Peripheral precocious puberty

Summary

Peripheral precocious puberty (MONDO:0015791) is a disease with 5 cohort genes.

At a glance

• Cohort genes: 5
• ClinVar variants: 6

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	peripheral precocious puberty
Mondo ID	MONDO:0015791
Orphanet	178040
ICD-11	1495024153
SNOMED CT	736606009
UMLS	C5680513
MedGen	1842596
GARD	0020141
Is cancer (heuristic)	no

Also known as: GIPP · gonadotropin independent precocious puberty · gonadotropin-independent precocious puberty · precocious pseudopuberty

Data availability: 6 ClinVar variants.

Disease family

An umbrella term covering 1 Mondo subtype.

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

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

Subtypes (1): familial male-limited precocious puberty

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

6 retrieved; paginated sample, class counts are floors:

6 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
1064507	NM_001378964.1(CDON):c.1109T>C (p.Val370Ala)	CDON	Uncertain significance	criteria provided, single submitter
1064515	NM_001291415.2(KDM6A):c.139G>A (p.Glu47Lys)	KDM6A	Uncertain significance	no assertion criteria provided
1064513	NM_002303.6(LEPR):c.2728C>T (p.Pro910Ser)	LEPR	Uncertain significance	no assertion criteria provided
1064506	NM_003611.3(OFD1):c.951G>T (p.Gln317His)	OFD1	Uncertain significance	no assertion criteria provided
1064514	NM_003611.3(OFD1):c.950A>G (p.Gln317Arg)	OFD1	Uncertain significance	no assertion criteria provided
1064517	NM_001166114.2(PNPLA6):c.46A>T (p.Lys16Ter)	PNPLA6	Uncertain significance	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 19 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KDM6A	Orphanet:2322	Kabuki syndrome
PNPLA6	Orphanet:1173	Cerebellar ataxia-hypogonadism syndrome
PNPLA6	Orphanet:1180	Ataxia-hypogonadism-choroidal dystrophy syndrome
PNPLA6	Orphanet:139480	Autosomal recessive spastic paraplegia type 39
PNPLA6	Orphanet:2377	Laurence-Moon syndrome
PNPLA6	Orphanet:3363	Trichomegaly-retina pigmentary degeneration-dwarfism syndrome
CDON	Orphanet:220386	Semilobar holoprosencephaly
CDON	Orphanet:280195	Septopreoptic holoprosencephaly
CDON	Orphanet:280200	Microform holoprosencephaly
CDON	Orphanet:93924	Lobar holoprosencephaly
CDON	Orphanet:93925	Alobar holoprosencephaly
CDON	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly
CDON	Orphanet:95496	Pituitary stalk interruption syndrome
OFD1	Orphanet:244	Primary ciliary dyskinesia
OFD1	Orphanet:2750	Orofaciodigital syndrome type 1
OFD1	Orphanet:2754	Orofaciodigital syndrome type 6
OFD1	Orphanet:475	Isolated Joubert syndrome
OFD1	Orphanet:791	Retinitis pigmentosa
LEPR	Orphanet:179494	Obesity due to leptin receptor gene deficiency

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KDM6A	HGNC:12637	ENSG00000147050	O15550	Lysine-specific demethylase 6A	clinvar
PNPLA6	HGNC:16268	ENSG00000032444	Q8IY17	Patatin-like phospholipase domain-containing protein 6	clinvar
CDON	HGNC:17104	ENSG00000064309	Q4KMG0	Cell adhesion molecule-related/down-regulated by oncogenes	clinvar
OFD1	HGNC:2567	ENSG00000046651	O75665	Centriole and centriolar satellite protein OFD1	clinvar
LEPR	HGNC:6554	ENSG00000116678	P48357	Leptin receptor	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KDM6A	Lysine-specific demethylase 6A	Histone demethylase that specifically demethylates ‘Lys-27’ of histone H3, thereby playing a central role in histone code.
PNPLA6	Patatin-like phospholipase domain-containing protein 6	Phospholipase B that deacylates intracellular phosphatidylcholine (PtdCho), generating glycerophosphocholine (GroPtdCho).
CDON	Cell adhesion molecule-related/down-regulated by oncogenes	Component of a cell-surface receptor complex that mediates cell-cell interactions between muscle precursor cells.
OFD1	Centriole and centriolar satellite protein OFD1	Component of the centrioles controlling mother and daughter centrioles length.
LEPR	Leptin receptor	Receptor for hormone LEP/leptin.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.6

