Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 1

Summary

Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 1 (MONDO:0100297) is a disease caused by BMP2 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: BMP2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 16

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 1
Mondo ID	MONDO:0100297
OMIM	617877
DOID	DOID:0060989
UMLS	C5542952
MedGen	1778119
Is cancer (heuristic)	no

Also known as: SSFSC

Data availability: 16 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies › short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 1

Related subtypes (1): short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2

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

16 retrieved; paginated sample, class counts are floors:

6 uncertain significance, 4 likely pathogenic, 3 pathogenic/likely pathogenic, 3 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2431356	NM_001200.4(BMP2):c.275C>A (p.Ser92Ter)	BMP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2506485	NM_001200.4(BMP2):c.405_409del (p.Asn135fs)	BMP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2573988	NM_001200.4(BMP2):c.231dup (p.Tyr78fs)	BMP2	Pathogenic	criteria provided, multiple submitters, no conflicts
492935	NM_001200.4(BMP2):c.953dup (p.Tyr320fs)	BMP2	Pathogenic	no assertion criteria provided
492936	NM_001200.4(BMP2):c.-7-2_-7-1delinsCC	BMP2	Pathogenic	no assertion criteria provided
816934	NM_001200.4(BMP2):c.508C>T (p.Arg170Ter)	BMP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1699318	NM_001200.4(BMP2):c.1191G>C (p.Ter397Tyr)	BMP2	Likely pathogenic	criteria provided, single submitter
3362909	NM_001200.4(BMP2):c.843dup (p.Arg282fs)	BMP2	Likely pathogenic	no assertion criteria provided
492934	NM_001200.4(BMP2):c.79G>T (p.Glu27Ter)	BMP2	Likely pathogenic	criteria provided, single submitter
492937	NM_001200.4(BMP2):c.987C>A (p.Cys329Ter)	BMP2	Likely pathogenic	criteria provided, single submitter
1377393	NM_001200.4(BMP2):c.509G>A (p.Arg170Gln)	BMP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1679583	NM_001200.4(BMP2):c.922G>A (p.Val308Met)	BMP2	Uncertain significance	criteria provided, single submitter
2584624	GRCh38/hg38 20p12.3(chr20:6773385-6822115)	BMP2	Uncertain significance	criteria provided, single submitter
2901659	NM_001200.4(BMP2):c.805C>T (p.His269Tyr)	BMP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3778899	NM_001200.4(BMP2):c.896A>G (p.His299Arg)	BMP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
4293771	NM_001200.4(BMP2):c.1088C>G (p.Pro363Arg)	BMP2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
BMP2	Strong	Autosomal dominant	short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 1	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BMP2	Orphanet:261295	20p12.3 microdeletion syndrome
BMP2	Orphanet:93396	Brachydactyly type A2

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
BMP2	HGNC:1069	ENSG00000125845	P12643	Bone morphogenetic protein 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BMP2	Bone morphogenetic protein 2	Growth factor of the TGF-beta superfamily that plays essential roles in many developmental processes, including cardiogenesis, neurogenesis, and osteogenesis.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BMP2	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGF-beta-like

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
cartilage tissue	1
pancreatic ductal cell	1
pigmented layer of retina	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BMP2	238	broad	marker	cartilage tissue, pancreatic ductal cell, pigmented layer of retina

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BMP2	3,131

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BMP2	P12643	21

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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
Signaling by BMP	1	356.9×	0.011	BMP2
Elastic fibre formation	1	335.9×	0.011	BMP2
Molecules associated with elastic fibres	1	308.6×	0.011	BMP2
Transcriptional regulation by RUNX2	1	253.8×	0.011	BMP2
Regulation of RUNX2 expression and activity	1	181.3×	0.012	BMP2
Signaling by TGFB family members	1	115.3×	0.016	BMP2
Extracellular matrix organization	1	63.1×	0.025	BMP2
RNA Polymerase II Transcription	1	22.5×	0.061	BMP2
Gene expression (Transcription)	1	17.8×	0.068	BMP2
Generic Transcription Pathway	1	15.1×	0.073	BMP2
Signal Transduction	1	10.2×	0.098	BMP2

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 calcium-independent cell-cell adhesion	1	16852.0×	0.002	BMP2
endodermal-mesodermal cell signaling	1	8426.0×	0.002	BMP2
cardiac atrium formation	1	8426.0×	0.002	BMP2
cardiocyte differentiation	1	8426.0×	0.002	BMP2
mesenchymal cell proliferation involved in ureteric bud development	1	8426.0×	0.002	BMP2
positive regulation of extracellular matrix constituent secretion	1	5617.3×	0.002	BMP2
embryonic heart tube anterior/posterior pattern specification	1	5617.3×	0.002	BMP2
corticotropin hormone secreting cell differentiation	1	5617.3×	0.002	BMP2
positive regulation of bone mineralization involved in bone maturation	1	5617.3×	0.002	BMP2
cardiac jelly development	1	5617.3×	0.002	BMP2
positive regulation of phosphatase activity	1	4213.0×	0.002	BMP2
negative regulation of aldosterone biosynthetic process	1	4213.0×	0.002	BMP2
atrioventricular canal morphogenesis	1	4213.0×	0.002	BMP2
negative regulation of cortisol biosynthetic process	1	4213.0×	0.002	BMP2
aortic valve development	1	3370.4×	0.002	BMP2
negative regulation of steroid biosynthetic process	1	3370.4×	0.002	BMP2
positive regulation of odontogenesis	1	3370.4×	0.002	BMP2
telencephalon regionalization	1	2808.7×	0.002	BMP2
thyroid-stimulating hormone-secreting cell differentiation	1	2808.7×	0.002	BMP2
regulation of odontogenesis of dentin-containing tooth	1	2407.4×	0.002	BMP2
mesenchyme development	1	2407.4×	0.002	BMP2
positive regulation of odontoblast differentiation	1	2407.4×	0.002	BMP2
negative regulation of cardiac muscle cell differentiation	1	2407.4×	0.002	BMP2
heart induction	1	2106.5×	0.002	BMP2
ameloblast differentiation	1	2106.5×	0.002	BMP2
negative regulation of insulin-like growth factor receptor signaling pathway	1	2106.5×	0.002	BMP2
mesenchymal cell differentiation	1	2106.5×	0.002	BMP2
proteoglycan metabolic process	1	1872.4×	0.002	BMP2
pericardium development	1	1872.4×	0.002	BMP2
positive regulation of peroxisome proliferator activated receptor signaling pathway	1	1685.2×	0.002	BMP2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BMP2	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
BMP2	22	Binding:18, Functional:4

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

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	BMP2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
BMP2	22	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.