Loeys-Dietz syndrome 4

Summary

Loeys-Dietz syndrome 4 (MONDO:0013897) is a disease caused by TGFB2 (GenCC Definitive), with 10 cohort genes.

At a glance

• Causal gene: TGFB2 (GenCC Definitive)
• Cohort genes: 10
• ClinVar variants: 612

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Loeys-Dietz syndrome 4
Mondo ID	MONDO:0013897
OMIM	614816
DOID	DOID:0070233
UMLS	C3553762
MedGen	766676
GARD	0010588
Is cancer (heuristic)	no

Also known as: LDS4 · Loeys-Dietz syndrome 4 · Loeys-Dietz syndrome caused by mutation in TGFB2 · Loeys-Dietz syndrome type 4 · TGFB2 Loeys-Dietz syndrome

Data availability: 612 ClinVar variants · 5 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 4

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

273 uncertain significance, 166 likely benign, 58 pathogenic, 25 conflicting classifications of pathogenicity, 25 benign, 19 benign/likely benign, 17 likely pathogenic, 17 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1199386	Single allele	AIDA	Pathogenic	no assertion criteria provided
224870	Single allele	BPNT1	Pathogenic	criteria provided, single submitter
224871	Single allele	EPRS1	Pathogenic	criteria provided, single submitter
1199384	Single allele	ESRRG	Pathogenic	no assertion criteria provided
1199385	Single allele	RRP15	Pathogenic	no assertion criteria provided
1199383	Single allele	SPATA17	Pathogenic	no assertion criteria provided
1068936	NM_003238.6(TGFB2):c.986dup (p.Asp329fs)	TGFB2	Pathogenic	criteria provided, single submitter
1075270	NM_003238.6(TGFB2):c.194dup (p.Glu66fs)	TGFB2	Pathogenic	criteria provided, multiple submitters, no conflicts
1075660	NM_003238.6(TGFB2):c.274G>T (p.Glu92Ter)	TGFB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076183	NM_003238.6(TGFB2):c.404C>G (p.Ser135Ter)	TGFB2	Pathogenic	criteria provided, single submitter
1199382	Single allele	TGFB2	Pathogenic	no assertion criteria provided
1205778	NM_003238.6(TGFB2):c.821del (p.Asn274fs)	TGFB2	Pathogenic	criteria provided, multiple submitters, no conflicts
1299635	NM_003238.6(TGFB2):c.912_930del (p.Asp305fs)	TGFB2	Pathogenic	criteria provided, single submitter
1351917	NM_003238.6(TGFB2):c.456dup (p.Arg153fs)	TGFB2	Pathogenic	criteria provided, single submitter
1393330	NM_003238.6(TGFB2):c.329_330dup (p.Phe111fs)	TGFB2	Pathogenic	criteria provided, single submitter
1451388	NM_003238.6(TGFB2):c.145A>T (p.Lys49Ter)	TGFB2	Pathogenic	criteria provided, multiple submitters, no conflicts
1452939	NM_003238.6(TGFB2):c.196del (p.Glu66fs)	TGFB2	Pathogenic	criteria provided, multiple submitters, no conflicts
1452940	NM_003238.6(TGFB2):c.171T>A (p.Tyr57Ter)	TGFB2	Pathogenic	criteria provided, single submitter
1455704	NC_000001.10:g.(?218520044)(218607810_?)del	TGFB2	Pathogenic	criteria provided, single submitter
1458168	NC_000001.10:g.(?218520044)(218614704_?)del	TGFB2	Pathogenic	criteria provided, single submitter
1458546	NM_003238.6(TGFB2):c.868dup (p.Arg290fs)	TGFB2	Pathogenic	criteria provided, single submitter
1741047	NM_003238.6(TGFB2):c.450_451del (p.Arg150fs)	TGFB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1804996	NM_003238.6(TGFB2):c.933-1G>A	TGFB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1804997	NM_003238.6(TGFB2):c.127C>T (p.Gln43Ter)	TGFB2	Pathogenic	criteria provided, single submitter
180536	NM_003238.6(TGFB2):c.544C>T (p.Gln182Ter)	TGFB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2002460	NM_003238.6(TGFB2):c.655G>T (p.Gly219Ter)	TGFB2	Pathogenic	criteria provided, single submitter
2031447	NM_003238.6(TGFB2):c.765del (p.Thr256fs)	TGFB2	Pathogenic	criteria provided, single submitter
213841	NM_003238.6(TGFB2):c.583G>T (p.Glu195Ter)	TGFB2	Pathogenic	criteria provided, multiple submitters, no conflicts
213845	NM_003238.6(TGFB2):c.895C>T (p.Arg299Trp)	TGFB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
213849	NM_003238.6(TGFB2):c.821dup (p.Asn274fs)	TGFB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 7 · 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
TGFB2	Definitive	Autosomal dominant	Loeys-Dietz syndrome 4	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TGFB2	Orphanet:60030	Loeys-Dietz syndrome
TGFB2	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
TGFB3	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
TGFB3	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
TGFB3	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
TGFB3	Orphanet:60030	Loeys-Dietz syndrome
TGFB3	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection

