Background: Mutations and deletions of the homeobox transcription factor gene SHOX are known to cause short stature. We have analyzed SHOX enhancer regions in a large cohort of short stature patients to study the importance of regulatory regions in developmentally relevant genes like SHOX.
Methods: We tested for the presence of copy number variations in the pseudoautosomal region of the sex chromosomes in 735 individuals with idiopathic short stature and compared the results to 58 cases with Leri-Weill syndrome and 100 normal height controls, using FISH, SNP, microsatellites and MLPA analysis.
Results: A total of 31/735 (4.2%) microdeletions were identified in the pseudoautosomal region in patients with idiopathic short stature; eight of these microdeletions (8/31; 26%) involved only enhancer sequences residing a considerable distance away from the gene. In 58 Leri-Weill syndrome patients, a total of 29 microdeletions were identified; almost half of these (13/29; 45%) involve enhancer sequences and leave the SHOX gene intact. These deletions were absent in 100 control persons.
Conclusion: We conclude that enhancer deletions in the SHOX gene region are a relatively frequent cause of growth failure in patients with idiopathic short stature and Leri-Weill syndrome. Our data highlight the growing recognition that regulatory sequences are of crucial importance in the genome when diagnosing and understanding the etiology of disease.