LEOPARD syndrome 1

Summary

LEOPARD syndrome 1 (MONDO:0100082) is a disease caused by PTPN11 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: PTPN11 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 231

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	LEOPARD syndrome 1
Mondo ID	MONDO:0100082
OMIM	151100
DOID	DOID:0080548
UMLS	C4551484
MedGen	1631694
GARD	0026037
Is cancer (heuristic)	no

Also known as: lentiginosis, cardiomyopathic · LEOPARD syndrome 1 · LEOPARD syndrome type 1 · LPRD1 · multiple lentigines syndrome

Data availability: 231 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › Noonan syndrome with multiple lentigines › LEOPARD syndrome 1

Related subtypes (2): LEOPARD syndrome 2, LEOPARD syndrome 3

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

231 retrieved; paginated sample, class counts are floors:

99 uncertain significance, 35 pathogenic, 27 conflicting classifications of pathogenicity, 20 pathogenic/likely pathogenic, 17 benign/likely benign, 15 benign, 14 likely benign, 4 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
13324	NM_002834.5(PTPN11):c.214G>T (p.Ala72Ser)	PTPN11	Pathogenic	criteria provided, multiple submitters, no conflicts
13325	NM_002834.5(PTPN11):c.215C>G (p.Ala72Gly)	PTPN11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13326	NM_002834.5(PTPN11):c.922A>G (p.Asn308Asp)	PTPN11	Pathogenic	reviewed by expert panel
13327	NM_002834.5(PTPN11):c.923A>G (p.Asn308Ser)	PTPN11	Pathogenic	criteria provided, multiple submitters, no conflicts
13328	NM_002834.5(PTPN11):c.836A>G (p.Tyr279Cys)	PTPN11	Pathogenic	reviewed by expert panel
13329	NM_002834.5(PTPN11):c.184T>G (p.Tyr62Asp)	PTPN11	Pathogenic	reviewed by expert panel
13330	NM_002834.5(PTPN11):c.182A>G (p.Asp61Gly)	PTPN11	Pathogenic	criteria provided, multiple submitters, no conflicts
13331	NM_002834.5(PTPN11):c.1403C>T (p.Thr468Met)	PTPN11	Pathogenic	reviewed by expert panel
13332	NM_002834.5(PTPN11):c.1504T>A (p.Ser502Thr)	PTPN11	Pathogenic	criteria provided, multiple submitters, no conflicts
13333	NM_002834.5(PTPN11):c.188A>G (p.Tyr63Cys)	PTPN11	Pathogenic	reviewed by expert panel
13334	NM_002834.5(PTPN11):c.218C>T (p.Thr73Ile)	PTPN11	Pathogenic	criteria provided, multiple submitters, no conflicts
13335	NM_002834.5(PTPN11):c.854T>C (p.Phe285Ser)	PTPN11	Pathogenic	criteria provided, multiple submitters, no conflicts
13342	NM_002834.5(PTPN11):c.1381G>A (p.Ala461Thr)	PTPN11	Pathogenic	reviewed by expert panel
13343	NM_002834.5(PTPN11):c.1391G>C (p.Gly464Ala)	PTPN11	Pathogenic	reviewed by expert panel
13344	NM_002834.5(PTPN11):c.1529A>C (p.Gln510Pro)	PTPN11	Pathogenic	reviewed by expert panel
13345	NM_002834.5(PTPN11):c.1529A>G (p.Gln510Arg)	PTPN11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13349	NM_002834.5(PTPN11):c.5C>T (p.Thr2Ile)	PTPN11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1367799	NM_002834.5(PTPN11):c.691C>T (p.Arg231Ter)	PTPN11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
164997	NM_002834.5(PTPN11):c.206A>T (p.Glu69Val)	PTPN11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
181503	NM_002834.5(PTPN11):c.1471C>G (p.Pro491Ala)	PTPN11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40482	NM_002834.5(PTPN11):c.124A>G (p.Thr42Ala)	PTPN11	Pathogenic	criteria provided, multiple submitters, no conflicts
40487	NM_002834.5(PTPN11):c.172A>G (p.Asn58Asp)	PTPN11	Pathogenic	criteria provided, multiple submitters, no conflicts
40488	NM_002834.5(PTPN11):c.174C>A (p.Asn58Lys)	PTPN11	Pathogenic	criteria provided, multiple submitters, no conflicts
40489	NM_002834.5(PTPN11):c.174C>G (p.Asn58Lys)	PTPN11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40490	NM_002834.5(PTPN11):c.178G>A (p.Gly60Ser)	PTPN11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40495	NM_002834.5(PTPN11):c.181G>A (p.Asp61Asn)	PTPN11	Pathogenic	criteria provided, multiple submitters, no conflicts
40502	NM_002834.5(PTPN11):c.228G>T (p.Glu76Asp)	PTPN11	Pathogenic	criteria provided, multiple submitters, no conflicts
40508	NM_002834.5(PTPN11):c.329A>C (p.Glu110Ala)	PTPN11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40513	NM_002834.5(PTPN11):c.417G>C (p.Glu139Asp)	PTPN11	Pathogenic	reviewed by expert panel
40520	NM_002834.5(PTPN11):c.781C>T (p.Leu261Phe)	PTPN11	Pathogenic	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 19 · Orphanet: 4 · 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
PTPN11	Definitive	Autosomal dominant	LEOPARD syndrome 1	19

