Obesity due to congenital leptin deficiency

Summary

Obesity due to congenital leptin deficiency (MONDO:0013991) is a disease caused by LEP (GenCC Definitive), with 2 cohort genes and 1 clinical trial. Top therapeutic interventions include metreleptin.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: LEP (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 48
• Phenotypes (HPO): 20
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		30	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

20 HPO clinical features (Orphanet curated; top 20 by frequency):

HPO ID	Term	Frequency
HP:0001513	Obesity	Obligate (100%)
HP:0003292	Decreased serum leptin	Obligate (100%)
HP:0032218	Decreased proportion of CD4-positive T cells	Very frequent (80-99%)
HP:0000771	Gynecomastia	Very frequent (80-99%)
HP:0000786	Primary amenorrhea	Very frequent (80-99%)
HP:0000815	Hypergonadotropic hypogonadism	Very frequent (80-99%)
HP:0000842	Hyperinsulinemia	Very frequent (80-99%)
HP:0002591	Polyphagia	Very frequent (80-99%)
HP:0005419	Decreased T cell activation	Very frequent (80-99%)
HP:0008187	Absence of secondary sex characteristics	Very frequent (80-99%)
HP:0008214	Decreased serum estradiol	Very frequent (80-99%)
HP:0008724	Hypoplasia of the ovary	Very frequent (80-99%)
HP:0008734	Decreased testicular size	Very frequent (80-99%)
HP:0040171	Decreased serum testosterone concentration	Very frequent (80-99%)
HP:0000831	Insulin-resistant diabetes mellitus	Frequent (30-79%)
HP:0002155	Hypertriglyceridemia	Frequent (30-79%)
HP:0002788	Recurrent upper respiratory tract infections	Frequent (30-79%)
HP:0004926	Orthostatic hypotension due to autonomic dysfunction	Frequent (30-79%)
HP:0005616	Accelerated skeletal maturation	Frequent (30-79%)
HP:0008245	Pituitary hypothyroidism	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	obesity due to congenital leptin deficiency
Mondo ID	MONDO:0013991
OMIM	614962
Orphanet	66628
DOID	DOID:0111334
ICD-11	591009309
UMLS	C3554224
MedGen	767138
GARD	0013015
NORD	110641
Is cancer (heuristic)	no

Also known as: Congenital Leptin Deficiency · LEPD · leptin deficiency or dysfunction · obesity, morbid, due to leptin deficiency

Data availability: 48 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › reproductive system disorder › gonadal disorder › hypogonadism › hypogonadotropic hypogonadism › congenital hypogonadotropic hypogonadism › obesity due to congenital leptin deficiency

Related subtypes (24): brachytelephalangy-dysmorphism-Kallmann syndrome, hypogonadotropic hypogonadism 7 with or without anosmia, Prader-Willi syndrome, familial adrenal hypoplasia with absent pituitary luteinizing hormone, cerebellar ataxia-hypogonadism syndrome, CHARGE syndrome, ataxia-hypogonadism-choroidal dystrophy syndrome, Woodhouse-Sakati syndrome, Laurence-Moon syndrome, X-linked adrenal hypoplasia congenita, obesity due to prohormone convertase I deficiency, arhinia, choanal atresia, and microphthalmia, ANE syndrome, combined pituitary hormone deficiencies, genetic form, obesity due to leptin receptor gene deficiency, polyendocrine-polyneuropathy syndrome, hypogonadotropic hypogonadism-frontoparietal alopecia syndrome, hypogonadotropic hypogonadism-retinitis pigmentosa syndrome, Kallmann syndrome-heart disease syndrome, isolated congenital hypogonadotropic hypogonadism, Moebius syndrome-axonal neuropathy-hypogonadotropic hypogonadism syndrome, hypogonadotropic hypogonadism-severe microcephaly-sensorineural hearing loss-dysmorphism syndrome, Prader-Willi-like syndrome, Martsolf syndrome 1

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

48 retrieved; paginated sample, class counts are floors:

