Central precocious puberty

Summary

Central precocious puberty (MONDO:0019165) is a disease (an umbrella term covering 7 Mondo subtypes) caused by DLK1 (GenCC Strong), with 1 cohort gene (14 GWAS associations across 1 studies) and 25 clinical trials. Top therapeutic interventions include leuprolide, triptorelin, and gonadorelin.

At a glance

• Causal gene: DLK1 (GenCC Strong)
• Umbrella term: 7 Mondo subtypes
• Cohort genes: 1
• GWAS associations: 14
• ClinVar variants: 2
• Clinical trials: 25

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	central precocious puberty
Mondo ID	MONDO:0019165
EFO	EFO:0009029
MeSH	C562787
OMIM	176400
Orphanet	650063, 759
DOID	DOID:0112308
ICD-11	1749914533
SNOMED CT	237816004
UMLS	C0342543
MedGen	90985
GARD	0016546
Is cancer (heuristic)	no

Also known as: gonadotropin-dependant precocious puberty · gonadotropin-dependent precocious puberty · precocious puberty, central

Data availability: 2 ClinVar variants · 14 GWAS associations (1 study) · 1 GenCC gene-disease record · 1 cell line.

Disease family

An umbrella term covering 7 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › reproductive system disorder › gonadal disorder › precocious puberty › central precocious puberty

Related subtypes (2): peripheral precocious puberty, precocious puberty in female

Subtypes (7): central precocious puberty 1, precocious puberty, central, 2, idiopathic central precocious puberty, secondary central precocious puberty, central precocious puberty in male, genetic central precocious puberty in female, secondary central precocious puberty in female

Genetics & variants

GWAS landscape

14 GWAS associations across 1 studies. Top hits map to 14 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs1024889	7e-22	SAMMSON	A	10.67
rs11130329	3e-09	STIMATE-MUSTN1, STIMATE	C	7.65
rs56698321	3e-08	IL23R, C1orf141	A	5.49
rs12662085	6e-08	OFCC1	C	7.91
rs117195585	1e-07	DBX2-AS1, PLEKHA8P1	G	4.83
rs4543136	1e-07	Y_RNA - LINC01095	A	15.54
rs76540613	2e-07	LINC02964	A	4.43
rs118156955	7e-07	RPL23AP28 - PAX3	T	4.25
rs4654084	9e-07	SMYD3	G	3.03
rs2347637	1e-06	ESR1	G	4.73
rs7851008	3e-06	LINC01507	G	2
rs77000039	3e-06	LINC02763 - NCAM1-AS2	A	2.81
rs9997440	5e-06	LINC02497	A	2.83
rs56810982	8e-06	PRKCQ	A	1.94

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90027238	Lin WD	2021	256	0	Genetic factors of idiopathic central precocious puberty and their polygenic risk in early puberty.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	14

MAF distribution

Bucket	Variants
common (>=0.05)	11
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	3

Functional consequences

Consequence	Count
intron_variant	10
intergenic_variant	4

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs1024889	3	70414179	A>G	0.05	intergenic_variant	SAMMSON	7e-22	Tier 4: intronic/intergenic
rs11130329	3	52862839	C>A,G	0.05	intron_variant	STIMATE-MUSTN1, STIMATE	3e-09	Tier 4: intronic/intergenic
rs56698321	1	67205695	T>A	0.05	intron_variant	IL23R, C1orf141	3e-08	Tier 4: intronic/intergenic
rs12662085	6	9894200	C>T	0.05	intron_variant	OFCC1	6e-08	Tier 4: intronic/intergenic
rs117195585	12	45147536	A>G		intron_variant	DBX2-AS1, PLEKHA8P1	1e-07	Tier 4: intronic/intergenic
rs4543136	4	145972800	A>C,G,T	0.05	intron_variant	Y_RNA - LINC01095	1e-07	Tier 4: intronic/intergenic
rs76540613	8	125761515	C>A,T	0.05	intron_variant	LINC02964	2e-07	Tier 4: intronic/intergenic
rs118156955	2	222131550	G>A,T		intergenic_variant	RPL23AP28 - PAX3	7e-07	Tier 4: intronic/intergenic
rs4654084	1	245760413	T>G	0.05	intron_variant	SMYD3	9e-07	Tier 4: intronic/intergenic
rs2347637	6	151707344	T>G	0.05	intron_variant	ESR1	1e-06	Tier 4: intronic/intergenic
rs7851008	9	79981586	G>A	0.05	intergenic_variant	LINC01507	3e-06	Tier 4: intronic/intergenic
rs77000039	11	112808338	A>G		intergenic_variant	LINC02763 - NCAM1-AS2	3e-06	Tier 4: intronic/intergenic
rs9997440	4	31206989	A>C,T	0.05	intron_variant	LINC02497	5e-06	Tier 4: intronic/intergenic
rs56810982	10	6554370	A>G,T	0.05	intron_variant	PRKCQ	8e-06	Tier 4: intronic/intergenic

