vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/vjgb-25-33vavilov-4549Research ArticleМЕДИЦИНСКАЯ ГЕНЕТИКАMEDICAL GENETICSГенетические варианты генов DLK1, KISS1R, MKRN3 у девочек с преждевременным половым созреваниемGenetic variants of the DLK1, KISS1R, MKRN3 genes in girls with precocious pubertyhttps://orcid.org/0000-0003-3875-3932СаженоваЕ. А.SazhenovaE. A.

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Tomsk

elena.sazhenova@medgenetics.ruhttps://orcid.org/0000-0001-5797-0014ВасильеваО. Ю.VasilyevaO. Yu.

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Tomsk

https://orcid.org/0000-0002-1338-5451ФоноваЕ. А.FonovaE. A.

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Tomsk

https://orcid.org/0009-0004-9026-0582Канканам ПатиранагеМ. Б.Kankanam PathiranageM. B.

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Tomsk

https://orcid.org/0000-0001-5790-6282СамбяловаА. Ю.SambyalovaA. Yu.

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Irkutsk

https://orcid.org/0000-0002-8042-6276ХрамоваЕ. Е.KhramovaE. E.

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Irkutsk

https://orcid.org/0000-0003-2910-0737РычковаЛ. В.RychkovaL. V.

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 Irkutsk

https://orcid.org/0000-0002-5301-070XВасильевС. А.VasilyevS. A.

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Tomsk

https://orcid.org/0000-0002-0482-8046ЛебедевИ. Н.LebedevI. N.

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Tomsk

Научно-исследовательский институт медицинской генетики, Томский национальный исследовательский медицинский центр Российской академии наукРоссияResearch Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of SciencesRussian FederationНациональный исследовательский Томский государственный университетРоссияTomsk State UniversityRussian FederationНаучный центр проблем здоровья семьи и репродукции человекаРоссияScientific Center for Family Health and Human Reproduction ProblemsRussian Federation202511042025292301309Copyright © Саженова Е.А., Васильева О.Ю., Фонова Е.А., Канканам Патиранаге М.Б., Самбялова А.Ю., Храмова Е.Е., Рычкова Л.В., Васильев С.А., Лебедев И.Н., 20252025Саженова Е.А., Васильева О.Ю., Фонова Е.А., Канканам Патиранаге М.Б., Самбялова А.Ю., Храмова Е.Е., Рычкова Л.В., Васильев С.А., Лебедев И.Н.Sazhenova E.A., Vasilyeva O.Y., Fonova E.A., Kankanam Pathiranage M.B., Sambyalova A.Y., Khramova E.E., Rychkova L.V., Vasilyev S.A., Lebedev I.N.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/4549

Преждевременное половое созревание (ППС, Е30.1, Е22.8, Е30.9 по МКБ 10, MIM 176400, 615346) у детей – заболевание, при котором вторичные половые признаки появляются раньше возрастной нормы. Сроки полового созревания регулируются сложным взаимодействием генетических и эпигенетических факторов, а также факторов окружающей среды и питания. Цель настоящего исследования – поиск генетических причин формирования у девочек клинической картины ППС. Поиск клинически значимых генетических вариантов (патогенных, вероятно патогенных вариантов или вариантов с неопределенным клиническим значением (variant of uncertain significance, VUS)) проведен в генах KISS1, KISS1R (GPR54), DLK1 и MKRN3 у девочек с клинической картиной ППС и нормальным кариотипом методом таргетного массового параллельного секвенирования. Все найденные генетические варианты были подтверждены методом секвенирования ДНК по Сэнгеру. Патогенность идентифицированных генетических вариантов и функциональная значимость кодируемого ими белка проанализированы с использованием онлайн-алгоритмов прогнозирования патогенности Variant Effect Predictor, Franklin и Varsome, а также PolyPhen2 (согласно рекомендациям по интерпретации результатов анализа NGS). Клинически значимые генетические варианты были обнаружены в гетерозиготном состоянии в генах KISS1R, DLK1 и MKRN3 у 5 из 52 пробандов (9.6 %) с ППС, из них 3 из 33 (9.1 %) – в группе с центральным ППС и 2 из 19 (10.5 %) – в группе с гонадотропин-независимой формой ППС. Два ребенка с гонадотропин-независимой формой ППС имели VUS в гене KISS1R (c.191T>C, p.Ile64Thr и c.233A>G, p.Asn78Ser), один из которых был унаследован от отца, второй – от матери. У остальных пациентов с центральным ППС были вероятно патогенные генетические варианты DLK1:c.373delC(p.Gln125fs) de novo и DLK1:c.480delT(p.Gly161Alafs*49) отцовского происхождения. Еще один пробанд имел вариант VUS в гене MKRN3 (c.1487A>G, p.His496Arg), унаследованный от отца. Все выявленные генетические варианты описаны впервые при ППС. Таким образом, в настоящем исследовании найдены новые генетические варианты в генах KISS1R, DLK1 и MKRN3 у девочек с преждевременным половым созреванием.

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.

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The authors declare that there are no conflicts of interest present.