Marfan syndrome

Summary

Marfan syndrome (MONDO:0007947) is a disease caused by FBN1 (GenCC Definitive), with 24 cohort genes and 57 clinical trials. The dominant Reactome pathway is TGF-beta receptor signaling activates SMADs (6 cohort genes). Top therapeutic interventions include losartan, atenolol, and perindopril.

At a glance

• Prevalence: 1-5 / 10 000 (Europe) [Orphanet-validated]
• Causal gene: FBN1 (GenCC Definitive)
• Cohort genes: 24
• ClinVar variants: 7,247
• Phenotypes (HPO): 68
• Clinical trials: 57

Clinical features

Epidemiology

Prevalence records

6 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000	20	Europe	Validated
Point prevalence	1-9 / 100 000	7	United Kingdom	Validated
Point prevalence	1-5 / 10 000	10	United States	Validated
Prevalence at birth	1-5 / 10 000	10.2	United Kingdom	Validated
Point prevalence	1-5 / 10 000	15	Worldwide	Not yet validated
Annual incidence	1-5 / 10 000	25	Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

68 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0001519	Disproportionate tall stature	Very frequent (80-99%)
HP:0001533	Slender build	Very frequent (80-99%)
HP:0001763	Pes planus	Very frequent (80-99%)
HP:0002108	Spontaneous pneumothorax	Very frequent (80-99%)
HP:0002616	Aortic root aneurysm	Very frequent (80-99%)
HP:0004942	Aortic aneurysm	Very frequent (80-99%)
HP:0012432	Chronic fatigue	Very frequent (80-99%)
HP:0000768	Pectus carinatum	Very frequent (80-99%)
HP:0001065	Striae distensae	Very frequent (80-99%)
HP:0001166	Arachnodactyly	Very frequent (80-99%)
HP:0000275	Narrow face	Frequent (30-79%)
HP:0000505	Visual impairment	Frequent (30-79%)
HP:0000545	Myopia	Frequent (30-79%)
HP:0000678	Dental crowding	Frequent (30-79%)
HP:0000767	Pectus excavatum	Frequent (30-79%)
HP:0001083	Ectopia lentis	Frequent (30-79%)
HP:0001132	Lens subluxation	Frequent (30-79%)
HP:0001382	Joint hypermobility	Frequent (30-79%)
HP:0001634	Mitral valve prolapse	Frequent (30-79%)
HP:0001653	Mitral regurgitation	Frequent (30-79%)
HP:0001659	Aortic regurgitation	Frequent (30-79%)
HP:0001704	Tricuspid valve prolapse	Frequent (30-79%)
HP:0002360	Sleep abnormality	Frequent (30-79%)
HP:0002647	Aortic dissection	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0002705	High, narrow palate	Frequent (30-79%)
HP:0003179	Protrusio acetabuli	Frequent (30-79%)
HP:0004970	Ascending tubular aorta aneurysm	Frequent (30-79%)
HP:0005059	Arthralgia/arthritis	Frequent (30-79%)
HP:0007800	Increased axial length of the globe	Frequent (30-79%)
HP:0010535	Sleep apnea	Frequent (30-79%)
HP:0010668	Abnormal zygomatic bone morphology	Frequent (30-79%)
HP:0012019	Lens luxation	Frequent (30-79%)
HP:0100775	Dural ectasia	Frequent (30-79%)
HP:0000023	Inguinal hernia	Occasional (5-29%)
HP:0000175	Cleft palate	Occasional (5-29%)
HP:0000268	Dolichocephaly	Occasional (5-29%)
HP:0000278	Retrognathia	Occasional (5-29%)
HP:0000347	Micrognathia	Occasional (5-29%)
HP:0000494	Downslanted palpebral fissures	Occasional (5-29%)
HP:0000501	Glaucoma	Occasional (5-29%)
HP:0000541	Retinal detachment	Occasional (5-29%)
HP:0000938	Osteopenia	Occasional (5-29%)
HP:0000939	Osteoporosis	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0001635	Congestive heart failure	Occasional (5-29%)
HP:0002097	Emphysema	Occasional (5-29%)
HP:0002105	Hemoptysis	Occasional (5-29%)
HP:0002435	Meningocele	Occasional (5-29%)
HP:0002636	Aneurysm of an abdominal artery	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Marfan syndrome
Mondo ID	MONDO:0007947
MeSH	D008382
OMIM	154700
Orphanet	558, 284963
DOID	DOID:14323
ICD-10-CM	Q87.4
ICD-11	236564145
NCIT	C34807
SNOMED CT	19346006
UMLS	C0024796
MedGen	44287
GARD	0016535
MedDRA	10026829
NORD	1403
Is cancer (heuristic)	no

Also known as: Marfan syndrome · Marfan syndrome type 1 · Marfan syndrome, type 1 · Marfan’s syndrome · MFS · MFS1

Data availability: 7,247 ClinVar variants · 114 ClinGen variant curations · 6 GenCC gene-disease records · 116 cell lines.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › Marfan syndrome

