Genetic variants of the DLK1, KISS1R, MKRN3 genes in girls with precocious puberty

Precocious puberty (PP, E30.1, Е22.8, Е30.9 according to ICD 10, MIM 176400, 615346) in children is a disorder in which secondary sexual characteristics appear earlier than the age norm. The timing of puberty is regulated by a complex interaction of genetic and epigenetic factors, as well as environmental and nutritional factors. This study aimed to search for pathogenic, likely pathogenic variants or variants of uncertain significance (VUS) in the KISS1, GPR54, DLK1, and MKRN3 genes in patients with the clinical picture of PP and normal karyotype by massive parallel sequencing. All identified genetic variants were confirmed by Sanger sequencing. The pathogenicity of identified genetic variants and the functional significance of the protein synthesized by them were analyzed according to recommendations for interpretation of NGS analysis results using online algorithms for pathogenicity prediction (Variant Effect Predictor, Franklin, Varsome, and PolyPhen2). Clinically significant genetic variants were detected in the heterozygous state in the KISS1R, DLK1, and MKRN3 genes in 5 of 52 probands (9.6 %) with PP, including 3 of 33 (9.1 %) in the group with central PP and 2 of 19 (10.5 %) in the group with gonadotropin-independent PP. Two children with gonadotropin-independent PP had VUS in the KISS1R gene (c.191T>C, p.Ile64Thr and c.233A>G, p.Asn78Ser), one of which was inherited from the father and the second, from the mother. The remaining patients with central PP had likely pathogenic genetic variants: DLK1:c.373delC(p.Gln125fs) de novo and DLK1:c.480delT(p.Gly161Alafs*49) of paternal origin. The third proband had a VUS variant in the MKRN3 gene (c.1487A>G, p.His496Arg), inherited from the father. All identified genetic variants were described for the first time in PP. Thus, in the present study, genetic variants in the KISS1R, DLK1, and MKRN3 genes in girls with PP were characterized.