Methylation index of the DLK1 and MKRN3 genes in precocious puberty

Precocious puberty (PP, OMIM 176400, 615346) is an autosomal dominant disorder caused by the premature reactivation of the hypothalamic-pituitary-gonadal axis. Genetic, epigenetic, and environmental factors play a decisive role in determining the timing of puberty. In recent years, genetic variants in the KISS1, KISS1R, MKRN3, and DLK1 genes have been identified as genetic causes of PP. The MKRN3 and DLK1 genes are imprinted, and therefore epigenetic modifications, such as DNA methylation, which alter the expression of these genes, can also contribute to the development of PP. The aim of this study is to determine the methylation index of the imprinting centers of the DLK1 and MKRN3 genes in girls with a clinical presentation of PP. The methylation index of the imprinting centers of the DLK1 and MKRN3 genes was analyzed in a group of 45 girls (age 7.2 ± 1.9 years) with a clinical presentation of PP and a normal karyotype using targeted massive parallel sequencing after sodium bisulfite treatment of DNA. The control group consisted of girls without PP (n = 15, age 7.9 ± 1.6 years). No significant age differences were observed between the groups (p > 0.8). Analysis of the methylation index of the imprinting centers of the DLK1 and MKRN3 genes revealed no significant differences between patients with PP and the control group. However, in the group of patients with isolated adrenarche, an increased methylation index of the imprinting center of the MKRN3 gene was observed (72 ± 7.84 vs 56.92 ± 9.44 %, p = 0.005). In the group of patients with central PP, 3.8 % of patients showed a decreased methylation index of the imprinting center of the DLK1 gene, and 11.5 % of probands had a decreased methylation index of the imprinting center of the MKRN3 gene. Thus, this study demonstrates that not only genetic variants but also alterations in the methylation index of the imprinting centers of the DLK1 and MKRN3 genes can contribute to the development of PP.

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