Related subtypes (191): autosomal dominant polycystic liver disease, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, tuberous sclerosis, Treacher-Collins syndrome, hereditary breast ovarian cancer syndrome, autosomal dominant polycystic kidney disease, Lynch syndrome, branchio-oto-renal syndrome, autosomal dominant Aarskog syndrome, acroosteolysis dominant type, ADULT syndrome, autosomal dominant Alport syndrome, amelogenesis imperfecta type 1B, Townes-Brocks syndrome, nevoid basal cell carcinoma syndrome, blepharophimosis, ptosis, and epicanthus inversus syndrome, autosomal dominant brachyolmia, branchiooculofacial syndrome, pheochromocytoma/paraganglioma syndrome 4, cataract-aberrant oral frenula-growth delay syndrome, cherubism, autosomal dominant chondrodysplasia punctata, autosomal dominant popliteal pterygium syndrome, blepharocheilodontic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Beare-Stevenson cutis gyrata syndrome, autosomal dominant vibratory urticaria, neurohypophyseal diabetes insipidus, autosomal dominant Kenny-Caffey syndrome, Rapp-Hodgkin syndrome, Ehlers-Danlos syndrome, classic type, autosomal dominant Ehlers-Danlos syndrome, vascular type, multiple endocrine neoplasia type 1, Coffin-Siris syndrome 1, isolated congenital adermatoglyphia, Flynn-Aird syndrome, Frasier syndrome, hand-foot-genital syndrome, Holt-Oram syndrome, hyperkeratosis-hyperpigmentation syndrome, autosomal dominant ichthyosis vulgaris, hyper-IgE recurrent infection syndrome 1, autosomal dominant, autosomal dominant keratitis, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, LADD syndrome, trichorhinophalangeal syndrome type II, Noonan syndrome with multiple lentigines, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, melanoma, cutaneous malignant, susceptibility to, 2, autosomal dominant primary microcephaly, autosomal dominant progressive external ophthalmoplegia, monilethrix, Muir-Torre syndrome, autosomal dominant myoglobinuria, autosomal dominant centronuclear myopathy, nail-patella syndrome, multiple endocrine neoplasia type 2B, autosomal dominant omodysplasia, pheochromocytoma/paraganglioma syndrome 1, Pelger-Huet anomaly, multiple endocrine neoplasia type 2A, piebaldism, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, generalized juvenile polyposis/juvenile polyposis coli, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Peutz-Jeghers syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, autosomal dominant distal renal tubular acidosis, retinoschisis, autosomal dominant, autosomal dominant Robinow syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, autosomal dominant sideroblastic anemia, spondyloepiphyseal dysplasia tarda, autosomal dominant, proximal symphalangism, calcaneonavicular coalition, thanatophoric dysplasia type 1, trichorhinophalangeal syndrome type I, Muckle-Wells syndrome, autosomal dominant hypophosphatemic rickets, von Hippel-Lindau disease, Denys-Drash syndrome, autosomal dominant severe congenital neutropenia, Costello syndrome, EEC syndrome, multiple cutaneous and mucosal venous malformations, diffuse nonepidermolytic palmoplantar keratoderma, Timothy syndrome, pheochromocytoma/paraganglioma syndrome 2, spondyloepimetaphyseal dysplasia with multiple dislocations, Brooke-Spiegler syndrome, macrocephaly-autism syndrome, pheochromocytoma/paraganglioma syndrome 3, Duane-radial ray syndrome, PCWH syndrome, heart-hand syndrome, Slovenian type, congenital stationary night blindness autosomal dominant 3, mandibulofacial dysostosis-microcephaly syndrome, multiple endocrine neoplasia type 4, juvenile cataract-microcornea-renal glucosuria syndrome, Crouzon syndrome-acanthosis nigricans syndrome, Birk-Barel syndrome, thrombophilia due to protein S deficiency, autosomal dominant, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, colorectal cancer, hereditary nonpolyposis, type 6, colorectal cancer, hereditary nonpolyposis, type 7, brain small vessel disease 2A, autosomal dominant, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, hypopigmentation-punctate palmoplantar keratoderma syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, Houge-Janssens syndrome 2, severe achondroplasia-developmental delay-acanthosis nigricans syndrome, dyskeratosis congenita, autosomal dominant 6, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, autosomal dominant complex spastic paraplegia, early-onset autosomal dominant Alzheimer disease, muscular dystrophy, limb-girdle, autosomal dominant, Feingold syndrome, Carney complex, neuronopathy, distal hereditary motor, autosomal dominant, autosomal dominant coarctation of aorta, autosomal dominant spondylocostal dysostosis, autosomal dominant hypohidrotic ectodermal dysplasia, Cowden disease, autosomal dominant distal myopathy, autosomal dominant rhegmatogenous retinal detachment, palmoplantar keratoderma-spastic paralysis syndrome, Alagille syndrome due to a JAG1 point mutation, PTEN hamartoma tumor syndrome, gastric adenocarcinoma and proximal polyposis of the stomach, autosomal dominant proximal renal tubular acidosis, autosomal dominant spastic ataxia, Waardenburg syndrome, hereditary retinoblastoma, autosomal dominant hypocalcemia, Li-Fraumeni syndrome, Loeys-Dietz syndrome, hereditary hemorrhagic telangiectasia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, microcephalic osteodysplastic dysplasia, Saul-Wilson type, autosomal dominant intermediate Charcot-Marie-Tooth disease, autosomal dominant cutis laxa, autosomal dominant nonsyndromic hearing loss, autosomal dominant optic atrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, autosomal dominant cerebellar ataxia, autosomal dominant osteopetrosis, autosomal dominant epidermolytic ichthyosis, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, distal arthrogryposis type 2B1, neurofibromatosis, autosomal dominant cataract, arthrogryposis, distal, type 2B2, arthrogryposis, distal, type 2B3, Charcot-Marie-Tooth disease, demyelinating, type 1G, Delpire-McNeill syndrome, LAMA5-related multisystemic syndrome, autosomal dominant oculocutaneous albinism, Charcot-Marie-tooth disease, axonal, type 2DD, Pilarowski-Bjornsson syndrome, intellectual disability, autosomal dominant, fatty acyl-CoA reductase 1 upregulation, GUCY2D-related dominant retinopathy, RPE65-related dominant retinopathy, autosomal dominant titinopathy, NOG-related symphalangism spectrum disorder, ALPL-related autosomal dominant hypophosphatasia, MYH10-related neurodevelopmental disorder with congenital anomalies, spastic paraplegia 30A, autosomal dominant, TMEM127-related tumor predisposition, MAX-related tumor predisposition, BMPR1A-related juvenile polyposis syndrome, RP1-related dominant retinopathy, Birt-Hogg-Dube syndrome, inclusion body myopathy and brain white matter abnormalities, KINSSHIP syndrome, autosomal dominant nebulin-related myopathy, IMPG1-related dominant retinopathy, PROM1-related dominant retinopathy, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome, ALG8-related autosomal dominant polycystic kidney and/or liver disease, NOTCH1-related AOS spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder, familial antiphospholipid syndrome

Subtypes (1): neonatal Marfan 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

