Sazhenova E A, Vasilyeva O Yu, Fonova E A, Kankanam Pathiranage M B, Sambyalova A Yu, Khramova E E, Rychkova L V, Vasilyev S A, Lebedev I N
Research Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of Sciences, Tomsk, Russia.
Tomsk State University, Tomsk, Russia.
Vavilovskii Zhurnal Genet Selektsii. 2025 Apr;29(2):301-309. doi: 10.18699/vjgb-25-33.
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.
儿童性早熟（根据国际疾病分类第10版为PP，E30.1、E22.8、E30.9，孟德尔遗传在线编号176400、615346）是一种继发性特征出现早于年龄标准的疾病。青春期的时间由遗传和表观遗传因素以及环境和营养因素的复杂相互作用调节。本研究旨在通过大规模平行测序，在具有性早熟临床表现且核型正常的患者中，寻找KISS1、GPR54、DLK1和MKRN3基因中的致病、可能致病变异或意义未明的变异（VUS）。所有鉴定出的基因变异均通过桑格测序进行确认。根据使用致病性预测在线算法（变异效应预测器、富兰克林、Varsome和多酚氧化酶2）解释二代测序分析结果的建议，分析鉴定出的基因变异的致病性及其合成蛋白质的功能意义。在52名性早熟先证者中的5名（9.6%）中，在KISS1R、DLK1和MKRN3基因的杂合状态中检测到具有临床意义的基因变异，其中中枢性性早熟组33名中的3名（9.1%），非促性腺激素依赖性性早熟组19名中的2名（10.5%）。两名非促性腺激素依赖性性早熟儿童在KISS1R基因中有VUS（c.191T>C，p.Ile64Thr和c.233A>G，p.Asn78Ser），其中一个来自父亲，另一个来自母亲。其余中枢性性早熟患者有可能致病的基因变异：DLK1:c.373delC（p.Gln125fs）新发变异和父源的DLK1:c.480delT（p.Gly161Alafs*49）。第三名先证者在MKRN3基因中有一个VUS变异（c.1487A>G，p.His496Arg），来自父亲。所有鉴定出的基因变异在性早熟中均为首次描述。因此，在本研究中，对性早熟女孩的KISS1R、DLK1和MKRN3基因中的基因变异进行了特征分析。
