{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T10:08:52Z","timestamp":1785146932894,"version":"3.55.0"},"reference-count":45,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T00:00:00Z","timestamp":1785110400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Identifying genetic contributors to idiopathic central precocious puberty (CPP) beyond established monogenic causes remains a research priority, as most cases lack a resolved genetic basis. We performed comprehensive Sanger sequencing of all 34 coding exons of NOTCH2 in 100 Korean girls with idiopathic CPP and 100 age-matched healthy female controls. Among 55 identified sequence variants, including 11 missense variants, the primary finding was a statistically significant frequency difference for the NOTCH2 heterodimerization domain C (HD-C) subdomain variant p.Ile1689Phe: this variant was absent from all 200 CPP alleles while present in 6.5% of control alleles (Fisher\u2019s exact p = 0.0002), raising the hypothesis of a candidate protective association that requires independent replication before any causal inference can be drawn. Three additional missense variants, including p.Thr235Ser, p.Ala1361Thr, and the novel ankyrin (ANK) domain variant p.Ala1992Val, were identified exclusively in CPP patients as singletons; however, no pathogenic interpretation is warranted from these observations alone. This preliminary study reports a significant NOTCH2 variant frequency difference and raises the hypothesis that NOTCH2 coding variants may contribute to pubertal timing modulation within the Notch signaling pathway; independent replication and functional validation are required before causal conclusions can be established.<\/jats:p>","DOI":"10.3390\/ijms27156686","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T09:47:41Z","timestamp":1785145661000},"page":"6686","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Association Study Between NOTCH2 Gene and Idiopathic Central Precocious Puberty in Korean Girls"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0850-5279","authenticated-orcid":false,"given":"Young Suk","family":"Shim","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Ajou University School of Medicine, Suwon 164999, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyung Hee","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Ajou University School of Medicine, Suwon 164999, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min Hyung","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Ajou University School of Medicine, Suwon 164999, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae Hyuk","family":"Oh","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Ajou University School of Medicine, Suwon 164999, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hae Sang","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Ajou University School of Medicine, Suwon 164999, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3073","DOI":"10.1007\/s00431-021-04022-1","article-title":"Diagnosis and management of precocious sexual maturation: An updated review","volume":"180","author":"Cheuiche","year":"2021","journal-title":"Eur. J. Pediatr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"172","DOI":"10.3345\/cep.2021.00521","article-title":"Genetic factors in precocious puberty","volume":"65","author":"Shim","year":"2022","journal-title":"Clin. Exp. Pediatr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"211","DOI":"10.6065\/apem.2346238.119","article-title":"The role of MicroRNAs as fine-tuners in the onset of puberty: A comprehensive review","volume":"29","author":"Jeong","year":"2024","journal-title":"Ann. Pediatr. Endocrinol. Metab."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1080\/17446651.2019.1575726","article-title":"Update on central precocious puberty: From etiologies to outcomes","volume":"14","author":"Eugster","year":"2019","journal-title":"Expert Rev. Endocrinol. Metab."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1093\/nsr\/nwaa023","article-title":"MKRN3 regulates the epigenetic switch of mammalian puberty via ubiquitination of MBD3","volume":"7","author":"Li","year":"2020","journal-title":"Natl. Sci. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Livadas, S., and Chrousos, G.P. (2019). Molecular and Environmental Mechanisms Regulating Puberty Initiation: An Integrated Approach. Front. Endocrinol., 10.","DOI":"10.3389\/fendo.2019.00828"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"R107","DOI":"10.1530\/EJE-20-0103","article-title":"GENETICS IN ENDOCRINOLOGY: Genetic etiologies of central precocious puberty and the role of imprinted genes","volume":"183","author":"Roberts","year":"2020","journal-title":"Eur. J. Endocrinol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1093\/humrep\/deaa306","article-title":"Insights from the genetic characterization of central precocious puberty associated with multiple anomalies","volume":"36","author":"Canton","year":"2021","journal-title":"Hum. Reprod."