600 retrieved; paginated sample, class counts are floors:

187 pathogenic, 141 uncertain significance, 116 likely benign, 59 likely pathogenic, 48 conflicting classifications of pathogenicity, 28 pathogenic/likely pathogenic, 15 benign/likely benign, 6 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1013590	NM_000138.5(FBN1):c.5196del (p.Cys1733fs)	FBN1	Pathogenic	no assertion criteria provided
1013603	NM_000138.5(FBN1):c.4878del (p.Phe1626fs)	FBN1	Pathogenic	criteria provided, single submitter
1014036	NM_000138.5(FBN1):c.5095T>A (p.Tyr1699Asn)	FBN1	Pathogenic	criteria provided, single submitter
1018383	NM_000138.5(FBN1):c.169A>G (p.Asn57Asp)	FBN1	Pathogenic	criteria provided, single submitter
1060002	NM_000138.5(FBN1):c.5174T>A (p.Ile1725Asn)	FBN1	Pathogenic	criteria provided, single submitter
1066301	NM_000138.5(FBN1):c.1883G>A (p.Cys628Tyr)	FBN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068546	NM_000138.5(FBN1):c.7409_7410delinsAT (p.Cys2470Tyr)	FBN1	Pathogenic	criteria provided, single submitter
1068666	NM_000138.5(FBN1):c.6564_6565insTTTTTTTTTTTTTTTTTTTTNNNNNNNNNNGTTTCACCGTTTTAGCCGGGATGGTCTCGATCTCCTGACCTCGTGATCCGCCCGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACCGCGCCCGGCGATTGGAGGTTTT (p.Glu2189delinsPhePhePhePhePhePheXaaXaaXaaXaaValSerProPheTer)	FBN1	Pathogenic	criteria provided, single submitter
1068667	NM_000138.5(FBN1):c.127A>T (p.Lys43Ter)	FBN1	Pathogenic	criteria provided, multiple submitters, no conflicts
1068676	NM_000138.5(FBN1):c.6253T>G (p.Cys2085Gly)	FBN1	Pathogenic	criteria provided, single submitter
1068829	NM_000138.5(FBN1):c.2764A>T (p.Lys922Ter)	FBN1	Pathogenic	criteria provided, single submitter
1069285	NM_000138.5(FBN1):c.4504T>C (p.Cys1502Arg)	FBN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069308	NM_000138.5(FBN1):c.8118del (p.Asp2706fs)	FBN1	Pathogenic	criteria provided, single submitter
1069359	NM_000138.5(FBN1):c.7382dup (p.Asn2461fs)	FBN1	Pathogenic	criteria provided, single submitter
1069382	NM_000138.5(FBN1):c.6793T>A (p.Cys2265Ser)	FBN1	Pathogenic	criteria provided, single submitter
1069383	NM_000138.5(FBN1):c.6769_6773del (p.Asp2257fs)	FBN1	Pathogenic	criteria provided, multiple submitters, no conflicts
1069412	NM_000138.5(FBN1):c.5716del (p.Arg1906fs)	FBN1	Pathogenic	criteria provided, single submitter
1069595	NM_000138.5(FBN1):c.4942+2T>C	FBN1	Pathogenic	criteria provided, single submitter
1069625	NM_000138.5(FBN1):c.5066-1G>T	FBN1	Pathogenic	criteria provided, multiple submitters, no conflicts
1069627	NM_000138.5(FBN1):c.8016_8017insAG (p.Gly2673fs)	FBN1	Pathogenic	criteria provided, single submitter
1069628	NM_000138.5(FBN1):c.4382G>A (p.Cys1461Tyr)	FBN1	Pathogenic	criteria provided, single submitter
1069717	NM_000138.5(FBN1):c.3583del (p.Cys1195fs)	FBN1	Pathogenic	criteria provided, single submitter
1069718	NM_000138.5(FBN1):c.3511T>C (p.Cys1171Arg)	FBN1	Pathogenic	criteria provided, single submitter
1069719	NM_000138.5(FBN1):c.3116G>A (p.Cys1039Tyr)	FBN1	Pathogenic	criteria provided, single submitter
1069830	NC_000015.9:g.(?48902915)(48905299_?)del	FBN1	Pathogenic	criteria provided, single submitter
1069831	NC_000015.9:g.(?48703181)(48744887_?)del	FBN1	Pathogenic	criteria provided, single submitter
1069957	NM_000138.5(FBN1):c.3906dup (p.Phe1303fs)	FBN1	Pathogenic	criteria provided, single submitter
1070334	NM_000138.5(FBN1):c.6331T>G (p.Cys2111Gly)	FBN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070369	NM_000138.5(FBN1):c.4731T>A (p.Cys1577Ter)	FBN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070664	NM_000138.5(FBN1):c.1540C>T (p.Gln514Ter)	FBN1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 24 · Orphanet: 85 · 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
FBN1	Definitive	Autosomal dominant	Marfan syndrome	24

