Loeys-Dietz syndrome 2

Summary

Loeys-Dietz syndrome 2 (MONDO:0012427) is a disease caused by TGFBR2 (GenCC Definitive), with 4 cohort genes.

At a glance

• Causal gene: TGFBR2 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 976

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Loeys-Dietz syndrome 2
Mondo ID	MONDO:0012427
MeSH	C537783
OMIM	610168
Orphanet	284973
DOID	DOID:0070234
NCIT	C114768
UMLS	C2674574
MedGen	382398
GARD	0010586
Is cancer (heuristic)	no

Also known as: LDS2 · Loeys-Dietz syndrome 2 · Loeys-Dietz syndrome caused by mutation in TGFBR2 · Loeys-Dietz syndrome type 2 · Loeys-Dietz syndrome type II · TGFBR2 Loeys-Dietz syndrome

Data availability: 976 ClinVar variants · 4 GenCC gene-disease records · 3 cell lines.

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 2

Related subtypes (5): Loeys-Dietz syndrome 1, aneurysm-osteoarthritis syndrome, Loeys-Dietz syndrome 4, Rienhoff syndrome, Loeys-Dietz syndrome 6

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

600 retrieved; paginated sample, class counts are floors:

321 uncertain significance, 158 likely benign, 54 conflicting classifications of pathogenicity, 18 benign/likely benign, 16 pathogenic, 11 likely pathogenic, 10 pathogenic/likely pathogenic, 7 benign, 5 uncertain significance/uncertain risk allele

ClinVar	Variant (HGVS)	Gene	Classification	Review
1028591	NM_003242.6(TGFBR2):c.1134G>C (p.Arg378Ser)	TGFBR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12504	NM_003242.6(TGFBR2):c.1524G>A (p.Gln508=)	TGFBR2	Pathogenic	criteria provided, single submitter
12505	NM_003242.6(TGFBR2):c.923T>C (p.Leu308Pro)	TGFBR2	Pathogenic	no assertion criteria provided
12506	NM_003242.6(TGFBR2):c.1346C>T (p.Ser449Phe)	TGFBR2	Pathogenic	no assertion criteria provided
12507	NM_003242.6(TGFBR2):c.1609C>T (p.Arg537Cys)	TGFBR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12508	NM_003242.6(TGFBR2):c.1006T>A (p.Tyr336Asn)	TGFBR2	Pathogenic	no assertion criteria provided
12510	NM_003242.6(TGFBR2):c.1069G>T (p.Gly357Trp)	TGFBR2	Pathogenic	no assertion criteria provided
12511	NM_003242.6(TGFBR2):c.1583G>A (p.Arg528His)	TGFBR2	Pathogenic	criteria provided, multiple submitters, no conflicts
12512	NM_003242.6(TGFBR2):c.1582C>T (p.Arg528Cys)	TGFBR2	Pathogenic	criteria provided, multiple submitters, no conflicts
12514	NM_003242.6(TGFBR2):c.1378C>T (p.Arg460Cys)	TGFBR2	Pathogenic	criteria provided, multiple submitters, no conflicts
12515	NM_003242.6(TGFBR2):c.1379G>A (p.Arg460His)	TGFBR2	Pathogenic	criteria provided, multiple submitters, no conflicts
12517	NM_003242.6(TGFBR2):c.1273A>G (p.Met425Val)	TGFBR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12518	NM_003242.6(TGFBR2):c.1280C>T (p.Pro427Leu)	TGFBR2	Pathogenic	no assertion criteria provided
12519	NM_003242.6(TGFBR2):c.1483C>T (p.Arg495Ter)	TGFBR2	Pathogenic	criteria provided, multiple submitters, no conflicts
1299545	NM_003242.6(TGFBR2):c.1582C>A (p.Arg528Ser)	TGFBR2	Pathogenic	criteria provided, single submitter
1332771	NM_003242.6(TGFBR2):c.1379G>C (p.Arg460Pro)	TGFBR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
165398	NM_003242.6(TGFBR2):c.1580C>T (p.Ala527Val)	TGFBR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1687722	NM_003242.6(TGFBR2):c.1301T>A (p.Met434Lys)	TGFBR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
177704	NM_003242.6(TGFBR2):c.1067G>C (p.Arg356Pro)	TGFBR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
180541	NM_003242.6(TGFBR2):c.1570G>A (p.Asp524Asn)	TGFBR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
213934	NM_003242.6(TGFBR2):c.1489C>T (p.Arg497Ter)	TGFBR2	Pathogenic	criteria provided, multiple submitters, no conflicts
217016	NM_003242.6(TGFBR2):c.1408T>G (p.Tyr470Asp)	TGFBR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2574078	NM_003242.6(TGFBR2):c.1330C>T (p.Gln444Ter)	TGFBR2	Pathogenic	no assertion criteria provided
263412	NM_003242.6(TGFBR2):c.831G>T (p.Lys277Asn)	TGFBR2	Pathogenic	criteria provided, multiple submitters, no conflicts
265447	NM_003242.6(TGFBR2):c.1336G>A (p.Asp446Asn)	TGFBR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3363263	NM_003242.6(TGFBR2):c.1070G>A (p.Gly357Glu)	TGFBR2	Pathogenic	criteria provided, multiple submitters, no conflicts
12516	NM_003242.6(TGFBR2):c.1397-2A>G	TGFBR2	Likely pathogenic	criteria provided, single submitter
1297003	NM_003242.6(TGFBR2):c.860G>C (p.Trp287Ser)	TGFBR2	Likely pathogenic	criteria provided, single submitter
1332770	NM_003242.6(TGFBR2):c.1378C>A (p.Arg460Ser)	TGFBR2	Likely pathogenic	criteria provided, single submitter
1332843	NM_003242.6(TGFBR2):c.1102T>C (p.Cys368Arg)	TGFBR2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 8 · 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
TGFBR2	Definitive	Autosomal dominant	Loeys-Dietz syndrome 2	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TGFBR2	Orphanet:144	Lynch syndrome
TGFBR2	Orphanet:284973	Marfan syndrome type 2
TGFBR2	Orphanet:60030	Loeys-Dietz syndrome
TGFBR2	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
TGFBR2	Orphanet:99977	Squamous cell carcinoma of the esophagus
TMPO	Orphanet:154	Familial isolated dilated cardiomyopathy
ACOX1	Orphanet:2971	Peroxisomal acyl-CoA oxidase deficiency
ACOX1	Orphanet:631248	Mitchell Syndrome