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PTPN11	Orphanet:2499	Metachondromatosis
PTPN11	Orphanet:500	Noonan syndrome with multiple lentigines
PTPN11	Orphanet:648	Noonan syndrome
PTPN11	Orphanet:86834	Juvenile myelomonocytic leukemia

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
PTPN11	HGNC:9644	ENSG00000179295	Q06124	Tyrosine-protein phosphatase non-receptor type 11	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PTPN11	Tyrosine-protein phosphatase non-receptor type 11	Acts downstream of various receptor and cytoplasmic protein tyrosine kinases to participate in the signal transduction from the cell surface to the nucleus.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Phosphatase	1	83.9×	0.012

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PTPN11	Phosphatase	yes	3.1.3.48	PTP_cat, Tyr_Pase_dom, SH2

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
dorsal motor nucleus of vagus nerve	1
globus pallidus	1
medial globus pallidus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PTPN11	295	ubiquitous	marker	medial globus pallidus, dorsal motor nucleus of vagus nerve, globus pallidus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PTPN11	6,009

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PTPN11	Q06124	115

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 52. 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
MET activates PTPN11	1	2284.0×	0.003	PTPN11
Co-inhibition by BTLA	1	2284.0×	0.003	PTPN11
STAT5 Activation	1	1631.4×	0.003	PTPN11
Netrin mediated repulsion signals	1	1268.9×	0.003	PTPN11
MAPK1 (ERK2) activation	1	1142.0×	0.003	PTPN11
STAT5 activation downstream of FLT3 ITD mutants	1	1142.0×	0.003	PTPN11
MAPK3 (ERK1) activation	1	1038.2×	0.003	PTPN11
Signaling by Leptin	1	1038.2×	0.003	PTPN11
Interleukin-6 signaling	1	951.7×	0.003	PTPN11
Activated NTRK2 signals through FRS2 and FRS3	1	951.7×	0.003	PTPN11
PECAM1 interactions	1	878.5×	0.003	PTPN11
Regulation of IFNG signaling	1	815.7×	0.003	PTPN11
Prolactin receptor signaling	1	761.3×	0.003	PTPN11
Signaling by FLT3 ITD and TKD mutants	1	761.3×	0.003	PTPN11
Spry regulation of FGF signaling	1	713.8×	0.003	PTPN11
Signal regulatory protein family interactions	1	671.8×	0.003	PTPN11
Platelet sensitization by LDL	1	671.8×	0.003	PTPN11
Regulation of RUNX1 Expression and Activity	1	671.8×	0.003	PTPN11
GAB1 signalosome	1	634.4×	0.003	PTPN11
PI-3K cascade:FGFR3	1	634.4×	0.003	PTPN11
Tie2 Signaling	1	601.0×	0.003	PTPN11
Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE)	1	601.0×	0.003	PTPN11
PI-3K cascade:FGFR4	1	571.0×	0.003	PTPN11
Signaling by CSF3 (G-CSF)	1	571.0×	0.003	PTPN11
FRS-mediated FGFR3 signaling	1	543.8×	0.003	PTPN11
Co-inhibition by CTLA4	1	519.1×	0.003	PTPN11
Co-inhibition by PD-1	1	519.1×	0.003	PTPN11
PI-3K cascade:FGFR1	1	519.1×	0.003	PTPN11
Interleukin-37 signaling	1	519.1×	0.003	PTPN11
PI-3K cascade:FGFR2	1	496.5×	0.003	PTPN11