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FBN1	Orphanet:1885	Isolated ectopia lentis
FBN1	Orphanet:2084	Glaucoma-ectopia lentis-microspherophakia-stiff joints-short stature syndrome
FBN1	Orphanet:2462	Shprintzen-Goldberg syndrome
FBN1	Orphanet:2623	Geleophysic dysplasia
FBN1	Orphanet:2833	Stiff skin syndrome
FBN1	Orphanet:284963	Marfan syndrome type 1
FBN1	Orphanet:284979	Neonatal Marfan syndrome
FBN1	Orphanet:300382	Progeroid and marfanoid aspect-lipodystrophy syndrome
FBN1	Orphanet:3449	Weill-Marchesani syndrome
FBN1	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
FBN1	Orphanet:969	Acromicric dysplasia
TGFB2	Orphanet:60030	Loeys-Dietz syndrome
TGFB2	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
TGFBR1	Orphanet:284973	Marfan syndrome type 2
TGFBR1	Orphanet:60030	Loeys-Dietz syndrome
TGFBR1	Orphanet:65748	Multiple self-healing squamous epithelioma
TGFBR1	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
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
ACTA2	Orphanet:2573	Moyamoya disease
ACTA2	Orphanet:404463	Multisystemic smooth muscle dysfunction syndrome
ACTA2	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
COL11A1	Orphanet:2021	Fibrochondrogenesis
COL11A1	Orphanet:440354	Autosomal dominant myopia-midfacial retrusion-sensorineural hearing loss-rhizomelic dysplasia syndrome
COL11A1	Orphanet:560	Marshall syndrome
COL11A1	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
COL11A1	Orphanet:90654	Stickler syndrome type 2
COL2A1	Orphanet:137678	Spondyloepiphyseal dysplasia with metatarsal shortening
COL2A1	Orphanet:166100	Autosomal dominant otospondylomegaepiphyseal dysplasia
COL2A1	Orphanet:1856	Spondyloperipheral dysplasia-short ulna syndrome
COL2A1	Orphanet:209867	Autosomal dominant rhegmatogenous retinal detachment
COL2A1	Orphanet:2380	Legg-Calvé-Perthes disease
COL2A1	Orphanet:459051	Spondyloepiphyseal dysplasia, Stanescu type
COL2A1	Orphanet:485	Kniest dysplasia
COL2A1	Orphanet:85166	Platyspondylic dysplasia, Torrance type
COL2A1	Orphanet:85198	Dysspondyloenchondromatosis
COL2A1	Orphanet:86820	Familial avascular necrosis of femoral head
COL2A1	Orphanet:90653	Stickler syndrome type 1
COL2A1	Orphanet:93279	Mild spondyloepiphyseal dysplasia due to COL2A1 mutation with early-onset osteoarthritis
COL2A1	Orphanet:93296	Achondrogenesis type 2
COL2A1	Orphanet:93297	Hypochondrogenesis
COL2A1	Orphanet:93315	Spondylometaphyseal dysplasia, ‘corner fracture’ type
COL2A1	Orphanet:93316	Spondylometaphyseal dysplasia, Schmidt type
COL2A1	Orphanet:93346	Spondyloepimetaphyseal dysplasia congenita, Strudwick type
COL2A1	Orphanet:94068	Spondyloepiphyseal dysplasia congenita
COL3A1	Orphanet:231160	Familial cerebral saccular aneurysm
COL3A1	Orphanet:2500	Acrogeria

Cohort genes → proteins

24 cohort genes, 23 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	24

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FBN1	HGNC:3603	ENSG00000166147	P35555	Fibrillin-1	gencc,clinvar
TGFB2	HGNC:11768	ENSG00000092969	P61812	Transforming growth factor beta-2 proprotein	clinvar
TGFBR1	HGNC:11772	ENSG00000106799	P36897	TGF-beta receptor type-1	clinvar
TGFBR2	HGNC:11773	ENSG00000163513	P37173	TGF-beta receptor type-2	clinvar
ACTA2	HGNC:130	ENSG00000107796	P62736	Actin, aortic smooth muscle	clinvar
MYEF2	HGNC:17940	ENSG00000104177	Q9P2K5	Myelin expression factor 2	clinvar
COL11A1	HGNC:2186	ENSG00000060718	P12107	Collagen alpha-1(XI) chain	clinvar
COL2A1	HGNC:2200	ENSG00000139219	P02458	Collagen alpha-1(II) chain	clinvar
COL3A1	HGNC:2201	ENSG00000168542	P02461	Collagen alpha-1(III) chain	clinvar
COL5A1	HGNC:2209	ENSG00000130635	P20908	Collagen alpha-1(V) chain	clinvar
COL5A2	HGNC:2210	ENSG00000204262	P05997	Collagen alpha-2(V) chain	clinvar
COL9A1	HGNC:2217	ENSG00000112280	P20849	Collagen alpha-1(IX) chain	clinvar
CEP152	HGNC:29298	ENSG00000103995	O94986	Centrosomal protein of 152 kDa	clinvar
DUT	HGNC:3078	ENSG00000128951	P33316	Deoxyuridine 5’-triphosphate nucleotidohydrolase, mitochondrial	clinvar
CTXN2	HGNC:31109	ENSG00000233932	P0C2S0	Cortexin-2	clinvar
FBN2	HGNC:3604	ENSG00000138829	P35556	Fibrillin-2	clinvar
FLII	HGNC:3750	ENSG00000177731	Q13045	Protein flightless-1 homolog	clinvar
FLNA	HGNC:3754	ENSG00000196924	P21333	Filamin-A	clinvar
FBN1-DT	HGNC:55413	ENSG00000259705		FBN1 divergent transcript	clinvar
LTBP2	HGNC:6715	ENSG00000119681	Q14767	Latent-transforming growth factor beta-binding protein 2	clinvar
LTBP3	HGNC:6716	ENSG00000168056	Q9NS15	Latent-transforming growth factor beta-binding protein 3	clinvar
MYH11	HGNC:7569	ENSG00000133392	P35749	Myosin-11	clinvar
MYLK	HGNC:7590	ENSG00000065534	Q15746	Myosin light chain kinase, smooth muscle	clinvar
NOTCH1	HGNC:7881	ENSG00000148400	P46531	Neurogenic locus notch homolog protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FBN1	Fibrillin-1	Structural component of the 10-12 nm diameter microfibrils of the extracellular matrix, which conveys both structural and regulatory properties to load-bearing connective tissues.
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.
TGFBR1	TGF-beta receptor type-1	Transmembrane serine/threonine kinase forming with the TGF-beta type II serine/threonine kinase receptor, TGFBR2, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3.
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.
ACTA2	Actin, aortic smooth muscle	Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells.
MYEF2	Myelin expression factor 2	Transcriptional repressor of the myelin basic protein gene (MBP).
COL11A1	Collagen alpha-1(XI) chain	May play an important role in fibrillogenesis by controlling lateral growth of collagen II fibrils.
COL2A1	Collagen alpha-1(II) chain	Type II collagen is specific for cartilaginous tissues.
COL3A1	Collagen alpha-1(III) chain	Collagen type III occurs in most soft connective tissues along with type I collagen.
COL5A1	Collagen alpha-1(V) chain	Type V collagen is a member of group I collagen (fibrillar forming collagen).
COL5A2	Collagen alpha-2(V) chain	Type V collagen is a member of group I collagen (fibrillar forming collagen).
COL9A1	Collagen alpha-1(IX) chain	Structural component of hyaline cartilage and vitreous of the eye.
CEP152	Centrosomal protein of 152 kDa	Necessary for centrosome duplication; the function also seems to involve CEP63, CDK5RAP2 and WDR62 through a stepwise assembled complex at the centrosome that recruits CDK2 required for centriole duplication.
DUT	Deoxyuridine 5’-triphosphate nucleotidohydrolase, mitochondrial	Catalyzes the cleavage of 2’-deoxyuridine 5’-triphosphate (dUTP) into 2’-deoxyuridine 5’-monophosphate (dUMP) and inorganic pyrophosphate and through its action efficiently prevents uracil misincorporation into DNA and at the same time pro…
FBN2	Fibrillin-2	Fibrillins are structural components of 10-12 nm extracellular calcium-binding microfibrils, which occur either in association with elastin or in elastin-free bundles.
FLII	Protein flightless-1 homolog	Is a regulator of actin polymerization, required for proper myofibril organization and regulation of the length of sarcomeric thin filaments.
FLNA	Filamin-A	Promotes orthogonal branching of actin filaments and links actin filaments to membrane glycoproteins.
LTBP2	Latent-transforming growth factor beta-binding protein 2	May play an integral structural role in elastic-fiber architectural organization and/or assembly.
LTBP3	Latent-transforming growth factor beta-binding protein 3	Key regulator of transforming growth factor beta (TGFB1, TGFB2 and TGFB3) that controls TGF-beta activation by maintaining it in a latent state during storage in extracellular space.
MYH11	Myosin-11	Muscle contraction.
MYLK	Myosin light chain kinase, smooth muscle	Calcium/calmodulin-dependent myosin light chain kinase implicated in smooth muscle contraction via phosphorylation of myosin light chains (MLC).
NOTCH1	Neurogenic locus notch homolog protein 1	Functions as a receptor for membrane-bound ligands Jagged-1 (JAG1), Jagged-2 (JAG2) and Delta-1 (DLL1) to regulate cell-fate determination.

