Isolated GH deficiency: mutation screening and copy number analysis of HMGA2 and CDK6 genes

Abstract

ObjectiveIn most patients, the genetic cause of isolated GH deficiency (IGHD) is unknown. By identifying several genes associated with height variability within the normal population, three separate genome-wide association studies provided new candidate genes for human growth disorders. We selected two of them for genetic screening of our IGHD population.AimWe aimed to determine whether high-mobility group A2 (HMGA2) and cyclin-dependent protein kinase 6 (CDK6) are involved in the pathogenicity of IGHD.MethodsWe directly sequenced coding regions and exon–intron boundaries of the genesHMGA2andCDK6in 105 Caucasian IGHD patients from the Dutch HYPOPIT study. In addition, we developed a new probe set of multiplex ligation-dependent probe amplification for both genes in order to detect copy number variations.ResultsIn one patient with classical IGHD phenotype, we identified a new heterozygous 20 bp deletion in the intronic region ofHMGA2(c.250-29_-9del), which was absent in the databases and healthy controls. Together, with recently published data concerning the 12q14 microdeletion syndrome, where patients with anHMGA2haploinsufficiency had proportionate short stature, this study provides further support of the important role for HMGA2 in growth. InCDK6, we found only known polymorphisms.ConclusionsThis study provides the first report of a deletion in theHMGA2gene that might be related to IGHD. We suggest that this gene is investigated as a second screening in patients with a classical IGHD phenotype in which mutations in classical candidate genes have been excluded.