Cohort genes → proteins

4 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TGFBR2	HGNC:11773	ENSG00000163513	P37173	TGF-beta receptor type-2	gencc,clinvar
TMPO	HGNC:11875	ENSG00000120802	P42166	Lamina-associated polypeptide 2, isoform alpha	clinvar
ACOX1	HGNC:119	ENSG00000161533	Q15067	Peroxisomal acyl-coenzyme A oxidase 1	clinvar
TMPO-AS1	HGNC:44158	ENSG00000257167		TMPO antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TGFBR2	TGF-beta receptor type-2	Transmembrane serine/threonine kinase forming with the TGF-beta type I serine/threonine kinase receptor, TGFBR1, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3.
TMPO	Lamina-associated polypeptide 2, isoform alpha	May be involved in the structural organization of the nucleus and in the post-mitotic nuclear assembly.
ACOX1	Peroxisomal acyl-coenzyme A oxidase 1	Involved in the initial and rate-limiting step of peroxisomal beta-oxidation of straight-chain saturated and unsaturated very-long-chain fatty acids.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.5

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	6.9×	0.410
Enzyme (other)	1	3.0×	0.441
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TGFBR2	Kinase	yes	2.7.10.2	TGFB_receptor, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
TMPO	Other/Unknown	no		LEM_dom, LEM/LEM-like_dom_sf, LEM-like_dom
ACOX1	Enzyme (other)	yes	1.3.3.6	Acyl-CoA_oxidase_C, AcylCoA_DH/ox_M, AcylCoA_DH/oxidase_NM_dom_sf
TMPO-AS1	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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
parietal pleura	1
pericardium	1
tibia	1
embryo	1
ganglionic eminence	1
ventricular zone	1
buccal mucosa cell	1
duodenum	1
jejunal mucosa	1
left testis	1
male germ line stem cell (sensu Vertebrata) in testis	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TGFBR2	289	ubiquitous	marker	pericardium, tibia, parietal pleura
TMPO	287	ubiquitous	marker	ventricular zone, ganglionic eminence, embryo
ACOX1	290	ubiquitous	marker	jejunal mucosa, buccal mucosa cell, duodenum
TMPO-AS1	157	ubiquitous	yes	male germ line stem cell (sensu Vertebrata) in testis, left testis, right testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TGFBR2	5,777
ACOX1	3,503
TMPO	1,127
TMPO-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TGFBR2	P37173	22
TMPO	P42166	14

