Association Study Between NOTCH2 Gene and Idiopathic Central Precocious Puberty in Korean Girls

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’s 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.