Rienhoff syndrome

Summary

Rienhoff syndrome (MONDO:0014262) is a disease caused by TGFB3 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: TGFB3 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 514

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Rienhoff syndrome
Mondo ID	MONDO:0014262
EFO	EFO:1000012
OMIM	615582
DOID	DOID:0070236
UMLS	C3810012
MedGen	816342
GARD	0012356
Is cancer (heuristic)	no

Also known as: LDS5 · Loeys-Dietz syndrome 5 · Loeys-Dietz syndrome type 5 · Rienhoff syndrome

Data availability: 514 ClinVar variants · 6 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › Rienhoff syndrome

Related subtypes (47): symphalangism, cartilage cancer, vertebral column disorder, patellar tendinitis, necrosis of ear ossicle, laryngeal cartilage cancer, ochronosis disorder, chondroma, periodontal disorder, posterior cranial fossa meningioma, anterior cranial fossa meningioma, middle cranial fossa meningioma, bone marrow disorder, cranial nodular fasciitis, flatfoot, bone disorder, skeletal tuberculosis, arthropathy, tooth disorder, primary basilar invagination, Brachymorphism-onychodysplasia-dysphalangism syndrome, cherubism, fibrodysplasia ossificans progressiva, Marfan syndrome, Buschke-Ollendorff syndrome, scalp defects-postaxial polydactyly syndrome, cartilage-hair hypoplasia, Teebi-Shaltout syndrome, short stature-auditory canal atresia-mandibular hypoplasia-skeletal anomalies syndrome, ossification of the posterior longitudinal ligament of the spine, temtamy preaxial brachydactyly syndrome, metaphyseal undermodeling, spondylar dysplasia, and overgrowth, Al-Gazali syndrome, brachydactyly-syndactyly syndrome, endocrine-cerebro-osteodysplasia syndrome, metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria, multiple congenital anomalies-hypotonia-seizures syndrome 3, Coffin-Siris syndrome, microcephaly-brachydactyly-kyphoscoliosis syndrome, cartilage development disorder, syndactyly, polydactyly, brachydactyly, sternal neoplasm, short stature, amelogenesis imperfecta, and skeletal dysplasia with scoliosis, skeletal ligament disorder, brachydactyly-syndactyly-oligodactyly 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

514 retrieved; paginated sample, class counts are floors:

