ABSTRACT SHOX gene haploinsufficiency is associated with Léri‐Weill dyschondrosteosis (LWD) or idiopathic short stature (ISS) and could be caused by the structural and point mutations in the coding region and by the deletions in SHOX gene regulatory sequences. The role of the duplications in regulatory sequences is ambivalent. The unanswered question is what the role of changes in SHOX gene methylation is and if they could arise as a result of SHOX area duplication. Material consisted of DNA samples from 20 LWD patients with duplication involving SHOX regulatory elements, 30 patients with LWD/ISS phenotype without any known causal mutation in the SHOX region, and 23 healthy individuals as controls. We investigated the DNA methylation status of two CpG islands in the upstream region of the SHOX using bisulfite sequencing. Our results indicate that both CpG islands in the SHOX area show a lower level of methylation in LWD patients carrying duplications than in healthy individuals, but only one island showed a statistically significant difference. The results of methylation profiling of CpG islands in patients without any known causal mutation indicate that the methylation levels of the majority of patients differed in both CpG islands from the average of the group of healthy individuals by at least ±2 SD. However, the biological effect of these differences will probably be clinically insignificant due to the generally very low level of methylation.
Kopytko et al. (Mon,) studied this question.
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