Cohort genes → proteins

10 cohort genes, 8 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	10

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TGFB2	HGNC:11768	ENSG00000092969	P61812	Transforming growth factor beta-2 proprotein	gencc,clinvar
BPNT1	HGNC:1096	ENSG00000162813	O95861	3’(2’),5’-bisphosphate nucleotidase 1	clinvar
TGFB3	HGNC:11769	ENSG00000119699	P10600	Transforming growth factor beta-3 proprotein	clinvar
RRP15	HGNC:24255	ENSG00000067533	Q9Y3B9	RRP15-like protein	clinvar
SPATA17	HGNC:25184	ENSG00000162814	Q96L03	Spermatogenesis-associated protein 17	clinvar
AIDA	HGNC:25761	ENSG00000186063	Q96BJ3	Axin interactor, dorsalization-associated protein	clinvar
EPRS1	HGNC:3418	ENSG00000136628	P07814	Bifunctional glutamate/proline–tRNA ligase	clinvar
ESRRG	HGNC:3474	ENSG00000196482	P62508	Estrogen-related receptor gamma	clinvar
TGFB2-AS1	HGNC:50628	ENSG00000232480		TGFB2 antisense RNA 1	clinvar
TGFB2-OT1	HGNC:50629	ENSG00000281453		TGFB2 overlapping transcript 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TGFB2	Transforming growth factor beta-2 proprotein	Precursor of the Latency-associated peptide (LAP) and Transforming growth factor beta-2 (TGF-beta-2) chains, which constitute the regulatory and active subunit of TGF-beta-2, respectively.
BPNT1	3’(2’),5’-bisphosphate nucleotidase 1	Phosphatase that converts 3’(2’)-phosphoadenosine 5’-phosphate (PAP) to AMP and inositol 1,4-bisphosphate (Ins(1,4)P2) to inositol 4-phosphate.
TGFB3	Transforming growth factor beta-3 proprotein	Transforming growth factor beta-3 proprotein: Precursor of the Latency-associated peptide (LAP) and Transforming growth factor beta-3 (TGF-beta-3) chains, which constitute the regulatory and active subunit of TGF-beta-3, respectively.
AIDA	Axin interactor, dorsalization-associated protein	Acts as a ventralizing factor during embryogenesis.
EPRS1	Bifunctional glutamate/proline–tRNA ligase	Multifunctional protein which primarily functions within the aminoacyl-tRNA synthetase multienzyme complex, also known as multisynthetase complex.
ESRRG	Estrogen-related receptor gamma	Orphan receptor that acts as a transcription activator in the absence of bound ligand.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 7 · Druggable fraction: 0.3

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
Nuclear receptor	1	38.6×	0.102
Phosphatase	1	8.4×	0.226
Other/Unknown	7	1.2×	0.378
Enzyme (other)	1	1.2×	0.581

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TGFB2	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGFb2
BPNT1	Phosphatase	yes	3.1.3.7	Inositol_monophosphatase-like, Inositol_monophosphatase_CS, Inositol_monoP_metal-BS
TGFB3	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGF-beta-like
RRP15	Other/Unknown	no		Rrp15
SPATA17	Other/Unknown	no		IQ_motif_EF-hand-BS, P-loop_NTPase, ASPM
AIDA	Other/Unknown	no		AIDA_N, Aida_C, C2_domain_sf
EPRS1	Enzyme (other)	yes	6.1.1.15	WHEP-TRS_dom, Glu/Gln-tRNA-synth, aa-tRNA-synth_I_CS
ESRRG	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
TGFB2-AS1	Other/Unknown	no
TGFB2-OT1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