228 uncertain significance, 171 likely benign, 35 pathogenic, 34 conflicting classifications of pathogenicity, 18 likely pathogenic, 16 benign/likely benign, 10 pathogenic/likely pathogenic, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1072149	NM_003239.5(TGFB3):c.990G>A (p.Trp330Ter)	TGFB3	Pathogenic	criteria provided, single submitter
1075580	NM_003239.5(TGFB3):c.170dup (p.Pro57_Glu58insTer)	TGFB3	Pathogenic	criteria provided, single submitter
1215028	NM_003239.5(TGFB3):c.621del (p.Val208fs)	TGFB3	Pathogenic	criteria provided, multiple submitters, no conflicts
1369504	NM_003239.5(TGFB3):c.996G>A (p.Trp332Ter)	TGFB3	Pathogenic	criteria provided, single submitter
1392107	NM_003239.5(TGFB3):c.723del (p.Asn241fs)	TGFB3	Pathogenic	criteria provided, single submitter
143945	NM_003239.5(TGFB3):c.899G>A (p.Arg300Gln)	TGFB3	Pathogenic	criteria provided, multiple submitters, no conflicts
1451952	NM_003239.5(TGFB3):c.355del (p.Glu119fs)	TGFB3	Pathogenic	criteria provided, single submitter
1453884	NM_003239.5(TGFB3):c.436del (p.Leu146fs)	TGFB3	Pathogenic	criteria provided, single submitter
1764874	NM_003239.5(TGFB3):c.884dup (p.Gln296fs)	TGFB3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2014576	NM_003239.5(TGFB3):c.170del (p.Pro57fs)	TGFB3	Pathogenic	criteria provided, single submitter
2022384	NM_003239.5(TGFB3):c.170_171del (p.Pro57fs)	TGFB3	Pathogenic	criteria provided, single submitter
2026166	NM_003239.5(TGFB3):c.722del (p.Asn241fs)	TGFB3	Pathogenic	criteria provided, single submitter
2029032	NM_003239.5(TGFB3):c.95_96insA (p.Phe32fs)	TGFB3	Pathogenic	criteria provided, single submitter
203489	NM_003239.5(TGFB3):c.754+2T>C	TGFB3	Pathogenic	no assertion criteria provided
203490	NM_003239.5(TGFB3):c.898C>T (p.Arg300Trp)	TGFB3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
203491	NM_003239.5(TGFB3):c.704del (p.Asn235fs)	TGFB3	Pathogenic	no assertion criteria provided
2084927	NM_003239.5(TGFB3):c.912dup (p.Asn305fs)	TGFB3	Pathogenic	criteria provided, single submitter
2117806	NM_003239.5(TGFB3):c.878del (p.Gln293fs)	TGFB3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2126250	NM_003239.5(TGFB3):c.638del (p.Leu212_Leu213insTer)	TGFB3	Pathogenic	criteria provided, single submitter
2138172	NM_003239.5(TGFB3):c.427A>T (p.Arg143Ter)	TGFB3	Pathogenic	criteria provided, single submitter
2751751	NM_003239.5(TGFB3):c.516+1G>T	TGFB3	Pathogenic	criteria provided, single submitter
2783914	NM_003239.5(TGFB3):c.547C>T (p.Gln183Ter)	TGFB3	Pathogenic	criteria provided, single submitter
2806440	NM_003239.5(TGFB3):c.496C>T (p.Gln166Ter)	TGFB3	Pathogenic	criteria provided, single submitter
2862180	NM_003239.5(TGFB3):c.496_497del (p.Gln166fs)	TGFB3	Pathogenic	criteria provided, single submitter
3244030	NC_000014.8:g.(?76425530)(76447236_?)del	TGFB3	Pathogenic	criteria provided, single submitter
3244031	NC_000014.8:g.(?76446865)(76447236_?)del	TGFB3	Pathogenic	criteria provided, single submitter
3244032	NC_000014.8:g.(?76425530)(76427439_?)del	TGFB3	Pathogenic	criteria provided, single submitter
3632516	NM_003239.5(TGFB3):c.466dup (p.Val156fs)	TGFB3	Pathogenic	criteria provided, single submitter
3644729	NM_003239.5(TGFB3):c.583_584dup (p.Thr196fs)	TGFB3	Pathogenic	criteria provided, single submitter
3654964	NM_003239.5(TGFB3):c.973del (p.Arg325fs)	TGFB3	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 6 · 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
TGFB3	Definitive	Autosomal dominant	Rienhoff syndrome	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
ESRRB	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TGFB3	HGNC:11769	ENSG00000119699	P10600	Transforming growth factor beta-3 proprotein	gencc,clinvar
ESRRB	HGNC:3473	ENSG00000119715	O95718	Steroid hormone receptor ERR2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
ESRRB	Steroid hormone receptor ERR2	Transcription factor that binds a canonical ESRRB recognition (ERRE) sequence 5’TCAAGGTCA-3’ localized on promoter and enhancer of targets genes regulating their expression or their transcription activity.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · 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
Nuclear receptor	1	192.9×	0.010
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TGFB3	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGF-beta-like
ESRRB	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
endocervix	1
gall bladder	1
saphenous vein	1
adult mammalian kidney	1
male germ line stem cell (sensu Vertebrata) in testis	1
metanephros cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TGFB3	244	broad	marker	saphenous vein, endocervix, gall bladder
ESRRB	131	tissue_specific	marker	metanephros cortex, male germ line stem cell (sensu Vertebrata) in testis, adult mammalian kidney