Protein-family classification

Druggable: 5 · Difficult: 2 · Unknown: 17 · Druggable fraction: 0.21

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	3	3.5×	0.249
Other/Unknown	17	1.3×	0.249
Scaffold/PPI	2	1.4×	0.680
Antibody/Immunoglobulin	1	1.2×	0.709
Enzyme (other)	1	0.5×	0.876

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FBN1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom
TGFB2	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGFb2
TGFBR1	Kinase	yes	2.7.10.2	TGFB_receptor, Activin_recp, Prot_kinase_dom
TGFBR2	Kinase	yes	2.7.10.2	TGFB_receptor, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
ACTA2	Other/Unknown	no		Actin, Actin_CS, Actin/actin-like_CS
MYEF2	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, MYEF2_RRM1
COL11A1	Other/Unknown	no		Fib_collagen_C, Laminin_G, Collagen
COL2A1	Other/Unknown	no		Fib_collagen_C, VWF_dom, Collagen
COL3A1	Other/Unknown	no		Fib_collagen_C, VWF_dom, Collagen
COL5A1	Other/Unknown	no		Fib_collagen_C, Laminin_G, Collagen
COL5A2	Other/Unknown	no		Fib_collagen_C, VWF_dom, Collagen
COL9A1	Other/Unknown	no		Collagen, ConA-like_dom_sf, TSPN-like_N
CEP152	Other/Unknown	no		CEP152/SHC-Transforming, CEP152_CC, CEP152_PLK4_bind
DUT	Enzyme (other)	yes	3.6.1.23	dUTPase, dUTPase-like, dUTPase_trimeric
CTXN2	Other/Unknown	no		Cortexin
FBN2	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom
FLII	Other/Unknown	no		Leu-rich_rpt, Leu-rich_rpt_typical-subtyp, Villin/Gelsolin
FLNA	Antibody/Immunoglobulin	yes		Filamin/ABP280_rpt, Actinin_actin-bd_CS, CH_dom
FBN1-DT	Other/Unknown	no
LTBP2	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom
LTBP3	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom
MYH11	Scaffold/PPI	no		IQ_motif_EF-hand-BS, Myosin_head_motor_dom-like, Myosin_tail
MYLK	Kinase	yes	2.7.11.18	Prot_kinase_dom, Ig_sub2, Ig_sub
NOTCH1	Scaffold/PPI	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Notch_dom

Expression context

Cohort genes with no expression data: 0.

