Loeys-Dietz syndrome 6

Summary

Loeys-Dietz syndrome 6 (MONDO:0030500) 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: 15

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Loeys-Dietz syndrome 6
Mondo ID	MONDO:0030500
OMIM	619656
DOID	DOID:0060964
UMLS	C5562041
MedGen	1794251
GARD	0025581
Is cancer (heuristic)	no

Also known as: LDS6

Data availability: 15 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 › Loeys-Dietz syndrome › Loeys-Dietz syndrome 6

Related subtypes (5): Loeys-Dietz syndrome 1, Loeys-Dietz syndrome 2, aneurysm-osteoarthritis syndrome, Loeys-Dietz syndrome 4, Rienhoff syndrome

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

15 retrieved; paginated sample, class counts are floors:

6 uncertain significance, 4 likely pathogenic, 3 pathogenic, 1 pathogenic/likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1327531	NM_005901.6(SMAD2):c.1369G>A (p.Gly457Arg)	SMAD2	Pathogenic	criteria provided, single submitter
1327537	NM_005901.6(SMAD2):c.612dup (p.Asn205Ter)	SMAD2	Pathogenic/Likely pathogenic	no assertion criteria provided
1805110	NM_005901.6(SMAD2):c.748_754del (p.Ser250fs)	SMAD2	Pathogenic	criteria provided, single submitter
4082329	NM_005901.6(SMAD2):c.880C>T (p.Gln294Ter)	SMAD2	Pathogenic	criteria provided, single submitter
1685446	NM_005901.6(SMAD2):c.908C>G (p.Thr303Arg)	SMAD2	Likely pathogenic	criteria provided, single submitter
1722766	NM_005901.6(SMAD2):c.1059T>G (p.Ser353Arg)	SMAD2	Likely pathogenic	criteria provided, single submitter
3895478	NM_005901.6(SMAD2):c.941G>C (p.Gly314Ala)	SMAD2	Likely pathogenic	criteria provided, single submitter
4294517	NM_005901.6(SMAD2):c.1239del (p.Thr413_Ile414insTer)	SMAD2	Likely pathogenic	criteria provided, single submitter
1327530	NM_005901.6(SMAD2):c.1346T>C (p.Leu449Ser)	SMAD2	Uncertain significance	criteria provided, single submitter
1327533	NM_005901.6(SMAD2):c.1163A>G (p.Gln388Arg)	SMAD2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1327534	NM_005901.6(SMAD2):c.833C>T (p.Ala278Val)	SMAD2	Uncertain significance	criteria provided, single submitter
1327538	NM_005901.6(SMAD2):c.1082A>C (p.Asn361Thr)	SMAD2	Uncertain significance	criteria provided, single submitter
1521943	NM_005901.6(SMAD2):c.1384C>T (p.Arg462Cys)	SMAD2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1803705	NM_005901.6(SMAD2):c.998G>A (p.Gly333Glu)	SMAD2	Uncertain significance	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	Loeys-Dietz syndrome 6	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.