Congenital heart defects, multiple types, 8, with or without heterotaxy

Summary

Congenital heart defects, multiple types, 8, with or without heterotaxy (MONDO:0859213) is a disease caused by SMAD2 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: SMAD2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 8

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital heart defects, multiple types, 8, with or without heterotaxy
Mondo ID	MONDO:0859213
OMIM	619657
UMLS	C5562042
MedGen	1794252
Is cancer (heuristic)	no

Data availability: 8 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › congenital heart disease › congenital heart defects, multiple types › congenital heart defects, multiple types, 8, with or without heterotaxy

Related subtypes (7): congenital heart defects, multiple types, 6, congenital heart defects, multiple types, 3, congenital heart defects, multiple types, 2, congenital heart defects, multiple types, 4, congenital heart defects, multiple types, 5, MYH-6 related congenital heart defects, congenital heart defects, multiple types, 9

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

8 retrieved; paginated sample, class counts are floors:

6 pathogenic, 1 likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1327536	NM_005901.6(SMAD2):c.237-12A>G	SMAD2	Pathogenic	no assertion criteria provided
135628	NM_005901.6(SMAD2):c.822G>C (p.Trp274Cys)	SMAD2	Pathogenic	no assertion criteria provided
208683	NM_005901.6(SMAD2):c.935G>C (p.Cys312Ser)	SMAD2	Pathogenic	criteria provided, single submitter
3237537	NM_005901.6(SMAD2):c.544dup (p.Arg182fs)	SMAD2	Pathogenic	criteria provided, single submitter
419441	NM_005901.6(SMAD2):c.475G>T (p.Glu159Ter)	SMAD2	Pathogenic	criteria provided, single submitter
56824	NM_005901.6(SMAD2):c.784+1G>A	SMAD2	Pathogenic	no assertion criteria provided
4294517	NM_005901.6(SMAD2):c.1239del (p.Thr413_Ile414insTer)	SMAD2	Likely pathogenic	criteria provided, single submitter
787466	NM_005901.6(SMAD2):c.828G>A (p.Ser276=)	SMAD2	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · 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
SMAD2	Strong	Autosomal dominant	congenital heart defects, multiple types, 8, with or without heterotaxy	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SMAD2	Orphanet:60030	Loeys-Dietz syndrome
SMAD2	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection

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
SMAD2	HGNC:6768	ENSG00000175387	Q15796	SMAD family member 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SMAD2	SMAD family member 2	Receptor-regulated SMAD (R-SMAD) that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta (transforming growth factor) and activin type 1 receptor kinases.

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)
SMAD2	Other/Unknown	no		SMAD_dom, MAD_homology1_Dwarfin-type, SMAD_FHA_dom_sf

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
calcaneal tendon	1
male germ cell	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SMAD2	299	ubiquitous	marker	calcaneal tendon, sperm, male germ cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMAD2	5,751

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SMAD2	Q15796	10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 36. 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
Loss of Function of SMAD4 in Cancer	1	3806.7×	0.002	SMAD2
SMAD4 MH2 Domain Mutants in Cancer	1	3806.7×	0.002	SMAD2
SMAD2/3 MH2 Domain Mutants in Cancer	1	3806.7×	0.002	SMAD2
Loss of Function of TGFBR1 in Cancer	1	2284.0×	0.002	SMAD2
Loss of Function of SMAD2/3 in Cancer	1	1903.3×	0.002	SMAD2
Signaling by TGF-beta Receptor Complex in Cancer	1	1903.3×	0.002	SMAD2
SMAD2/3 Phosphorylation Motif Mutants in Cancer	1	1903.3×	0.002	SMAD2
TGFBR1 KD Mutants in Cancer	1	1903.3×	0.002	SMAD2
Formation of axial mesoderm	1	815.7×	0.004	SMAD2
Signaling by Activin	1	761.3×	0.004	SMAD2
Formation of definitive endoderm	1	713.8×	0.004	SMAD2
FOXO-mediated transcription of cell cycle genes	1	671.8×	0.004	SMAD2
Germ layer formation at gastrulation	1	671.8×	0.004	SMAD2
Transcriptional regulation of pluripotent stem cells	1	543.8×	0.005	SMAD2
Signaling by NODAL	1	496.5×	0.005	SMAD2
Downregulation of TGF-beta receptor signaling	1	407.9×	0.005	SMAD2
FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes	1	380.7×	0.005	SMAD2
Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer	1	368.4×	0.005	SMAD2
Downregulation of SMAD2/3:SMAD4 transcriptional activity	1	368.4×	0.005	SMAD2
FOXO-mediated transcription	1	335.9×	0.005	SMAD2
TGF-beta receptor signaling activates SMADs	1	326.3×	0.005	SMAD2
SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription	1	308.6×	0.005	SMAD2
Gastrulation	1	259.6×	0.006	SMAD2
Signaling by TGF-beta Receptor Complex	1	200.3×	0.007	SMAD2
Deubiquitination	1	124.1×	0.012	SMAD2
Signaling by TGFB family members	1	115.3×	0.012	SMAD2
Diseases of signal transduction by growth factor receptors and second messengers	1	56.8×	0.023	SMAD2
Ub-specific processing proteases	1	53.1×	0.024	SMAD2
RNA Polymerase II Transcription	1	22.5×	0.055	SMAD2
Post-translational protein modification	1	19.2×	0.063	SMAD2

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
zygotic specification of dorsal/ventral axis	1	5617.3×	0.003	SMAD2
paraxial mesoderm morphogenesis	1	5617.3×	0.003	SMAD2
trophoblast cell migration	1	2407.4×	0.003	SMAD2
odontoblast differentiation	1	2106.5×	0.003	SMAD2
determination of left/right asymmetry in lateral mesoderm	1	1872.4×	0.003	SMAD2
pericardium development	1	1872.4×	0.003	SMAD2
embryonic foregut morphogenesis	1	1685.2×	0.003	SMAD2
response to cholesterol	1	1685.2×	0.003	SMAD2
endoderm formation	1	1404.3×	0.003	SMAD2
primary miRNA processing	1	1296.3×	0.003	SMAD2
secondary palate development	1	1203.7×	0.003	SMAD2
nodal signaling pathway	1	1123.5×	0.003	SMAD2
pulmonary valve morphogenesis	1	936.2×	0.003	SMAD2
activin receptor signaling pathway	1	887.0×	0.003	SMAD2
endocardial cushion morphogenesis	1	842.6×	0.003	SMAD2
regulation of transforming growth factor beta receptor signaling pathway	1	802.5×	0.003	SMAD2
organ growth	1	732.7×	0.003	SMAD2
SMAD protein signal transduction	1	732.7×	0.003	SMAD2
gastrulation	1	702.2×	0.003	SMAD2
pancreas development	1	674.1×	0.003	SMAD2
negative regulation of ossification	1	624.1×	0.004	SMAD2
embryonic cranial skeleton morphogenesis	1	581.1×	0.004	SMAD2
mesoderm formation	1	495.6×	0.004	SMAD2
ureteric bud development	1	455.5×	0.004	SMAD2
positive regulation of BMP signaling pathway	1	455.5×	0.004	SMAD2
aortic valve morphogenesis	1	432.1×	0.004	SMAD2
insulin secretion	1	432.1×	0.004	SMAD2
positive regulation of epithelial to mesenchymal transition	1	318.0×	0.005	SMAD2
cell fate commitment	1	295.6×	0.005	SMAD2
negative regulation of cell differentiation	1	285.6×	0.005	SMAD2

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
SMAD2	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
SMAD2	20	Binding:20

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	SMAD2

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)
SMAD2	20	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.