Variations in the high-mobility group-A2 gene (HMGA2) are associated with idiopathic short stature

Several association studies confirmed high-mobility group-A2 gene (HMGA2) polymorphisms as the most relevant variants contributing to height variability. Animal models and deletions in humans suggest that alterations of HMGA2 might be relevant in causing short stature. Together, these observations led us to investigate the involvement of HMGA2 in idiopathic short stature (ISS) through an association study and a mutation screening. We conducted an association study (155 ISS patients and 318 normal stature controls) with three HMGA2 single-nucleotide polymorphisms (SNPs) (SNPs rs1042725, rs7968682, and rs7968902) using a TaqMan-based assay. The patients were then analyzed by direct sequencing and multiplex ligation-dependent probe amplification (MLPA) to detect point mutations and genomic micro-rearrangements. Considering a recessive model, an OR value >1 was observed for genotypes rs7968682 TT (Odds ratio (OR) = 1.72, confidence interval (CI): 1.14–2.58) and rs1042725 TT (OR = 1.51, CI: 1.00–2.28) in accordance to the effect exhibited by the single alleles in the general population. None of the patients carried possibly causative HMGA2 mutations. Besides the already known role in determining variability in human height, HMGA2 polymorphisms also contribute to susceptibility to ISS. Moreover, we here report the first mutation screening performed in ISS concluding that HMGA2 has not a significant impact on the monogenic form of ISS.