23 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)	24
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cartilage tissue	5
tibia	5
saphenous vein	3
visceral pleura	3
ventricular zone	3
periodontal ligament	3
skin of hip	2
parietal pleura	2
cauda epididymis	2
stromal cell of endometrium	2
tendon of biceps brachii	2
right coronary artery	2
ascending aorta	2
descending thoracic aorta	2
thoracic aorta	2
decidua	1
synovial joint	1
calcaneal tendon	1
tendon	1
pericardium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FBN1	275	ubiquitous	marker	synovial joint, skin of hip, decidua
TGFB2	206	ubiquitous	marker	calcaneal tendon, tendon, cartilage tissue
TGFBR1	269	ubiquitous	marker	saphenous vein, tibia, visceral pleura
TGFBR2	289	ubiquitous	marker	pericardium, tibia, parietal pleura
ACTA2	289	ubiquitous	marker	cauda epididymis, blood vessel layer, saphenous vein
MYEF2	249	ubiquitous	marker	ventricular zone, ganglionic eminence, mucosa of stomach
COL11A1	209	broad	marker	tibia, cartilage tissue, periodontal ligament
COL2A1	145	broad	marker	tibia, cartilage tissue, corpus epididymis
COL3A1	281	ubiquitous	marker	skin of hip, parietal pleura, visceral pleura
COL5A1	248	ubiquitous	marker	stromal cell of endometrium, periodontal ligament, tendon of biceps brachii
COL5A2	266	ubiquitous	marker	tendon of biceps brachii, periodontal ligament, stromal cell of endometrium
COL9A1	149	broad	marker	tibia, cartilage tissue, ventricular zone
CEP152	218	ubiquitous	marker	secondary oocyte, oocyte, sperm
DUT	295	ubiquitous	marker	pylorus, trabecular bone tissue, trigeminal ganglion
CTXN2	44	tissue_specific	marker	prefrontal cortex, frontal cortex, dorsolateral prefrontal cortex
FBN2	194	ubiquitous	marker	cartilage tissue, placenta, adrenal tissue
FLII	134	ubiquitous	marker	lower esophagus mucosa, apex of heart, hindlimb stylopod muscle
FLNA	285	ubiquitous	marker	right coronary artery, popliteal artery, tibial artery
FBN1-DT	116		yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, buccal mucosa cell
LTBP2	276	ubiquitous	marker	descending thoracic aorta, thoracic aorta, ascending aorta
LTBP3	279	broad	marker	descending thoracic aorta, thoracic aorta, ascending aorta
MYH11	143	broad	marker	right coronary artery, lower esophagus, lower esophagus muscularis layer
MYLK	289	ubiquitous	marker	cauda epididymis, saphenous vein, seminal vesicle
NOTCH1	272	ubiquitous	marker	ventricular zone, colonic epithelium, visceral pleura

Protein interactions among cohort

Intra-cohort edges: 25.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NOTCH1	7,411
TGFBR2	5,777
FLNA	5,321
TGFBR1	4,828
MYH11	3,818
FBN1	3,640
COL3A1	3,629
DUT	2,883
MYLK	2,763
LTBP2	2,658

Intra-cohort edges

A	B	Sources
COL11A1	COL2A1	string_interaction
COL11A1	COL3A1	string_interaction
COL11A1	COL5A2	string_interaction
COL11A1	COL9A1	string_interaction
COL2A1	COL9A1	biogrid_interaction, intact, string_interaction
COL3A1	COL5A1	string_interaction
COL3A1	COL5A2	string_interaction
COL3A1	FBN1	string_interaction
COL3A1	FBN2	string_interaction
COL5A1	COL5A2	string_interaction
COL5A1	FBN1	string_interaction
CTXN2	MYEF2	string_interaction
FBN1	FBN2	intact, string_interaction
FBN1	LTBP2	string_interaction
FBN1	LTBP3	string_interaction
FBN1	MYLK	string_interaction
FBN1	TGFBR1	string_interaction
FBN1	TGFBR2	string_interaction
FBN2	LTBP2	biogrid_interaction
FBN2	TGFBR1	string_interaction
FBN2	TGFBR2	string_interaction
FLNA	MYH11	biogrid_interaction
MYH11	MYLK	string_interaction
NOTCH1	TGFBR1	biogrid_interaction
TGFBR1	TGFBR2	string_interaction

Structural data

PDB: 14 · AlphaFold-only: 9 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TGFBR1	P36897	44
NOTCH1	P46531	29
FLNA	P21333	26
TGFBR2	P37173	22
DUT	P33316	12
FBN1	P35555	11
TGFB2	P61812	11
COL2A1	P02458	11
COL3A1	P02461	11
MYLK	Q15746	8
COL9A1	P20849	5
CEP152	O94986	3
COL5A1	P20908	1
MYH11	P35749	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ACTA2	P62736	95.43
FLII	Q13045	81.20
CTXN2	P0C2S0	70.79
LTBP3	Q9NS15	64.21
MYEF2	Q9P2K5	62.49
LTBP2	Q14767	58.33
COL5A2	P05997	53.15
COL11A1	P12107	53.06
FBN2	P35556

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 116. Enrichment computed across 24 evidence-associated genes (20 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 20 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
TGF-beta receptor signaling activates SMADs	6	97.9×	2e-09	FBN1, TGFB2, TGFBR1, TGFBR2, LTBP2, LTBP3
Collagen chain trimerization	6	77.9×	5e-09	COL11A1, COL2A1, COL3A1, COL5A1, COL5A2, COL9A1
Assembly of collagen fibrils and other multimeric structures	6	60.1×	2e-08	COL11A1, COL2A1, COL3A1, COL5A1, COL5A2, COL9A1
MET activates PTK2 signaling	5	95.2×	3e-08	COL11A1, COL2A1, COL3A1, COL5A1, COL5A2
Collagen degradation	6	52.7×	3e-08	COL11A1, COL2A1, COL3A1, COL5A1, COL5A2, COL9A1
Collagen biosynthesis and modifying enzymes	6	51.1×	3e-08	COL11A1, COL2A1, COL3A1, COL5A1, COL5A2, COL9A1
Elastic fibre formation	5	84.0×	3e-08	FBN1, TGFB2, FBN2, LTBP2, LTBP3
Non-integrin membrane-ECM interactions	6	46.3×	3e-08	ACTA2, COL11A1, COL2A1, COL3A1, COL5A1, COL5A2
ECM proteoglycans	6	45.1×	3e-08	TGFB2, COL2A1, COL3A1, COL5A1, COL5A2, COL9A1
Molecules associated with elastic fibres	5	77.2×	5e-08	FBN1, TGFB2, FBN2, LTBP2, LTBP3
Integrin cell surface interactions	6	40.3×	5e-08	FBN1, COL2A1, COL3A1, COL5A1, COL5A2, COL9A1
Signaling by PDGF	5	63.4×	1e-07	COL2A1, COL3A1, COL5A1, COL5A2, COL9A1
NCAM1 interactions	5	62.1×	1e-07	COL2A1, COL3A1, COL5A1, COL5A2, COL9A1
Developmental Lineage of Pancreatic Ductal Cells	5	57.1×	2e-07	COL11A1, COL2A1, COL3A1, COL5A1, COL5A2
Fibronectin matrix formation	4	114.2×	3e-07	COL2A1, COL3A1, COL5A1, COL5A2
Signaling by TGF-beta Receptor Complex	5	50.1×	3e-07	TGFB2, TGFBR1, TGFBR2, LTBP2, LTBP3
TGFBR3 regulates TGF-beta signaling	3	214.1×	2e-06	TGFB2, TGFBR1, TGFBR2
Signaling by TGFB family members	5	28.8×	4e-06	TGFB2, TGFBR1, TGFBR2, LTBP2, LTBP3
RHO GTPases activate PAKs	3	81.6×	4e-05	FLNA, MYH11, MYLK
Loss of Function of TGFBR2 in Cancer	2	380.7×	5e-05	TGFBR1, TGFBR2
TGFBR2 Kinase Domain Mutants in Cancer	2	380.7×	5e-05	TGFBR1, TGFBR2
Syndecan interactions	3	63.4×	7e-05	COL3A1, COL5A1, COL5A2
TGFBR1 LBD Mutants in Cancer	2	285.5×	9e-05	TGFBR1, TGFBR2
Signaling by TGFBR3	3	55.3×	1e-04	TGFB2, TGFBR1, TGFBR2
Loss of Function of TGFBR1 in Cancer	2	228.4×	1e-04	TGFBR1, TGFBR2
Loss of Function of SMAD2/3 in Cancer	2	190.3×	2e-04	TGFBR1, TGFBR2
Signaling by TGF-beta Receptor Complex in Cancer	2	190.3×	2e-04	TGFBR1, TGFBR2
SMAD2/3 Phosphorylation Motif Mutants in Cancer	2	190.3×	2e-04	TGFBR1, TGFBR2
TGFBR1 KD Mutants in Cancer	2	190.3×	2e-04	TGFBR1, TGFBR2
Smooth Muscle Contraction	3	39.8×	2e-04	ACTA2, MYH11, MYLK