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ACOX1	Q15067	93.95

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 45. Enrichment computed across 4 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
TGFBR2 MSI Frameshift Mutants in Cancer	1	1903.3×	0.008	TGFBR2
Loss of Function of TGFBR2 in Cancer	1	1268.9×	0.008	TGFBR2
TGFBR2 Kinase Domain Mutants in Cancer	1	1268.9×	0.008	TGFBR2
TGFBR1 LBD Mutants in Cancer	1	951.7×	0.008	TGFBR2
Loss of Function of TGFBR1 in Cancer	1	761.3×	0.008	TGFBR2
Loss of Function of SMAD2/3 in Cancer	1	634.4×	0.008	TGFBR2
Signaling by TGF-beta Receptor Complex in Cancer	1	634.4×	0.008	TGFBR2
SMAD2/3 Phosphorylation Motif Mutants in Cancer	1	634.4×	0.008	TGFBR2
TGFBR1 KD Mutants in Cancer	1	634.4×	0.008	TGFBR2
TYSND1 cleaves peroxisomal proteins	1	475.8×	0.009	ACOX1
TGFBR3 regulates TGF-beta signaling	1	475.8×	0.009	TGFBR2
Beta-oxidation of very long chain fatty acids	1	292.8×	0.013	ACOX1
Depolymerization of the Nuclear Lamina	1	253.8×	0.013	TMPO
alpha-linolenic acid (ALA) metabolism	1	237.9×	0.013	ACOX1
TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition)	1	223.9×	0.013	TGFBR2
Initiation of Nuclear Envelope (NE) Reformation	1	200.3×	0.014	TMPO
Nuclear Envelope Breakdown	1	152.3×	0.017	TMPO
Downregulation of TGF-beta receptor signaling	1	135.9×	0.018	TGFBR2
Signaling by TGFBR3	1	122.8×	0.019	TGFBR2
TGF-beta receptor signaling activates SMADs	1	108.8×	0.021	TGFBR2
RHOF GTPase cycle	1	86.5×	0.025	TMPO
RHOD GTPase cycle	1	68.0×	0.028	TMPO
Signaling by TGF-beta Receptor Complex	1	66.8×	0.028	TGFBR2
RHOJ GTPase cycle	1	66.8×	0.028	TMPO
Protein localization	1	63.4×	0.028	ACOX1
Peroxisomal protein import	1	57.7×	0.030	ACOX1
RHOG GTPase cycle	1	49.4×	0.033	TMPO
RHOC GTPase cycle	1	48.8×	0.033	TMPO
RAC2 GTPase cycle	1	42.3×	0.035	TMPO
Deubiquitination	1	41.4×	0.035	TGFBR2