ClinVar germline variants

2 retrieved; paginated sample, class counts are floors:

1 likely pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
2506570	NM_003836.7(DLK1):c.357C>G (p.Tyr119Ter)	DLK1	Likely pathogenic	no assertion criteria provided
2506571	NM_003836.7(DLK1):c.67+78C>T	DLK1	Uncertain significance	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 1 · Orphanet: 8 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
DLK1	Strong	Autosomal dominant	central precocious puberty

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DLK1	Orphanet:254525	Temple syndrome due to paternal 14q32.2 microdeletion
DLK1	Orphanet:254528	Kagami-Ogata syndrome due to maternal 14q32.2 microdeletion
DLK1	Orphanet:254531	Temple syndrome due to paternal 14q32.2 hypomethylation
DLK1	Orphanet:254534	Kagami-Ogata syndrome due to maternal 14q32.2 hypermethylation
DLK1	Orphanet:650077	Genetic central precocious puberty in female
DLK1	Orphanet:650097	Genetic central precocious puberty in male
DLK1	Orphanet:96184	Temple syndrome due to maternal uniparental disomy of chromosome 14
DLK1	Orphanet:96334	Kagami-Ogata syndrome due to paternal uniparental disomy of chromosome 14

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DLK1	HGNC:2907	ENSG00000185559	P80370	Protein delta homolog 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DLK1	Protein delta homolog 1	May have a role in neuroendocrine differentiation.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DLK1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal cortex	1
right adrenal gland	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DLK1	199	broad	marker	right adrenal gland cortex, right adrenal gland, adrenal cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DLK1	186

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DLK1	P80370	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Activated NOTCH1 Transmits Signal to the Nucleus	1	356.9×	0.003	DLK1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of bone remodeling	1	2808.7×	0.002	DLK1
positive regulation of bone resorption	1	991.3×	0.003	DLK1
negative regulation of ossification	1	624.1×	0.003	DLK1
positive regulation of osteoclast differentiation	1	581.1×	0.003	DLK1
negative regulation of Notch signaling pathway	1	432.1×	0.003	DLK1
negative regulation of osteoblast differentiation	1	295.6×	0.004	DLK1
cell differentiation	1	29.1×	0.034	DLK1

Therapeutics

Drugs indicated for this disease

0 approved, 2 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Histrelin	Phase 3 (in late-stage trials)
Triptorelin	Phase 3 (in late-stage trials)

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
DLK1	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DLK1	15	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	DLK1
AXITINIB	4	DLK1
NERATINIB	4	DLK1
BOSUTINIB	4	DLK1
SUNITINIB	4	DLK1
CRIZOTINIB	4	DLK1
CEP-1347	3	DLK1
DOVITINIB	3	DLK1
LESTAURTINIB	3	DLK1
SU-014813	2	DLK1
TOZASERTIB	2	DLK1
PELITINIB	2	DLK1
KW-2449	1	DLK1
GDC-0134	1	DLK1
AST-487	1	DLK1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
DLK1	51	Binding:51

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

15 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
FEDRATINIB	4	DLK1
AXITINIB	4	DLK1
NERATINIB	4	DLK1
BOSUTINIB	4	DLK1
SUNITINIB	4	DLK1
CRIZOTINIB	4	DLK1
CEP-1347	3	DLK1
DOVITINIB	3	DLK1
LESTAURTINIB	3	DLK1
SU-014813	2	DLK1
TOZASERTIB	2	DLK1
PELITINIB	2	DLK1
KW-2449	1	DLK1
GDC-0134	1	DLK1
AST-487	1	DLK1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	DLK1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 25.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	10
PHASE4	8
Not specified	7

