{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T21:53:55Z","timestamp":1785189235265,"version":"3.55.0"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,9,24]],"date-time":"2021-09-24T00:00:00Z","timestamp":1632441600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004117","name":"A.G. Leventis Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004117","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Central precocious puberty (CPP) due to premature activation of GnRH secretion results in early epiphyseal fusion and to a significant compromise in the achieved final adult height. Currently, few genetic determinants of children with CPP have been described. In this translational study, rare sequence variants in <jats:italic>MKRN3<\/jats:italic>, <jats:italic>DLK1<\/jats:italic>, <jats:italic>KISS1<\/jats:italic>, and <jats:italic>KISS1R<\/jats:italic> genes were investigated in patients with CPP.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Fifty-four index girls and two index boys with CPP were first tested by Sanger sequencing for the <jats:italic>MKRN3<\/jats:italic> gene. All children found negative (<jats:italic>n<\/jats:italic> = 44) for the <jats:italic>MKRN3<\/jats:italic> gene were further investigated by whole exome sequencing (WES). In the latter analysis, the status of variants in genes known to be related with pubertal timing was compared with an in-house Cypriot control cohort (n = 43). The identified rare variants were initially examined by <jats:italic>in silico<\/jats:italic> computational algorithms and confirmed by Sanger sequencing. Additionally, a genetic network for the <jats:italic>MKRN3<\/jats:italic> gene, mimicking a holistic regulatory depiction of the crosstalk between <jats:italic>MKRN3<\/jats:italic> and other genes was designed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Three previously described pathogenic <jats:italic>MKRN3<\/jats:italic> variants located in the coding region of the gene were identified in 12 index girls with CPP. The most prevalent pathogenic <jats:italic>MKRN3<\/jats:italic> variant p.Gly312Asp was exclusively found among the Cypriot CPP cohort, indicating a founder effect phenomenon. Seven other CPP girls harbored rare likely pathogenic upstream variants in the <jats:italic>MKRN3.<\/jats:italic> Among the 44 CPP patients submitted to WES, nine rare <jats:italic>DLK1<\/jats:italic> variants were identified in 11 girls, two rare <jats:italic>KISS1<\/jats:italic> variants in six girls, and two rare <jats:italic>MAGEL2<\/jats:italic> variants in five girls. Interestingly, the frequent variant rs10407968 (p.Gly8Ter) of the <jats:italic>KISS1R<\/jats:italic> gene appeared to be less frequent in the cohort of patients with\u00a0CPP.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The results of the present study confirm the importance of the MKRN3-imprinted gene in genetics of CPP and its key role in pubertal timing. Overall, the results of the present study have emphasized the importance of an approach that aligns genetics and clinical aspects, which is necessary for the management and treatment of CPP.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2021.745048","type":"journal-article","created":{"date-parts":[[2021,9,25]],"date-time":"2021-09-25T00:52:25Z","timestamp":1632531145000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["Pathogenic and Low-Frequency Variants in Children With Central Precocious Puberty"],"prefix":"10.3389","volume":"12","author":[{"given":"Vassos","family":"Neocleous","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavlos","family":"Fanis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meropi","family":"Toumba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Gorka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioanna","family":"Kousiappa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George A.","family":"Tanteles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michalis","family":"Iasonides","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas C.","family":"Nicolaides","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiolanda P.","family":"Christou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyriaki","family":"Michailidou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stella","family":"Nicolaou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Savvas S.","family":"Papacostas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Athanasios","family":"Christoforidis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Kyriakou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitrios","family":"Vlachakis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicos","family":"Skordis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonidas A.","family":"Phylactou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,9,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1210\/edrv.22.1.0418","article-title":"Neurobiological Mechanisms of the Onset of Puberty in Primates","volume":"22","author":"Terasawa","year":"2001","journal-title":"Endocr Rev"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1210\/er.2002-0019","article-title":"The Timing of Normal Puberty and the Age Limits of Sexual Precocity: Variations Around the World, Secular Trends, and Changes After Migration","volume":"24","author":"Parent","year":"2003","journal-title":"Endocr Rev"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.84.2.5533","article-title":"Precocious Puberty: Who has it? 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