36 uncertain significance, 4 pathogenic, 4 conflicting classifications of pathogenicity, 2 likely pathogenic, 1 benign/likely benign, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
13986	NM_000230.3(LEP):c.398del (p.Gly133fs)	LEP	Pathogenic	criteria provided, single submitter
13987	NM_000230.3(LEP):c.313C>T (p.Arg105Trp)	LEP	Pathogenic	no assertion criteria provided
2428497	NM_000230.3(LEP):c.175G>A (p.Gly59Ser)	LEP	Pathogenic	criteria provided, single submitter
2428498	NM_000230.3(LEP):c.190C>T (p.Pro64Ser)	LEP	Pathogenic	criteria provided, single submitter
448905	NM_000230.3(LEP):c.461T>C (p.Leu154Pro)	LEP	Likely pathogenic	criteria provided, single submitter
3242154	NM_002303.6(LEPR):c.1752+1G>A	LEPR	Likely pathogenic	criteria provided, single submitter
358815	NM_000230.3(LEP):c.21C>T (p.Cys7=)	LEP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
724209	NM_000230.3(LEP):c.165G>A (p.Gln55=)	LEP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
910456	NM_000230.3(LEP):c.53A>G (p.Tyr18Cys)	LEP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
911680	NM_000230.3(LEP):c.*33C>T	LEP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
358817	NM_000230.3(LEP):c.181G>A (p.Asp61Asn)	LEP	Uncertain significance	criteria provided, single submitter
358818	NM_000230.3(LEP):c.212C>A (p.Thr71Asn)	LEP	Uncertain significance	criteria provided, single submitter
358821	NM_000230.3(LEP):c.*69A>G	LEP	Uncertain significance	criteria provided, single submitter
358832	NM_000230.3(LEP):c.*1014C>G	LEP	Uncertain significance	criteria provided, single submitter
358837	NM_000230.3(LEP):c.*1640C>T	LEP	Uncertain significance	criteria provided, single submitter
358844	NM_000230.3(LEP):c.*2234G>A	LEP	Uncertain significance	criteria provided, single submitter
358846	NM_000230.3(LEP):c.*2267A>C	LEP	Uncertain significance	criteria provided, single submitter
358848	NM_000230.3(LEP):c.*2527G>T	LEP	Uncertain significance	criteria provided, single submitter
358849	NM_000230.3(LEP):c.*2579G>A	LEP	Uncertain significance	criteria provided, single submitter
358852	NM_000230.3(LEP):c.*2738G>A	LEP	Uncertain significance	criteria provided, single submitter
908787	NM_000230.3(LEP):c.*1318G>C	LEP	Uncertain significance	criteria provided, single submitter
908788	NM_000230.3(LEP):c.*1369G>T	LEP	Uncertain significance	criteria provided, single submitter
908789	NM_000230.3(LEP):c.*1422A>T	LEP	Uncertain significance	criteria provided, single submitter
908851	NM_000230.3(LEP):c.*2110G>T	LEP	Uncertain significance	criteria provided, single submitter
909528	NM_000230.3(LEP):c.-14T>G	LEP	Uncertain significance	criteria provided, single submitter
909587	NM_000230.3(LEP):c.*373G>A	LEP	Uncertain significance	criteria provided, single submitter
909642	NM_000230.3(LEP):c.*1579G>A	LEP	Uncertain significance	criteria provided, single submitter
909643	NM_000230.3(LEP):c.*1637A>G	LEP	Uncertain significance	criteria provided, single submitter
909706	NM_000230.3(LEP):c.*2245C>G	LEP	Uncertain significance	criteria provided, single submitter
909707	NM_000230.3(LEP):c.*2263G>A	LEP	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · 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
LEP	Definitive	Autosomal recessive	obesity due to congenital leptin deficiency	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LEP	Orphanet:66628	Obesity due to congenital leptin deficiency
LEPR	Orphanet:179494	Obesity due to leptin receptor gene deficiency