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
Antibody/Immunoglobulin	2	11.7×	0.033
Enzyme (other)	1	2.4×	0.530
Other/Unknown	2	0.7×	0.877

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KDM6A	Enzyme (other)	yes	1.14.11.68	JmjC_dom, TPR-like_helical_dom_sf, TPR_rpt
PNPLA6	Other/Unknown	no		cNMP-bd_dom, LysoPLipase_patatin_CS, PNPLA_dom
CDON	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom
OFD1	Other/Unknown	no		LisH, OFD1
LEPR	Antibody/Immunoglobulin	yes		Hematopoietin_rcpt_Gp130_CS, Hempt_rcpt_S_F1_CS, FN3_dom

Expression context

Cohort genes with no expression data: 0.

4 cohort genes 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bone marrow cell	1
oocyte	1
secondary oocyte	1
granulocyte	1
metanephros cortex	1
upper lobe of left lung	1
calcaneal tendon	1
ganglionic eminence	1
ventricular zone	1
bronchial epithelial cell	1
cervix squamous epithelium	1
sperm	1
choroid plexus epithelium	1
trabecular bone tissue	1
trigeminal ganglion	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KDM6A	286	ubiquitous	yes	secondary oocyte, oocyte, bone marrow cell
PNPLA6	276	ubiquitous	marker	granulocyte, metanephros cortex, upper lobe of left lung
CDON	222	ubiquitous	marker	ventricular zone, ganglionic eminence, calcaneal tendon
OFD1	288	ubiquitous	marker	sperm, bronchial epithelial cell, cervix squamous epithelium
LEPR	272	broad	marker	trabecular bone tissue, choroid plexus epithelium, trigeminal ganglion

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KDM6A	8,825
OFD1	2,878
PNPLA6	2,676
LEPR	2,243
CDON	1,065

Structural data

PDB: 3 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LEPR	P48357	9
KDM6A	O15550	5
CDON	Q4KMG0	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PNPLA6	Q8IY17	69.75
OFD1	O75665	68.41