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Neocleous, V., Fanis, P., Toumba, M., Gorka, B., Kousiappa, I., Tanteles, G.A., Iasonides, M., Nicolaides, N.C., Christou, Y.P., and Michailidou, K. (2021). Pathogenic and Low-Frequency Variants in Children With Central Precocious Puberty. Front. Endocrinol., 12.","DOI":"10.3389\/fendo.2021.745048"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1055\/s-0039-3400963","article-title":"DLK1, Notch Signaling and the Timing of Puberty","volume":"37","author":"Macedo","year":"2019","journal-title":"Semin. Reprod. Med."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Shim, Y.S., Lee, H.S., and Hwang, J.S. (2022). Aberrant Notch Signaling Pathway as a Potential Mechanism of Central Precocious Puberty. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23063332"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"dgaa461","DOI":"10.1210\/clinem\/dgaa461","article-title":"Novel Genetic and Biochemical Findings of DLK1 in Children with Central Precocious Puberty: A Brazilian-Spanish Study","volume":"105","author":"Montenegro","year":"2020","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1080\/09513590.2020.1760241","article-title":"Identification of rare missense mutations in NOTCH2 and HERC2 associated with familial central precocious puberty via whole-exome sequencing","volume":"36","author":"Lee","year":"2020","journal-title":"Gynecol. Endocrinol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1557","DOI":"10.1210\/jc.2016-3677","article-title":"Paternally Inherited DLK1 Deletion Associated With Familial Central Precocious Puberty","volume":"102","author":"Dauber","year":"2017","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"135","DOI":"10.3345\/kjp.2018.61.5.135","article-title":"The 2017 Korean National Growth Charts for children and adolescents: Development, improvement, and prospects","volume":"61","author":"Kim","year":"2018","journal-title":"Korean J. Pediatr."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1743","DOI":"10.1242\/dev.148007","article-title":"The developmental biology of genetic Notch disorders","volume":"144","author":"Andersson","year":"2017","journal-title":"Development"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1111\/dgd.12640","article-title":"Making sense out of missense mutations: Mechanistic dissection of Notch receptors through structure-function studies in Drosophila","volume":"62","author":"Yamamoto","year":"2020","journal-title":"Dev. Growth Differ."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1038\/ng.779","article-title":"Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss","volume":"43","author":"Simpson","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Aida, N., Ohno, T., and Azuma, T. (2022). Progress and Current Status in Hajdu-Cheney Syndrome with Focus on Novel Genetic Research. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231911374"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/S2213-8587(22)00339-4","article-title":"Molecular basis of normal and pathological puberty: From basic mechanisms to clinical implications","volume":"11","author":"Argente","year":"2023","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1093\/biolre\/ioac106","article-title":"Recent advances on the relationship between the delta-like noncanonical Notch ligand 1 system and central precocious puberty","volume":"107","author":"Lin","year":"2022","journal-title":"Biol. Reprod."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1210\/me.2013-1425","article-title":"Notch signaling in postnatal pituitary expansion: Proliferation, progenitors, and cell specification","volume":"28","author":"Nantie","year":"2014","journal-title":"Mol. Endocrinol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2898","DOI":"10.1210\/me.2005-0394","article-title":"Persistent Expression of Notch2 Delays Gonadotrope Differentiation","volume":"20","author":"Raetzman","year":"2006","journal-title":"Mol. Endocrinol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e161998","DOI":"10.1172\/jci.insight.161998","article-title":"Defective jagged-1 signaling affects GnRH development and contributes to congenital hypogonadotropic hypogonadism","volume":"8","author":"Cotellessa","year":"2023","journal-title":"JCI Insight"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1210\/endrev\/bnac020","article-title":"The Congenital and Acquired Mechanisms Implicated in the Etiology of Central Precocious Puberty","volume":"44","author":"Brito","year":"2023","journal-title":"Endocr. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"bvae228","DOI":"10.1210\/jendso\/bvae228","article-title":"Genetics and Epigenetics of Human Pubertal Timing: The Contribution of Genes Associated With Central Precocious Puberty","volume":"9","author":"Canton","year":"2025","journal-title":"J. Endocr. Soc."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e70251","DOI":"10.1111\/liv.70251","article-title":"Phenotypic Divergence of JAG1- and NOTCH2-Associated Alagille Syndrome & Disease-Specific NOTCH2 Variant Classification Guidelines","volume":"45","author":"Vandriel","year":"2025","journal-title":"Liver Int."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"421","DOI":"10.3343\/alm.2019.39.5.421","article-title":"Challenges and Considerations in Sequence Variant Interpretation for Mendelian Disorders","volume":"39","author":"Kim","year":"2019","journal-title":"Ann. Lab. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e67","DOI":"10.1093\/nar\/gkp215","article-title":"Human Splicing Finder: An online bioinformatics tool to predict splicing signals","volume":"37","author":"Desmet","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.cell.2018.12.015","article-title":"Predicting Splicing from Primary Sequence with Deep Learning","volume":"176","author":"Jaganathan","year":"2019","journal-title":"Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1007\/978-1-60761-759-4_15","article-title":"Use of splicing reporter minigene assay to evaluate the effect on splicing of unclassified genetic variants","volume":"653","author":"Gaildrat","year":"2010","journal-title":"Methods Mol. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1758","DOI":"10.1210\/clinem\/dgac763","article-title":"Clinical and Genetic Characterization of Familial Central Precocious Puberty","volume":"108","author":"Tinano","year":"2023","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1038\/ng1847","article-title":"Principal components analysis corrects for stratification in genome-wide association studies","volume":"38","author":"Price","year":"2006","journal-title":"Nat. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Greulich, W.W., and Pyle, S.I. (1959). Radiologic Atlas of Skeletal Development of the Hand and Wrist, Stanford University Press. [2nd ed.].","DOI":"10.1097\/00000441-195909000-00030"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0889-8529(18)30279-2","article-title":"Physical changes of puberty","volume":"20","author":"Wheeler","year":"1991","journal-title":"Endocrinol. Metab. Clin. N. Am."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/S0022-3476(52)80205-7","article-title":"Tables for predicting adult height from skeletal age: Revised for use with the Greulich-Pyle hand standards","volume":"40","author":"Bayley","year":"1952","journal-title":"J. Pediatr."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Gordon, W.R., Vardar-Ulu, D., L\u2019Heureux, S., Ashworth, T., Malecki, M.J., Sanchez-Irizarry, C., McArthur, D.G., Histen, G., Mitchell, J.L., and Aster, J.C. (2009). Effects of S1 cleavage on the structure, surface export, and signaling activity of human Notch1 and Notch2. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0006613"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3812","DOI":"10.1093\/nar\/gkg509","article-title":"SIFT: Predicting amino acid changes that affect protein function","volume":"31","author":"Ng","year":"2003","journal-title":"Nucleic Acids Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/nmeth0410-248","article-title":"A method and server for predicting damaging missense mutations","volume":"7","author":"Adzhubei","year":"2010","journal-title":"Nat. Methods"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1038\/nmeth.2890","article-title":"MutationTaster2: Mutation prediction for the deep-sequencing age","volume":"11","author":"Schwarz","year":"2014","journal-title":"Nat. Methods"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"D886","DOI":"10.1093\/nar\/gky1016","article-title":"CADD: Predicting the deleteriousness of variants throughout the human genome","volume":"47","author":"Rentzsch","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1089\/1066527041410418","article-title":"Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals","volume":"11","author":"Yeo","year":"2004","journal-title":"J. Comput. Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/15\/6686\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T09:57:34Z","timestamp":1785146254000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/15\/6686"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,27]]},"references-count":45,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["ijms27156686"],"URL":"https:\/\/doi.org\/10.3390\/ijms27156686","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,27]]}}}