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
positive regulation of tolerance induction to self antigen	1	8426.0×	0.002	TGFBR2
positive regulation of B cell tolerance induction	1	8426.0×	0.002	TGFBR2
very long-chain fatty acid beta-oxidation	1	8426.0×	0.002	ACOX1
inferior endocardial cushion morphogenesis	1	8426.0×	0.002	TGFBR2
bronchus morphogenesis	1	4213.0×	0.003	TGFBR2
mammary gland morphogenesis	1	4213.0×	0.003	TGFBR2
miRNA transport	1	2808.7×	0.003	TGFBR2
positive regulation of T cell tolerance induction	1	2106.5×	0.003	TGFBR2
positive regulation of NK T cell differentiation	1	2106.5×	0.003	TGFBR2
Langerhans cell differentiation	1	2106.5×	0.003	TGFBR2
positive regulation of epithelial to mesenchymal transition involved in endocardial cushion formation	1	2106.5×	0.003	TGFBR2
tricuspid valve morphogenesis	1	1685.2×	0.003	TGFBR2
endocardial cushion fusion	1	1685.2×	0.003	TGFBR2
growth plate cartilage chondrocyte growth	1	1685.2×	0.003	TGFBR2
lens fiber cell apoptotic process	1	1685.2×	0.003	TGFBR2
trachea formation	1	1203.7×	0.004	TGFBR2
lung lobe morphogenesis	1	1053.2×	0.004	TGFBR2
membranous septum morphogenesis	1	842.6×	0.004	TGFBR2
response to cholesterol	1	842.6×	0.004	TGFBR2
positive regulation of CD4-positive, alpha-beta T cell proliferation	1	842.6×	0.004	TGFBR2
cardiac left ventricle morphogenesis	1	766.0×	0.004	TGFBR2
peroxisome fission	1	766.0×	0.004	ACOX1
fatty acid derivative biosynthetic process	1	766.0×	0.004	ACOX1
hydrogen peroxide biosynthetic process	1	702.2×	0.004	ACOX1
regulation of stem cell proliferation	1	702.2×	0.004	TGFBR2
fatty acid catabolic process	1	648.1×	0.005	ACOX1
atrioventricular valve morphogenesis	1	601.9×	0.005	TGFBR2
secondary palate development	1	601.9×	0.005	TGFBR2
fatty acid beta-oxidation using acyl-CoA oxidase	1	561.7×	0.005	ACOX1
fatty acid oxidation	1	526.6×	0.005	ACOX1

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 4 evidence-associated genes (75%) 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
TGFBR2	PONATINIB
ACOX1	ALECTINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TGFBR2	22	4
ACOX1	3	4
TMPO	0	0
TMPO-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	TGFBR2
VEMURAFENIB	4	TGFBR2
FEDRATINIB	4	TGFBR2
SORAFENIB	4	TGFBR2
DABRAFENIB	4	TGFBR2
TOVORAFENIB	4	TGFBR2
PAZOPANIB	4	TGFBR2
DASATINIB	4	TGFBR2
ALECTINIB	4	ACOX1
HYDRALAZINE	4	ACOX1
CANERTINIB	3	TGFBR2
ALVOCIDIB	3	TGFBR2
LESTAURTINIB	3	TGFBR2
MASITINIB	3	ACOX1
GALUNISERTIB	2	TGFBR2
SCH-900776	2	TGFBR2
DANUSERTIB	2	TGFBR2
TG100-801	2	TGFBR2
R-406	2	TGFBR2
ENMD-2076	2	TGFBR2
AT-9283	2	TGFBR2
BMS-387032	1	TGFBR2
RGB-286638	1	TGFBR2
CYC-116	1	TGFBR2
AST-487	1	TGFBR2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
TGFBR2	188	Binding:188
TMPO	7	Binding:7
ACOX1	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TGFBR2	2.7.10.2	non-specific protein-tyrosine kinase
ACOX1	1.3.3.6	acyl-CoA oxidase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TGFBR2	188

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

25 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)
PONATINIB	4	TGFBR2
VEMURAFENIB	4	TGFBR2
FEDRATINIB	4	TGFBR2
SORAFENIB	4	TGFBR2
DABRAFENIB	4	TGFBR2
TOVORAFENIB	4	TGFBR2
PAZOPANIB	4	TGFBR2
DASATINIB	4	TGFBR2
ALECTINIB	4	ACOX1
HYDRALAZINE	4	ACOX1
CANERTINIB	3	TGFBR2
ALVOCIDIB	3	TGFBR2
LESTAURTINIB	3	TGFBR2
MASITINIB	3	ACOX1
GALUNISERTIB	2	TGFBR2
SCH-900776	2	TGFBR2
DANUSERTIB	2	TGFBR2
TG100-801	2	TGFBR2
R-406	2	TGFBR2
ENMD-2076	2	TGFBR2
AT-9283	2	TGFBR2
BMS-387032	1	TGFBR2
RGB-286638	1	TGFBR2
CYC-116	1	TGFBR2
AST-487	1	TGFBR2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	TGFBR2, ACOX1
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	TMPO, TMPO-AS1

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)
TMPO	7	—
TMPO-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.