Delayed puberty, self-limited

Summary

Delayed puberty, self-limited (MONDO:0859205) is a disease with 4 cohort genes.

At a glance

• Cohort genes: 4
• ClinVar variants: 4

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	delayed puberty, self-limited
Mondo ID	MONDO:0859205
OMIM	619613
UMLS	C2874202
MedGen	1789612
Is cancer (heuristic)	no

Data availability: 4 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › reproductive system disorder › female reproductive system disorder › delayed puberty, self-limited

Related subtypes (33): ectopic pregnancy, pelvic inflammatory disease, endosalpingiosis, vaginal disorder, prolapse of female genital organ, Allen-Masters syndrome, fallopian tube disorder, vulvar disease, uterine disorder, gynatresia, Bartholin duct cyst, ovarian disorder, hymen, imperforate, preterm premature rupture of the membranes, mammary-digital-nail syndrome, Asherman syndrome, uterine cervical aplasia and agenesis, longitudinal vaginal septum, transverse vaginal septum, polycystic ovaries-urethral sphincter dysfunction syndrome, granulomatous mastitis, vaginal atresia, mullerian aplasia, vulvovaginal gingival syndrome, isolated partial vaginal agenesis, female infertility, female reproductive system neoplasm, polyp of vulva, vulval varices, vulvodynia, menstrual cycle-dependent periodic fever, Bartholin’s gland disease, menstrual disorder

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

4 retrieved; paginated sample, class counts are floors:

2 pathogenic, 1 benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1321210	NM_018490.5(LGR4):c.286A>G (p.Ile96Val)	LGR4	Pathogenic	no assertion criteria provided
1321211	NM_018490.5(LGR4):c.2531A>G (p.Asp844Gly)	LGR4	Pathogenic	no assertion criteria provided
2571587	NM_020796.5(SEMA6A):c.1268T>C (p.Ile423Thr)	SEMA6A	Likely pathogenic	criteria provided, single submitter
1321209	NM_018490.5(LGR4):c.1087G>T (p.Gly363Cys)	LGR4	Benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 0 · 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
DLG2	Limited	Autosomal dominant	delayed puberty, self-limited	4
LGR4	Limited	Unknown	delayed puberty, self-limited	2
MPP2	Limited	Autosomal dominant	delayed puberty, self-limited	4

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
LGR4	HGNC:13299	ENSG00000205213	Q9BXB1	Leucine-rich repeat-containing G-protein coupled receptor 4	gencc,clinvar
DLG2	HGNC:2901	ENSG00000150672	Q15700	Disks large homolog 2	gencc
MPP2	HGNC:7220	ENSG00000108852	Q14168	MAGUK p55 subfamily member 2	gencc
SEMA6A	HGNC:10738	ENSG00000092421	Q9H2E6	Semaphorin-6A	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LGR4	Leucine-rich repeat-containing G-protein coupled receptor 4	Receptor for R-spondins that potentiates the canonical Wnt signaling pathway and is involved in the formation of various organs.
DLG2	Disks large homolog 2	Required for perception of chronic pain through NMDA receptor signaling.
MPP2	MAGUK p55 subfamily member 2	Postsynaptic MAGUK scaffold protein that links CADM1 cell adhesion molecules to core components of the postsynaptic density.
SEMA6A	Semaphorin-6A	Cell surface receptor for PLXNA2 that plays an important role in cell-cell signaling.

Protein-family classification

Druggable: 3 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.75

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
Kinase	2	13.9×	0.022
GPCR	1	6.0×	0.212
Scaffold/PPI	1	4.3×	0.212

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LGR4	GPCR	yes		GPCR_Rhodpsn, LRRNT, Leu-rich_rpt
DLG2	Kinase	yes		SH3_domain, PDZ, Guanylate_kin-like_dom
MPP2	Kinase	yes		SH3_domain, PDZ, L27_dom
SEMA6A	Scaffold/PPI	no		Semap_dom, Plexin_repeat, WD40/YVTN_repeat-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

3 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	2
body of pancreas	1
hair follicle	1
corpus callosum	1
cortical plate	1
endothelial cell	1
C1 segment of cervical spinal cord	1
prefrontal cortex	1
spinal cord	1
inferior vagus X ganglion	1
lateral globus pallidus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LGR4	280	ubiquitous	marker	adrenal tissue, body of pancreas, hair follicle
DLG2	208	ubiquitous	marker	cortical plate, endothelial cell, corpus callosum
MPP2	210	ubiquitous	yes	C1 segment of cervical spinal cord, prefrontal cortex, spinal cord
SEMA6A	266	ubiquitous	marker	inferior vagus X ganglion, adrenal tissue, lateral globus pallidus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DLG2	4,147
MPP2	2,939
LGR4	2,525
SEMA6A	1,384

