Hereditary mixed polyposis syndrome

Summary

Hereditary mixed polyposis syndrome (MONDO:0011023) is a disease caused by GREM1 (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GREM1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 7
• Phenotypes (HPO): 18

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		15	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

18 HPO clinical features (Orphanet curated; top 18 by frequency):

HPO ID	Term	Frequency
HP:0001892	Abnormal bleeding	Very frequent (80-99%)
HP:0002573	Hematochezia	Very frequent (80-99%)
HP:0012183	Hyperplastic colonic polyposis	Very frequent (80-99%)
HP:0003003	Colon cancer	Frequent (30-79%)
HP:0005227	Adenomatous colonic polyposis	Frequent (30-79%)
HP:0005505	Refractory anemia	Frequent (30-79%)
HP:0007378	Neoplasm of the gastrointestinal tract	Frequent (30-79%)
HP:0012198	Juvenile colonic polyposis	Frequent (30-79%)
HP:0100896	Rectal polyposis	Frequent (30-79%)
HP:0200063	Colorectal polyposis	Frequent (30-79%)
HP:0002576	Intussusception	Occasional (5-29%)
HP:0040276	Adenocarcinoma of the colon	Occasional (5-29%)
HP:0100743	Neoplasm of the rectum	Occasional (5-29%)
HP:0002890	Thyroid carcinoma	Very rare (<1-4%)
HP:0006771	Duodenal adenocarcinoma	Very rare (<1-4%)
HP:0012114	Endometrial carcinoma	Very rare (<1-4%)
HP:0012125	Prostate cancer	Very rare (<1-4%)
HP:0100245	Desmoid tumors	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary mixed polyposis syndrome
Mondo ID	MONDO:0011023
MeSH	C563365
OMIM	601228
Orphanet	157794
DOID	DOID:0111684
ICD-11	219068911
UMLS	C5192681
MedGen	1672870
GARD	0016981
Is cancer (heuristic)	no

Also known as: hereditary mixed polyposis syndrome · HMPS

Data availability: 7 ClinVar variants · 4 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › digestive system disorder › hereditary mixed polyposis syndrome

Related subtypes (30): benign digestive system neoplasm, autoimmune disorder of gastrointestinal tract, gastrointestinal mucositis, diarrheal disease, pancreas disorder, hepatobiliary disorder, digestive system cancer, peptic ulcer disease, stomach disorder, intestinal disorder, Meckel diverticulum, Cronkhite-Canada syndrome, diverticulosis, small-intestinal, diverticulosis of bowel, hernia, and retinal detachment, congenital enteropathy due to enteropeptidase deficiency, caudal duplication, Moyamoya disease with early-onset achalasia, hyperplastic polyposis syndrome, thoraco-abdominal enteric duplication, digestive duplication, juvenile polyposis syndrome, umbilical cord ulceration-intestinal atresia syndrome, growth retardation-mild developmental delay-chronic hepatitis syndrome, common mesentery, neoplasm of oropharynx, gastrointestinal polyp, digestive system neuroendocrine neoplasm, digestive system infectious disorder, upper digestive tract disorder, congenital peritoneal encapsulation

Subtypes (2): polyposis syndrome, hereditary mixed, 2, polyposis syndrome, hereditary mixed, 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

7 retrieved; paginated sample, class counts are floors:

7 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
374976	NM_001144757.3(SCG5):c.532C>T (p.Arg178Ter)	ARHGAP11A-SCG5	Uncertain significance	criteria provided, single submitter
1691515	NM_013372.7(GREM1):c.307A>G (p.Ile103Val)	GREM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1701911	NM_013372.7(GREM1):c.190C>T (p.Arg64Trp)	GREM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1710971	NM_013372.7(GREM1):c.77A>G (p.Lys26Arg)	GREM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3282652	NM_013372.7(GREM1):c.146C>G (p.Ser49Trp)	GREM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3357297	NM_013372.7(GREM1):c.337A>G (p.Ile113Val)	GREM1	Uncertain significance	criteria provided, single submitter
375861	NM_013372.7(GREM1):c.169A>C (p.Asn57His)	GREM1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 17 · Orphanet: 5 · 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
BMPR1A	Definitive	Autosomal dominant	generalized juvenile polyposis/juvenile polyposis coli	12
GREM1	Definitive	Autosomal dominant	hereditary mixed polyposis syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GREM1	Orphanet:157794	Hereditary mixed polyposis syndrome
BMPR1A	Orphanet:157794	Hereditary mixed polyposis syndrome
BMPR1A	Orphanet:329971	Generalized juvenile polyposis/juvenile polyposis coli
BMPR1A	Orphanet:440437	Familial colorectal cancer Type X
BMPR1A	Orphanet:79076	Juvenile polyposis of infancy

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GREM1	HGNC:2001	ENSG00000166923	O60565	Gremlin-1	gencc,clinvar
BMPR1A	HGNC:1076	ENSG00000107779	P36894	Bone morphogenetic protein receptor type-1A	gencc
ARHGAP11A-SCG5	HGNC:56310	ENSG00000288864		ARHGAP11A-SCG5 readthrough	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GREM1	Gremlin-1	Cytokine that may play an important role during carcinogenesis and metanephric kidney organogenesis, as a BMP antagonist required for early limb outgrowth and patterning in maintaining the FGF4-SHH feedback loop.
BMPR1A	Bone morphogenetic protein receptor type-1A	On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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	1	9.2×	0.209
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GREM1	Other/Unknown	no		DAN_dom, Cys_knot_C, Gremlin-1/2
BMPR1A	Kinase	yes	2.7.10.2	TGFB_receptor, Activin_recp, Prot_kinase_dom
ARHGAP11A-SCG5	Other/Unknown	no