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 22 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
collagen fibril organization	7	71.5×	2e-09	TGFB2, TGFBR1, COL11A1, COL2A1, COL3A1, COL5A1, COL5A2
transforming growth factor beta receptor signaling pathway	6	43.4×	9e-07	TGFB2, TGFBR1, TGFBR2, COL3A1, LTBP2, LTBP3
positive regulation of epithelial to mesenchymal transition involved in endocardial cushion formation	3	574.5×	1e-06	TGFB2, TGFBR1, TGFBR2
ventricular septum morphogenesis	4	78.6×	2e-05	TGFB2, TGFBR1, TGFBR2, NOTCH1
heart development	6	21.5×	2e-05	FBN1, TGFB2, TGFBR1, TGFBR2, COL3A1, NOTCH1
atrioventricular valve morphogenesis	3	164.1×	4e-05	TGFB2, TGFBR2, NOTCH1
cardiac epithelial to mesenchymal transition	3	164.1×	4e-05	TGFB2, TGFBR1, NOTCH1
epithelial to mesenchymal transition	4	56.7×	4e-05	TGFB2, TGFBR1, TGFBR2, NOTCH1
skeletal system development	5	28.6×	4e-05	FBN1, TGFB2, TGFBR1, COL2A1, COL5A2
ventricular trabecula myocardium morphogenesis	3	143.6×	5e-05	TGFB2, TGFBR1, NOTCH1
supramolecular fiber organization	3	143.6×	5e-05	COL3A1, COL5A1, LTBP2
negative regulation of endodermal cell differentiation	2	766.0×	7e-05	COL5A1, COL5A2
cartilage condensation	3	104.5×	1e-04	TGFB2, COL11A1, COL2A1
obsolete sequestering of TGFbeta in extracellular matrix	2	383.0×	3e-04	FBN1, FBN2
tendon development	2	383.0×	3e-04	COL11A1, COL5A1
eye morphogenesis	2	383.0×	3e-04	COL5A1, COL5A2
aorta smooth muscle tissue morphogenesis	2	383.0×	3e-04	COL3A1, MYLK
glomerular mesangial cell development	2	383.0×	3e-04	ACTA2, NOTCH1
endocardial cushion fusion	2	306.4×	4e-04	TGFB2, TGFBR2
skin development	3	60.5×	4e-04	COL3A1, COL5A1, COL5A2
positive regulation of SMAD protein signal transduction	3	52.2×	6e-04	TGFB2, TGFBR1, TGFBR2
heart morphogenesis	3	51.1×	6e-04	TGFB2, COL2A1, COL5A1
positive regulation of epithelial to mesenchymal transition	3	43.4×	9e-04	TGFB2, TGFBR1, TGFBR2
positive regulation of mesenchymal stem cell proliferation	2	191.5×	9e-04	TGFBR1, LTBP3
chondrocyte differentiation	3	41.0×	1e-03	COL2A1, COL3A1, LTBP3
proteoglycan metabolic process	2	170.2×	0.001	COL11A1, COL2A1
coronary artery morphogenesis	2	170.2×	0.001	TGFBR1, NOTCH1
cellular response to transforming growth factor beta stimulus	3	37.7×	0.001	FBN1, TGFBR1, ACTA2
membranous septum morphogenesis	2	153.2×	0.001	TGFB2, TGFBR2
response to cholesterol	2	153.2×	0.001	TGFBR1, TGFBR2

Therapeutics

Drugs indicated for this disease

0 approved, 5 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Aliskiren	Phase 3 (in late-stage trials)
Atenolol	Phase 3 (in late-stage trials)
Losartan	Phase 3 (in late-stage trials)
Nebivolol	Phase 3 (in late-stage trials)
Perindopril	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Irbesartan, Propranolol.