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 31. Enrichment computed across 5 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Glycerophospholipid catabolism	1	326.3×	0.049	PNPLA6
Ligand-receptor interactions	1	285.5×	0.049	CDON
Signaling by Leptin	1	207.6×	0.049	LEPR
Maternal to zygotic transition (MZT)	1	142.8×	0.049	KDM6A
Activation of SMO	1	126.9×	0.049	CDON
Activation of HOX genes during differentiation	1	87.8×	0.053	KDM6A
Myogenesis	1	76.1×	0.053	CDON
Formation of WDR5-containing histone-modifying complexes	1	53.1×	0.053	KDM6A
HDMs demethylate histones	1	45.7×	0.053	KDM6A
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1	43.1×	0.053	KDM6A
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	1	39.4×	0.053	KDM6A
Signaling by Hedgehog	1	36.8×	0.053	CDON
Hedgehog ‘off’ state	1	35.7×	0.053	OFD1
Chromatin modifications during the maternal to zygotic transition (MZT)	1	32.6×	0.053	KDM6A
Loss of Nlp from mitotic centrosomes	1	31.7×	0.053	OFD1
Loss of proteins required for interphase microtubule organization from the centrosome	1	31.7×	0.053	OFD1
Hedgehog ‘on’ state	1	31.7×	0.053	CDON
Epigenetic regulation by WDR5-containing histone modifying complexes	1	30.9×	0.053	KDM6A
AURKA Activation by TPX2	1	30.4×	0.053	OFD1
Recruitment of mitotic centrosome proteins and complexes	1	27.2×	0.056	OFD1
Regulation of PLK1 Activity at G2/M Transition	1	25.4×	0.056	OFD1
Recruitment of NuMA to mitotic centrosomes	1	23.3×	0.056	OFD1
Anchoring of the basal body to the plasma membrane	1	22.6×	0.056	OFD1
Developmental Biology	2	5.8×	0.056	KDM6A, CDON
Activation of anterior HOX genes in hindbrain development during early embryogenesis	1	18.3×	0.066	KDM6A
MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis	1	16.6×	0.069	KDM6A
Chromatin organization	1	16.3×	0.069	KDM6A
Chromatin modifying enzymes	1	14.5×	0.073	KDM6A
Epigenetic regulation of gene expression	1	14.3×	0.073	KDM6A
Gene expression (Transcription)	1	3.6×	0.259	KDM6A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
embryonic body morphogenesis	2	842.6×	1e-04	CDON, OFD1
multicellular organism development	1	1685.2×	0.009	LEPR
regulation of transport	1	1685.2×	0.009	LEPR
obsolete negative regulation of fibroblast growth factor receptor signaling pathway involved in neural plate anterior/posterior pattern formation	1	1685.2×	0.009	OFD1
sexual reproduction	1	1123.5×	0.010	LEPR
regulation of bone remodeling	1	561.7×	0.011	LEPR
positive regulation of skeletal muscle tissue development	1	561.7×	0.011	CDON
leptin-mediated signaling pathway	1	481.5×	0.011	LEPR
response to leptin	1	481.5×	0.011	LEPR
embryonic retina morphogenesis in camera-type eye	1	481.5×	0.011	CDON
bone growth	1	481.5×	0.011	LEPR
skeletal muscle satellite cell differentiation	1	421.3×	0.011	CDON
positive regulation of small GTPase mediated signal transduction	1	421.3×	0.011	CDON
regulation of feeding behavior	1	374.5×	0.011	LEPR
negative regulation of biomineral tissue development	1	306.4×	0.012	CDON
cellular response to vitamin D	1	306.4×	0.012	CDON
epithelial cilium movement involved in determination of left/right asymmetry	1	259.3×	0.013	OFD1
energy reserve metabolic process	1	210.7×	0.014	LEPR
glycerophospholipid catabolic process	1	210.7×	0.014	PNPLA6
glial cell proliferation	1	177.4×	0.016	LEPR
negative regulation of gluconeogenesis	1	160.5×	0.016	LEPR
phosphatidylcholine metabolic process	1	160.5×	0.016	PNPLA6
myoblast fusion	1	120.4×	0.019	CDON
central nervous system neuron differentiation	1	120.4×	0.019	CDON
positive regulation of neuroblast proliferation	1	116.2×	0.019	CDON
cell surface receptor signaling pathway via STAT	1	112.3×	0.019	LEPR
axoneme assembly	1	108.7×	0.019	OFD1
cell fate specification	1	105.3×	0.019	CDON
glycogen metabolic process	1	105.3×	0.019	LEPR
T cell differentiation	1	76.6×	0.025	LEPR

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 5 evidence-associated genes (60%) 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
KDM6A	DEFERIPRONE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KDM6A	1	4
PNPLA6	0	0
CDON	0	0
OFD1	0	0
LEPR	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
DEFERIPRONE	4	KDM6A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
KDM6A	40	Binding:36, Functional:4
LEPR	3	Binding:3
PNPLA6	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
KDM6A	1.14.11.68	[histone H3]-trimethyl-L-lysine27 demethylase

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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)
DEFERIPRONE	4	KDM6A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	KDM6A
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	CDON, LEPR
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	PNPLA6, OFD1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PNPLA6	1	—
CDON	0	—
OFD1	0	—
LEPR	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.