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LGR4	Q9BXB1	23
DLG2	Q15700	2
MPP2	Q14168	1
SEMA6A	Q9H2E6	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 4 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Other semaphorin interactions	1	200.3×	0.017	SEMA6A
Ras activation upon Ca2+ influx through NMDA receptor	1	190.3×	0.017	DLG2
Unblocking of NMDA receptors, glutamate binding and activation	1	181.3×	0.017	DLG2
Negative regulation of NMDA receptor-mediated neuronal transmission	1	181.3×	0.017	DLG2
Regulation of FZD by ubiquitination	1	173.0×	0.017	LGR4
Long-term potentiation	1	158.6×	0.017	DLG2
Semaphorin interactions	1	131.3×	0.017	SEMA6A
Assembly and cell surface presentation of NMDA receptors	1	84.6×	0.024	DLG2
Neurexins and neuroligins	1	65.6×	0.027	DLG2
TCF dependent signaling in response to WNT	1	39.2×	0.039	LGR4
Signaling by WNT	1	37.3×	0.039	LGR4
RAF/MAP kinase cascade	1	20.4×	0.064	DLG2
Axon guidance	1	15.1×	0.078	SEMA6A
Nervous system development	1	14.3×	0.078	SEMA6A
Developmental Biology	1	4.8×	0.206	SEMA6A
Signal Transduction	1	3.4×	0.267	LGR4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of cell adhesion involved in sprouting angiogenesis	1	4213.0×	0.007	SEMA6A
metanephric glomerulus development	1	2106.5×	0.007	LGR4
retrograde axonal protein transport	1	2106.5×	0.007	DLG2
metanephric nephron tubule morphogenesis	1	1404.3×	0.008	LGR4
epithelial cell proliferation involved in renal tubule morphogenesis	1	842.6×	0.011	LGR4
intestinal stem cell homeostasis	1	601.9×	0.011	LGR4
receptor localization to synapse	1	526.6×	0.011	DLG2
anterograde axonal protein transport	1	526.6×	0.011	DLG2
negative regulation of vascular endothelial growth factor signaling pathway	1	324.1×	0.013	SEMA6A
negative regulation of sprouting angiogenesis	1	324.1×	0.013	SEMA6A
nervous system development	2	23.0×	0.013	SEMA6A, DLG2
cellular response to potassium ion	1	263.3×	0.014	DLG2
positive regulation of neuron migration	1	247.8×	0.014	SEMA6A
bone remodeling	1	234.1×	0.014	LGR4
male genitalia development	1	221.7×	0.014	LGR4
negative regulation of toll-like receptor signaling pathway	1	210.7×	0.014	LGR4
positive regulation of branching involved in ureteric bud morphogenesis	1	200.6×	0.014	LGR4
protein localization to synapse	1	191.5×	0.014	DLG2
receptor clustering	1	156.0×	0.016	DLG2
establishment or maintenance of epithelial cell apical/basal polarity	1	145.3×	0.016	DLG2
cellular response to vascular endothelial growth factor stimulus	1	140.4×	0.016	SEMA6A
digestive tract development	1	131.7×	0.016	LGR4
negative regulation of cytokine production	1	127.7×	0.016	LGR4
regulation of postsynaptic membrane neurotransmitter receptor levels	1	123.9×	0.016	DLG2
excitatory postsynaptic potential	1	110.9×	0.017	MPP2
semaphorin-plexin signaling pathway	1	100.3×	0.018	SEMA6A
hair follicle development	1	95.8×	0.018	LGR4
negative regulation of cold-induced thermogenesis	1	86.0×	0.019	LGR4
neural crest cell migration	1	84.3×	0.019	SEMA6A
long-term synaptic potentiation	1	70.2×	0.022	MPP2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LGR4	0	0
DLG2	0	0
MPP2	0	0
SEMA6A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
LGR4	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	3	LGR4, DLG2, MPP2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SEMA6A

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)
LGR4	2	—
DLG2	0	—
MPP2	0	—
SEMA6A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.