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)	2
unknown	1

Top tissues across cohort

Tissue	Cohort genes
gall bladder	1
mucosa of stomach	1
stromal cell of endometrium	1
calcaneal tendon	1
saphenous vein	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GREM1	126	ubiquitous	marker	stromal cell of endometrium, gall bladder, mucosa of stomach
BMPR1A	284	ubiquitous	marker	secondary oocyte, calcaneal tendon, saphenous vein
ARHGAP11A-SCG5			marker

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BMPR1A	3,316
GREM1	1,180
ARHGAP11A-SCG5	0

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BMPR1A	P36894	11
GREM1	O60565	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 3 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
Formation of the ureteric bud	1	248.3×	0.011	GREM1
Signaling by BMP	1	178.4×	0.011	BMPR1A
Signaling by TGFB family members	1	57.7×	0.023	BMPR1A
Signal Transduction	1	5.1×	0.187	BMPR1A

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
neural plate mediolateral regionalization	1	8426.0×	0.003	BMPR1A
paraxial mesoderm structural organization	1	8426.0×	0.003	BMPR1A
positive regulation of cardiac ventricle development	1	8426.0×	0.003	BMPR1A
fibrous ring of heart morphogenesis	1	8426.0×	0.003	BMPR1A
negative regulation of bone remodeling	1	4213.0×	0.003	GREM1
negative regulation of bone trabecula formation	1	4213.0×	0.003	GREM1
positive regulation of transforming growth factor beta2 production	1	2808.7×	0.003	BMPR1A
obsolete sequestering of BMP from receptor via BMP binding	1	2808.7×	0.003	GREM1
regulation of lateral mesodermal cell fate specification	1	2808.7×	0.003	BMPR1A
negative regulation of osteoclast proliferation	1	2808.7×	0.003	GREM1
atrioventricular valve development	1	2106.5×	0.003	BMPR1A
lateral mesoderm development	1	2106.5×	0.003	BMPR1A
atrioventricular node cell development	1	2106.5×	0.003	BMPR1A
negative regulation of bone mineralization involved in bone maturation	1	2106.5×	0.003	GREM1
Mullerian duct regression	1	1685.2×	0.003	BMPR1A
tricuspid valve morphogenesis	1	1685.2×	0.003	BMPR1A
determination of dorsal identity	1	1685.2×	0.003	GREM1
regulation of cardiac muscle cell proliferation	1	1685.2×	0.003	BMPR1A
heart formation	1	1685.2×	0.003	BMPR1A
hindlimb morphogenesis	1	1404.3×	0.004	BMPR1A
negative regulation of monocyte chemotaxis	1	1404.3×	0.004	GREM1
anti-Mullerian hormone receptor signaling pathway	1	1404.3×	0.004	BMPR1A
ventricular compact myocardium morphogenesis	1	1203.7×	0.004	BMPR1A
ureteric bud formation	1	1203.7×	0.004	GREM1
mesenchymal to epithelial transition involved in metanephros morphogenesis	1	1053.2×	0.004	GREM1
dorsal aorta morphogenesis	1	1053.2×	0.004	BMPR1A
mesendoderm development	1	936.2×	0.004	BMPR1A
mitral valve morphogenesis	1	842.6×	0.004	BMPR1A
negative regulation of muscle cell differentiation	1	842.6×	0.004	BMPR1A
pharyngeal arch artery morphogenesis	1	842.6×	0.004	BMPR1A

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) 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
BMPR1A	MOMELOTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BMPR1A	11	4
GREM1	0	0
ARHGAP11A-SCG5	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOMELOTINIB	4	BMPR1A
GILTERITINIB	4	BMPR1A
DASATINIB	4	BMPR1A
SARACATINIB	3	BMPR1A
LESTAURTINIB	3	BMPR1A
AT-9283	2	BMPR1A
ZILURGISERTIB	2	BMPR1A
KER-047	2	BMPR1A
KW-2449	1	BMPR1A
XL-228	1	BMPR1A
Y-39983	1	BMPR1A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
BMPR1A	169	Binding:166, ADMET:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BMPR1A	2.7.10.2	non-specific protein-tyrosine kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
BMPR1A	169

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

11 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)
MOMELOTINIB	4	BMPR1A
GILTERITINIB	4	BMPR1A
DASATINIB	4	BMPR1A
SARACATINIB	3	BMPR1A
LESTAURTINIB	3	BMPR1A
AT-9283	2	BMPR1A
ZILURGISERTIB	2	BMPR1A
KER-047	2	BMPR1A
KW-2449	1	BMPR1A
XL-228	1	BMPR1A
Y-39983	1	BMPR1A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	BMPR1A
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	2	GREM1, ARHGAP11A-SCG5

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)
GREM1	0	—
ARHGAP11A-SCG5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.