| Gene Symbol | Gene Name | Chromosomal Location | Inheritance Pattern | Protein Function | Type of Mutations Identified | Frequency/Prevalence in CPP |
|---|---|---|---|---|---|---|
| **MKRN3** | Makorin Ring Finger Protein 3 | **15q11.2** within the Prader-Willi syndrome critical region; **maternally imprinted / paternally expressed** | Familial CPP with **autosomal dominant inheritance and exclusive paternal transmission** due to imprinting | **Upstream inhibitor of GnRH secretion**; repressive neuroendocrine regulator of pubertal timing | Predominantly **loss-of-function germline variants**: nonsense, frameshift, splice-site, and missense variants. Examples noted in the literature include multiple familial LOF variants; recent reports describe **novel missense mutations with distinct effects on ubiquitination**. Functional effect: reduced inhibitory activity, permitting premature HPG-axis activation (pqac-00000003, pqac-00000013) | **Most common monogenic cause of CPP**. Review evidence states that among known monogenic causes, MKRN3 defects are the most frequent identified genetic cause (pqac-00000003, pqac-00000007). |
| **DLK1** | Delta Like Non-Canonical Notch Ligand 1 | **14q32** imprinted region; **maternally imprinted / paternally expressed** | Usually **paternal transmission** of pathogenic alleles in familial CPP because of imprinting; rare de novo cases reported | **Inhibitory regulator of Delta-Notch signaling**; transmembrane protein with soluble form; implicated in **pubertal timing** and links reproduction with metabolism | **Loss-of-function germline variants** including frameshift, splice-site, stop-gain, and start-loss variants. Specific examples: **c.372C>A (p.Cys124X)** stop-gain and **c.2T>G (p.Met1?, p.0)** start-loss in French girls; **c.288_289insC (p.Cys97Leufs*16)** in an affected family; **c.479delC (p.P160fs*50)** recurrent frameshift; **c.401_404+8del** splice-region deletion. Functional effect: absent or markedly reduced DLK1 production, loss of inhibitory signaling, and premature puberty; undetectable serum DLK1 reported in some carriers (pqac-00000006, pqac-00000010, pqac-00000011, pqac-00000015) | **Rare monogenic cause of CPP**. Multiple reviews and cohort studies describe DLK1 defects as uncommon compared with MKRN3, but clearly causal in familial non-syndromic CPP (pqac-00000003, pqac-00000006, pqac-00000015). |
| **KISS1** | KiSS-1 Metastasis Suppressor | **1q32** | Reported as **rare heterozygous activating** cause; inheritance not firmly established in most cases because reports are very limited | Encodes **kisspeptin**, a potent **activator of GnRH neurons** and key stimulator of the HPG axis | **Gain-of-function / activating variants** are reported in rare cases. Example cited in review literature: **p.Pro74Ser** kisspeptin variant in a boy with sporadic CPP; effect was **prolonged stimulatory signaling / increased resistance to degradation**, favoring premature GnRH activation (pqac-00000003, pqac-00000013) | **Very rare** cause of CPP; reviews emphasize that KISS1 mutations have been described but remain much less common than MKRN3 and rarer than DLK1-associated disease (pqac-00000003, pqac-00000013). |
| **KISS1R** | Kisspeptin Receptor (also known as GPR54) | **19p13.3** | Reported as **rare heterozygous activating** cause; inheritance pattern not well defined from limited case reports | G protein-coupled receptor for **kisspeptin**; mediates stimulatory signaling to GnRH neurons and drives gonadotropin release | **Activating missense variants**. Example cited in review literature: **p.Arg386Pro**, located in the receptor C-terminal tail, causing **prolonged intracellular signaling in response to kisspeptin** and premature HPG-axis activation (pqac-00000003, pqac-00000013) | **Very rare** monogenic cause; repeatedly described in reviews as an uncommon genetic etiology compared with MKRN3 and DLK1 (pqac-00000003, pqac-00000013). |


*Table: This table summarizes the principal monogenic causes of central precocious puberty discussed in the gathered literature, emphasizing imprinting effects, mutation classes, and relative frequency. It is useful for quickly comparing the major genes implicated in CPP and the mechanisms by which their variants alter pubertal timing.*