8 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)	10
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	3
cartilage tissue	1
tendon	1
islet of Langerhans	1
mucosa of transverse colon	1
rectum	1
endocervix	1
gall bladder	1
saphenous vein	1
oocyte	1
secondary oocyte	1
bronchial epithelial cell	1
left testis	1
sperm	1
pancreatic ductal cell	1
parietal pleura	1
visceral pleura	1
cortical plate	1
cranial nerve II	1
parotid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TGFB2	206	ubiquitous	marker	calcaneal tendon, tendon, cartilage tissue
BPNT1	232	ubiquitous	marker	islet of Langerhans, mucosa of transverse colon, rectum
TGFB3	244	broad	marker	saphenous vein, endocervix, gall bladder
RRP15	277	ubiquitous	marker	secondary oocyte, oocyte, calcaneal tendon
SPATA17	167	broad	marker	sperm, bronchial epithelial cell, left testis
AIDA	256	ubiquitous	marker	parietal pleura, pancreatic ductal cell, visceral pleura
EPRS1	295	ubiquitous	marker	parotid gland, cranial nerve II, cortical plate
ESRRG	250	broad	marker	pons, nephron tubule, endothelial cell
TGFB2-AS1	114	broad	yes	male germ line stem cell (sensu Vertebrata) in testis, skeletal muscle tissue, calcaneal tendon
TGFB2-OT1	127	broad	yes	amygdala, anterior cingulate cortex, Ammon’s horn

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EPRS1	7,775
TGFB3	2,972
RRP15	2,564
SPATA17	2,441
ESRRG	1,637
BPNT1	1,209
AIDA	392
TGFB2	43
TGFB2-AS1	0
TGFB2-OT1	0

Intra-cohort edges

A	B	Sources
BPNT1	EPRS1	string_interaction
RRP15	SPATA17	string_interaction

Structural data

PDB: 6 · AlphaFold-only: 2 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ESRRG	P62508	43
EPRS1	P07814	33
TGFB2	P61812	11
TGFB3	P10600	11
RRP15	Q9Y3B9	4
BPNT1	O95861	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
AIDA	Q96BJ3	86.37
SPATA17	Q96L03	81.98