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06487143	PHASE4	NOT_YET_RECRUITING	Efficacy, Metabolism and BMD of the 3-month TP Compared to the 1-month TP in ICPP
NCT00438217	PHASE4	UNKNOWN	Analysis of Genetic and Environmental Parameters Influencing Growth Rate of Precocious Puberty Children
NCT01634321	PHASE4	COMPLETED	The Clinical Trial to Evaluate the Efficacy and Safety of Luphere Depot Inj. 3.75mg(Leuprolide Acetate 3.75mg) in Patients With Precocious Puberty
NCT02427958	PHASE4	COMPLETED	A Study to Assess the Safety and Efficacy of Leuprorelin in Central Precocious Puberty in Chinese Participants
NCT02920515	PHASE4	COMPLETED	Study of Comprehensive Diagnosis and Treatment for Children Precocious Puberty
NCT02974270	PHASE4	UNKNOWN	Analysis of Body Mass Index in Central Precocious Puberty Patients Treated With Leuprolide Acetate
NCT03316482	PHASE4	COMPLETED	Leuprorelin Acetate DPS (Leuplin DPS) Treatment Quarterly in Patients With Central Precocious Puberty
NCT05341115	PHASE4	COMPLETED	A Study of Leuprolide Acetate Depot in Children With Central Precocious Puberty
NCT06129539	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Assess the Efficacy, Safety, and Pharmacokinetics of Debio 4326 in Pediatric Participants With Central Precocious Puberty (LIBELULA™ Clinical Trial)
NCT00667446	PHASE3	COMPLETED	Safety Extension Study Of Leuprolide Acetate (Lupron Depot) In The Treatment Of Central Precocious Puberty
NCT00779103	PHASE3	COMPLETED	Histrelin Subcutaneous Implant in Children With Central Precocious Puberty
NCT01278290	PHASE3	COMPLETED	Comparative Validation of the Triptorelin Test for the Diagnosis of CPP in Girls
NCT01467882	PHASE3	COMPLETED	Efficacy, Safety, and Pharmacokinetics (PK) of Triptorelin 6-month Formulation in Patients With Central Precocious Puberty
NCT02452931	PHASE3	COMPLETED	Study of Leuprolide Acetate Injectable Suspension in the Treatment of Central Precocious Puberty
NCT03695237	PHASE3	COMPLETED	A Study to Evaluate Leuprolide Acetate 45 mg 6-Month Formulation in Children With Central Precocious Puberty (CPP)
NCT04736602	PHASE3	COMPLETED	Efficacy and Safety Study of Triptorelin 3-Month Formulation in Chinese Children With Central Precocious Puberty.
NCT05029622	PHASE3	COMPLETED	A Study to Assess the Efficacy and Safety of the Triptorelin 6-month Formulation in Paediatric Participants With Central Precocious Puberty.
NCT06025409	PHASE3	UNKNOWN	Evaluate the Efficacy and Safety of DWJ108J
NCT06720844	Not specified	RECRUITING	Idiopathic Central Precocious Puberty and Associated Neurodevelopmental Syndromes and Pathologies: Evaluation of Frequency and Comparison of Diagnostic and Developmental Characteristics
NCT07411001	Not specified	ACTIVE_NOT_RECRUITING	Hypiend - Multicomponent Behavioral Intervention in Pre-puberal Children (Hypiend-PPC)
NCT02006680	Not specified	TERMINATED	Markers of Pubertal Suppression During Therapy for Precocious Puberty
NCT02993926	Not specified	COMPLETED	A Study to Assess the Safety and Efficacy of Enantone (Leuprorelin) in Central Precocious Puberty (CPP) Among Chinese Participants
NCT05341128	Not specified	COMPLETED	A Study of Medical Records From Children With Central Precocious Puberty (CPP) in China
NCT06720623	Not specified	COMPLETED	Diagnostic Power of Basal LH Compared to Peak LH After Stimulus Test in the Diagnosis of Central Precocious Puberty
NCT07359092	Not specified	COMPLETED	Spexin and Phoenixin-20 in Girls With Central Precocious Puberty

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
LEUPROLIDE	4	7
TRIPTORELIN	4	5
GONADORELIN	4	2
HISTRELIN	4	1
CHEMBL4073387	0	5
CHEMBL4068871	0	2
CHEMBL2370644	0	1