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
negative regulation of cortisol secretion	1	16852.0×	0.002	PTPN11
negative regulation of growth hormone secretion	1	16852.0×	0.002	PTPN11
microvillus organization	1	8426.0×	0.002	PTPN11
intestinal epithelial cell migration	1	8426.0×	0.002	PTPN11
cerebellar cortex formation	1	5617.3×	0.002	PTPN11
regulation of type I interferon-mediated signaling pathway	1	4213.0×	0.002	PTPN11
ERBB signaling pathway	1	3370.4×	0.002	PTPN11
negative regulation of neutrophil activation	1	2407.4×	0.003	PTPN11
positive regulation of hormone secretion	1	1685.2×	0.003	PTPN11
genitalia development	1	1685.2×	0.003	PTPN11
positive regulation of lipopolysaccharide-mediated signaling pathway	1	1532.0×	0.003	PTPN11
atrioventricular canal development	1	1532.0×	0.003	PTPN11
regulation of protein export from nucleus	1	1532.0×	0.003	PTPN11
Bergmann glial cell differentiation	1	1532.0×	0.003	PTPN11
negative regulation of cell adhesion mediated by integrin	1	1296.3×	0.003	PTPN11
neurotrophin TRK receptor signaling pathway	1	1053.2×	0.003	PTPN11
positive regulation of ossification	1	936.2×	0.003	PTPN11
peptidyl-tyrosine dephosphorylation	1	887.0×	0.003	PTPN11
hormone metabolic process	1	887.0×	0.003	PTPN11
positive regulation of insulin receptor signaling pathway	1	842.6×	0.003	PTPN11
organ growth	1	732.7×	0.003	PTPN11
regulation of protein-containing complex assembly	1	732.7×	0.003	PTPN11
platelet formation	1	702.2×	0.003	PTPN11
megakaryocyte development	1	702.2×	0.003	PTPN11
negative regulation of chondrocyte differentiation	1	674.1×	0.003	PTPN11
positive regulation of intracellular signal transduction	1	648.1×	0.003	PTPN11
platelet-derived growth factor receptor signaling pathway	1	561.7×	0.004	PTPN11
negative regulation of T cell activation	1	526.6×	0.004	PTPN11
negative regulation of type I interferon production	1	495.6×	0.004	PTPN11
negative regulation of insulin secretion	1	495.6×	0.004	PTPN11

Therapeutics

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
PTPN11	ESTRAMUSTINE PHOSPHATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PTPN11	8	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ESTRAMUSTINE PHOSPHATE	4	PTPN11
ENOXOLONE	2	PTPN11
CEFSULODIN	2	PTPN11
BATOPROTAFIB	2	PTPN11
VOCIPROTAFIB	2	PTPN11
JAB-3068	1	PTPN11
PF-07284892	1	PTPN11
BBP-398	1	PTPN11

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PTPN11	588	Binding:585, Functional:2, ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PTPN11	3.1.3.48	protein-tyrosine-phosphatase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
PTPN11	588

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

8 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)
ESTRAMUSTINE PHOSPHATE	4	PTPN11
ENOXOLONE	2	PTPN11
CEFSULODIN	2	PTPN11
BATOPROTAFIB	2	PTPN11
VOCIPROTAFIB	2	PTPN11
JAB-3068	1	PTPN11
PF-07284892	1	PTPN11
BBP-398	1	PTPN11

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PTPN11
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: 0.