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 31. Enrichment computed across 10 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Elastic fibre formation	2	134.3×	0.001	TGFB2, TGFB3
TGF-beta receptor signaling activates SMADs	2	130.5×	0.001	TGFB2, TGFB3
Molecules associated with elastic fibres	2	123.5×	0.001	TGFB2, TGFB3
Signaling by TGF-beta Receptor Complex	2	80.1×	0.002	TGFB2, TGFB3
Response to elevated platelet cytosolic Ca2+	2	65.3×	0.002	TGFB2, TGFB3
ECM proteoglycans	2	60.1×	0.002	TGFB2, TGFB3
Signaling by TGFB family members	2	46.1×	0.003	TGFB2, TGFB3
Platelet activation, signaling and aggregation	2	42.3×	0.003	TGFB2, TGFB3
Platelet degranulation	2	35.1×	0.004	TGFB2, TGFB3
Extracellular matrix organization	2	25.2×	0.008	TGFB2, TGFB3
TGFBR3 regulates TGF-beta signaling	1	285.5×	0.010	TGFB2
Hemostasis	2	14.4×	0.019	TGFB2, TGFB3
Cytosolic sulfonation of small molecules	1	103.8×	0.023	BPNT1
Cytosolic tRNA aminoacylation	1	87.8×	0.025	EPRS1
Signaling by TGFBR3	1	73.7×	0.027	TGFB2
tRNA processing	1	71.4×	0.027	EPRS1
tRNA modification in the nucleus and cytosol	1	58.6×	0.029	EPRS1
tRNA Aminoacylation	1	57.1×	0.029	EPRS1
Phase II - Conjugation of compounds	1	55.7×	0.029	BPNT1
Nuclear Receptor transcription pathway	1	40.1×	0.037	ESRRG
Selenoamino acid metabolism	1	39.4×	0.037	EPRS1
Transcriptional and post-translational regulation of MITF-M expression and activity	1	35.7×	0.039	EPRS1
Biological oxidations	1	25.9×	0.051	BPNT1
MITF-M-regulated melanocyte development	1	22.8×	0.056	EPRS1
Metabolism	2	4.7×	0.077	BPNT1, EPRS1
Metabolism of amino acids and derivatives	1	13.5×	0.086	EPRS1
Translation	1	12.4×	0.087	EPRS1
Signal Transduction	2	4.1×	0.087	TGFB2, TGFB3
Metabolism of RNA	1	8.3×	0.122	EPRS1
Developmental Biology	1	2.9×	0.311	EPRS1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
uterine wall breakdown	2	2407.4×	2e-05	TGFB2, TGFB3
salivary gland morphogenesis	2	687.8×	2e-04	TGFB2, TGFB3
negative regulation of macrophage cytokine production	2	343.9×	5e-04	TGFB2, TGFB3
secondary palate development	2	343.9×	5e-04	TGFB2, TGFB3
cell-cell junction organization	2	178.3×	0.001	TGFB2, TGFB3
odontogenesis	2	150.5×	0.001	TGFB2, TGFB3
response to progesterone	2	141.6×	0.001	TGFB2, TGFB3
face morphogenesis	2	141.6×	0.001	TGFB2, TGFB3
positive regulation of SMAD protein signal transduction	2	109.4×	0.002	TGFB2, TGFB3
positive regulation of protein secretion	2	98.3×	0.002	TGFB2, TGFB3
positive regulation of cell division	2	96.3×	0.002	TGFB2, TGFB3
positive regulation of epithelial to mesenchymal transition	2	90.8×	0.002	TGFB2, TGFB3
determination of ventral identity	1	2407.4×	0.003	AIDA
regulation of timing of catagen	1	2407.4×	0.003	TGFB2
positive regulation of activation-induced cell death of T cells	1	2407.4×	0.003	TGFB2
regulation of long-chain fatty acid import into cell	1	2407.4×	0.003	EPRS1
regulation of apoptotic process involved in outflow tract morphogenesis	1	2407.4×	0.003	TGFB2
negative regulation of epithelial to mesenchymal transition involved in endocardial cushion formation	1	2407.4×	0.003	TGFB2
glutamyl-tRNA aminoacylation	1	1203.7×	0.005	EPRS1
prolyl-tRNA aminoacylation	1	1203.7×	0.005	EPRS1
cardioblast differentiation	1	1203.7×	0.005	TGFB2
detection of hypoxia	1	1203.7×	0.005	TGFB3
substantia propria of cornea development	1	1203.7×	0.005	TGFB2
transforming growth factor beta receptor signaling pathway	2	45.4×	0.005	TGFB2, TGFB3
positive regulation of integrin biosynthetic process	1	802.5×	0.007	TGFB2
positive regulation of timing of catagen	1	802.5×	0.007	TGFB2
regulation of transforming growth factor beta2 production	1	601.9×	0.007	TGFB2
ascending aorta morphogenesis	1	601.9×	0.007	TGFB2
positive regulation of cardioblast differentiation	1	601.9×	0.007	TGFB2
positive regulation of epithelial to mesenchymal transition involved in endocardial cushion formation	1	601.9×	0.007	TGFB2

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 2 · Undrugged: 8

Druggability breadth: 6 of 10 evidence-associated genes (60%) 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
ESRRG	DIETHYLSTILBESTROL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ESRRG	2	4
TGFB2	1	2
BPNT1	0	0
TGFB3	0	0
RRP15	0	0
SPATA17	0	0
AIDA	0	0
EPRS1	0	0
TGFB2-AS1	0	0
TGFB2-OT1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
DIETHYLSTILBESTROL	4	ESRRG
TAMOXIFEN	4	ESRRG
GALUNISERTIB	2	TGFB2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
ESRRG	135	Binding:121, Functional:13, ADMET:1
EPRS1	5	Binding:5
TGFB2	3	Binding:3
BPNT1	1	Binding:1
TGFB3	1	Binding:1
RRP15	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BPNT1	3.1.3.7	3’(2’),5’-bisphosphate nucleotidase
EPRS1	6.1.1.15, 6.1.1.17	proline-tRNA ligase, glutamate-tRNA ligase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
ESRRG	135

Pharmacogenomics

Cohort genes with a PharmGKB record: 8; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

3 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)
DIETHYLSTILBESTROL	4	ESRRG
TAMOXIFEN	4	ESRRG
GALUNISERTIB	2	TGFB2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ESRRG
B	Phased (≥1) drug, not yet approved	1	TGFB2
C	Druggable family + PDB, no drug	2	BPNT1, EPRS1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	6	TGFB3, RRP15, SPATA17, AIDA, TGFB2-AS1, TGFB2-OT1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
BPNT1	1	—
TGFB3	1	—
RRP15	1	—
SPATA17	0	—
AIDA	0	—
EPRS1	5	—
TGFB2-AS1	0	—
TGFB2-OT1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.