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
LEP	HGNC:6553	ENSG00000174697	P41159	Leptin	gencc,clinvar
LEPR	HGNC:6554	ENSG00000116678	P48357	Leptin receptor	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LEP	Leptin	Key player in the regulation of energy balance and body weight control.
LEPR	Leptin receptor	Receptor for hormone LEP/leptin.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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	1	14.6×	0.135
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LEP	Other/Unknown	no		Leptin, 4_helix_cytokine-like_core
LEPR	Antibody/Immunoglobulin	yes		Hematopoietin_rcpt_Gp130_CS, Hempt_rcpt_S_F1_CS, FN3_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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
skin of hip	1
subcutaneous adipose tissue	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
LEP	140	tissue_specific	yes	skin of hip, buccal mucosa cell, subcutaneous adipose tissue
LEPR	272	broad	marker	trabecular bone tissue, choroid plexus epithelium, trigeminal ganglion

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LEP	4,556
LEPR	2,243

Intra-cohort edges

A	B	Sources
LEP	LEPR	biogrid_interaction, intact, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LEP	P41159	10
LEPR	P48357	9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Signaling by Leptin	2	1038.2×	8e-06	LEP, LEPR
Incretin synthesis, secretion, and inactivation	1	519.1×	0.010	LEP
Synthesis, secretion, and deacylation of Ghrelin	1	300.5×	0.010	LEP
Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1)	1	259.6×	0.010	LEP
Peptide hormone metabolism	1	135.9×	0.015	LEP
Adipogenesis	1	78.2×	0.021	LEP
Transcriptional regulation of white adipocyte differentiation	1	64.9×	0.022	LEP
Developmental Biology	1	7.2×	0.167	LEP
Metabolism of proteins	1	6.2×	0.172	LEP
Signal Transduction	1	5.1×	0.187	LEP

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
sexual reproduction	2	5617.3×	2e-06	LEP, LEPR
regulation of bone remodeling	2	2808.7×	4e-06	LEP, LEPR
leptin-mediated signaling pathway	2	2407.4×	4e-06	LEP, LEPR
bone growth	2	2407.4×	4e-06	LEP, LEPR
energy reserve metabolic process	2	1053.2×	2e-05	LEP, LEPR
cell surface receptor signaling pathway via STAT	2	561.7×	6e-05	LEP, LEPR
T cell differentiation	2	383.0×	1e-04	LEP, LEPR
negative regulation of autophagy	2	259.3×	2e-04	LEP, LEPR
phagocytosis	2	240.7×	2e-04	LEP, LEPR
cholesterol metabolic process	2	195.9×	3e-04	LEP, LEPR
positive regulation of cold-induced thermogenesis	2	163.6×	4e-04	LEP, LEPR
glucose homeostasis	2	130.6×	5e-04	LEP, LEPR
regulation of lipoprotein lipid oxidation	1	8426.0×	8e-04	LEP
cellular response to L-ascorbic acid	1	8426.0×	8e-04	LEP
positive regulation of fat cell apoptotic process	1	8426.0×	8e-04	LEP
activation of protein kinase C activity	1	8426.0×	8e-04	LEP
negative regulation of glutamine transport	1	8426.0×	8e-04	LEP
multicellular organism development	1	4213.0×	0.001	LEPR
regulation of natural killer cell proliferation	1	4213.0×	0.001	LEP
regulation of nitric-oxide synthase activity	1	4213.0×	0.001	LEP
regulation of transport	1	4213.0×	0.001	LEPR
elastin metabolic process	1	4213.0×	0.001	LEP
angiogenesis	2	62.4×	0.001	LEP, LEPR
glycerol biosynthetic process	1	2808.7×	0.002	LEP
negative regulation of glucagon secretion	1	2808.7×	0.002	LEP
regulation of endothelial cell proliferation	1	2106.5×	0.002	LEP
regulation of intestinal cholesterol absorption	1	2106.5×	0.002	LEP
negative regulation of appetite by leptin-mediated signaling pathway	1	2106.5×	0.002	LEP
regulation of natural killer cell mediated cytotoxicity	1	2106.5×	0.002	LEP
positive regulation of developmental growth	1	2106.5×	0.002	LEP

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LEP	0	0
LEPR	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
LEPR	3	Binding:3

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	1	LEPR
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	LEP

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
LEP	0	—
LEPR	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04063488	Not specified	COMPLETED	The Effects of Metreleptin in Congenital Leptin Deficiency

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
METRELEPTIN	4	1