia (LMD) and ~2.5% of patients with idiopathic short stature (ISS). SHOX deletions/duplications are a frequent alteration, with the majority encompassing the entire gene.

Objective and hypotheses: During routine SHOX diagnostics, a total of 15 partial SHOX deletions (14 LWD, one LMD), and 12 partial duplications (nine LWD, three ISS) were detected. We set out to characterise these 27 partial SHOX alterations and to determine if certain regions were more susceptible to breakages.

Method: A total of 15 partial SHOX deletions and 12 partial duplications were characterised using chromosome Y specific array-CGH (Nimblegen), two custom-designed MLPA assays and breakpoint junction PCR sequencing.

Results: Nine intragenic deletions and seven duplications were characterised, with the smallest involving a single exon. Six deletions and five duplications extended upstream (five and four, respectively) and downstream (one in each case) of SHOX. No reciprocal partial deletions and duplications were observed. To date, deletion breakpoints have been determined in four patients, three of which were located in intron 3. Although not all breakpoints have been finely characterised, we have observed that 13/27 (48%) alterations have a distal or proximal breakpoint in intron 3 (5994 bp, 28.6% repetitive elements).

Conclusion: We have characterised 15 partial deletions and 12 partial duplications of SHOX in patients with LWD, LMD, and ISS. Approximately half of the breakpoints are located in intron 3 which is rich in repetitive elements. Together with other reported cases, we propose that the highly repetitive intron 3 has a high predisposition to breakage and represents a hotspot region for deletions and duplications.

Funding: This work was supported by the MINECO (SAF2012-30871).