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TGFB3	2,972
ESRRB	1,965

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TGFB3	P10600	11
ESRRB	O95718	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 2 evidence-associated genes (2 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 2 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	1	167.9×	0.025	TGFB3
TGF-beta receptor signaling activates SMADs	1	163.1×	0.025	TGFB3
Molecules associated with elastic fibres	1	154.3×	0.025	TGFB3
Signaling by TGF-beta Receptor Complex	1	100.2×	0.025	TGFB3
Nuclear Receptor transcription pathway	1	100.2×	0.025	ESRRB
Response to elevated platelet cytosolic Ca2+	1	81.6×	0.025	TGFB3
ECM proteoglycans	1	75.1×	0.025	TGFB3
Signaling by TGFB family members	1	57.7×	0.027	TGFB3
Platelet activation, signaling and aggregation	1	52.9×	0.027	TGFB3
Platelet degranulation	1	43.9×	0.029	TGFB3
Extracellular matrix organization	1	31.6×	0.037	TGFB3
Hemostasis	1	18.0×	0.059	TGFB3
Signal Transduction	1	5.1×	0.187	TGFB3

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
uterine wall breakdown	1	4213.0×	0.005	TGFB3
detection of hypoxia	1	4213.0×	0.005	TGFB3
morula formation	1	2808.7×	0.005	ESRRB
positive regulation of tight junction disassembly	1	1685.2×	0.006	TGFB3
cell dedifferentiation	1	1404.3×	0.006	ESRRB
salivary gland morphogenesis	1	1203.7×	0.006	TGFB3
stem cell division	1	936.2×	0.007	ESRRB
regulation of stem cell division	1	702.2×	0.007	ESRRB
negative regulation of macrophage cytokine production	1	601.9×	0.007	TGFB3
secondary palate development	1	601.9×	0.007	TGFB3
positive regulation of DNA-templated transcription	2	27.9×	0.007	TGFB3, ESRRB
negative regulation of stem cell differentiation	1	421.3×	0.009	ESRRB
negative regulation of vascular associated smooth muscle cell proliferation	1	337.0×	0.009	TGFB3
mammary gland development	1	324.1×	0.009	TGFB3
positive regulation of collagen biosynthetic process	1	324.1×	0.009	TGFB3
cell-cell junction organization	1	312.1×	0.009	TGFB3
positive regulation of filopodium assembly	1	280.9×	0.009	TGFB3
odontogenesis	1	263.3×	0.009	TGFB3
response to progesterone	1	247.8×	0.009	TGFB3
face morphogenesis	1	247.8×	0.009	TGFB3
stem cell population maintenance	1	210.7×	0.009	ESRRB
positive regulation of SMAD protein signal transduction	1	191.5×	0.009	TGFB3
inner ear development	1	187.2×	0.009	ESRRB
photoreceptor cell maintenance	1	179.3×	0.009	ESRRB
lung alveolus development	1	175.5×	0.009	TGFB3
positive regulation of protein secretion	1	172.0×	0.009	TGFB3
positive regulation of stem cell population maintenance	1	172.0×	0.009	ESRRB
positive regulation of cell division	1	168.5×	0.009	TGFB3
positive regulation of transcription by RNA polymerase II	2	14.9×	0.009	TGFB3, ESRRB
positive regulation of epithelial to mesenchymal transition	1	159.0×	0.009	TGFB3

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) 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
ESRRB	ESTRADIOL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ESRRB	2	4
TGFB3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ESTRADIOL	4	ESRRB
GENISTEIN	2	ESRRB

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
ESRRB	27	Binding:19, Functional:8
TGFB3	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

2 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)
ESTRADIOL	4	ESRRB
GENISTEIN	2	ESRRB

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ESRRB
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	TGFB3

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)
TGFB3	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.