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 3 · Phased (≥1): 6 · Undrugged: 18

Druggability breadth: 12 of 24 evidence-associated genes (50%) 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
TGFBR1	MOMELOTINIB
TGFBR2	PONATINIB
MYLK	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TGFBR1	28	4
MYLK	28	4
TGFBR2	22	4
TGFB2	1	2
FLNA	1	2
NOTCH1	1	2
FBN1	0	0
ACTA2	0	0
MYEF2	0	0
COL11A1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOMELOTINIB	4	TGFBR1
DABRAFENIB	4	TGFBR1, TGFBR2
NINTEDANIB	4	MYLK, TGFBR1
DASATINIB	4	MYLK, TGFBR1, TGFBR2
CRIZOTINIB	4	TGFBR1
PONATINIB	4	MYLK, TGFBR2
VEMURAFENIB	4	TGFBR2
FEDRATINIB	4	MYLK, TGFBR2
SORAFENIB	4	TGFBR2
TOVORAFENIB	4	MYLK, TGFBR2
PAZOPANIB	4	TGFBR2
AFATINIB	4	MYLK
RUXOLITINIB	4	MYLK
NIFEDIPINE	4	MYLK
BOSUTINIB	4	MYLK
GILTERITINIB	4	MYLK
SUNITINIB	4	MYLK
QUIZARTINIB	4	MYLK
MIDOSTAURIN	4	MYLK
SARACATINIB	3	TGFBR1
CANERTINIB	3	TGFBR1, TGFBR2
TESEVATINIB	3	TGFBR1
CEDIRANIB	3	TGFBR1
LESTAURTINIB	3	MYLK, TGFBR1, TGFBR2
ALVOCIDIB	3	TGFBR2
FASUDIL	3	MYLK
DOVITINIB	3	MYLK
RUBOXISTAURIN	3	MYLK
GALUNISERTIB	2	TGFB2, TGFBR1, TGFBR2
OSI-632	2	TGFBR1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

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

Symbol	Assays	Type breakdown
TGFBR1	541	Binding:516, Functional:13, ADMET:12
MYLK	303	Binding:303
TGFBR2	188	Binding:188
DUT	27	Binding:27
NOTCH1	23	Binding:19, ADMET:4
FLNA	7	Binding:7
TGFB2	3	Binding:3
COL2A1	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TGFBR1	2.7.10.2, 2.7.11.30	non-specific protein-tyrosine kinase, receptor protein serine/threonine kinase
TGFBR2	2.7.10.2	non-specific protein-tyrosine kinase
DUT	3.6.1.23	dUTP diphosphatase
MYLK	2.7.11.18	myosin-light-chain kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TGFBR1	541
TGFBR2	188
MYLK	303

Pharmacogenomics

Cohort genes with a PharmGKB record: 23; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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)
MOMELOTINIB	4	TGFBR1
DABRAFENIB	4	TGFBR1, TGFBR2
NINTEDANIB	4	MYLK, TGFBR1
DASATINIB	4	MYLK, TGFBR1, TGFBR2
CRIZOTINIB	4	TGFBR1
PONATINIB	4	MYLK, TGFBR2
VEMURAFENIB	4	TGFBR2
FEDRATINIB	4	MYLK, TGFBR2
SORAFENIB	4	TGFBR2
TOVORAFENIB	4	MYLK, TGFBR2
PAZOPANIB	4	TGFBR2
AFATINIB	4	MYLK
RUXOLITINIB	4	MYLK
NIFEDIPINE	4	MYLK
BOSUTINIB	4	MYLK
GILTERITINIB	4	MYLK
SUNITINIB	4	MYLK
QUIZARTINIB	4	MYLK
MIDOSTAURIN	4	MYLK
SARACATINIB	3	TGFBR1
CANERTINIB	3	TGFBR1, TGFBR2
TESEVATINIB	3	TGFBR1
CEDIRANIB	3	TGFBR1
LESTAURTINIB	3	MYLK, TGFBR1, TGFBR2
ALVOCIDIB	3	TGFBR2
FASUDIL	3	MYLK
DOVITINIB	3	MYLK
RUBOXISTAURIN	3	MYLK
GALUNISERTIB	2	TGFB2, TGFBR1, TGFBR2
OSI-632	2	TGFBR1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	TGFBR1, TGFBR2, MYLK
B	Phased (≥1) drug, not yet approved	3	TGFB2, FLNA, NOTCH1
C	Druggable family + PDB, no drug	1	DUT
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	17	FBN1, ACTA2, MYEF2, COL11A1, COL2A1, COL3A1, COL5A1, COL5A2, COL9A1, CEP152 (+7 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
FBN1	0	—
ACTA2	0	—
MYEF2	0	—
COL11A1	0	—
COL2A1	2	—
COL3A1	0	—
COL5A1	0	—
COL5A2	0	—
COL9A1	0	—
CEP152	0	—
DUT	27	—
CTXN2	0	—
FBN2	0	—
FLII	0	—
FBN1-DT	0	—
LTBP2	0	—
LTBP3	0	—
MYH11	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 57.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	44
PHASE3	9
PHASE2	3
PHASE4	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01295047	PHASE4	COMPLETED	Comparison of Medical Therapies in Marfan Syndrome.
NCT00429364	PHASE3	COMPLETED	Comparison of Two Medications Aimed at Slowing Aortic Root Enlargement in Individuals With Marfan Syndrome
NCT00485368	PHASE3	COMPLETED	Angiotensin Converting Enzyme Inhibitors in Marfan Syndrome
NCT00683124	PHASE3	UNKNOWN	Nebivolol Versus Losartan Versus Nebivolol+Losartan Against Aortic Root Dilation in Genotyped Marfan Patients
NCT00723801	PHASE3	COMPLETED	Effects of Losartan Versus Atenolol on Aortic and Cardiac Muscle Stiffness in Adults With Marfan Syndrome
NCT00763893	PHASE3	TERMINATED	Study of the Efficacy of Losartan on Aortic Dilatation in Patients With Marfan Syndrome
NCT00782327	PHASE3	COMPLETED	Randomized, Double-blind Study for the Evaluation of the Effect of Losartan Versus Placebo on Aortic Root Dilatation in Patients With Marfan Syndrome Under Treatment With Beta-blockers
NCT01145612	PHASE3	UNKNOWN	Atenolol Versus Losartan in the Prevention of Progressive Dilation of the Aorta in Marfan Syndrome
NCT01361087	PHASE3	WITHDRAWN	Circulating Transforming Growth Factor Beta (TGF-β) in Individuals With Marfan Syndrome
NCT01715207	PHASE3	COMPLETED	Comparison of Aliskiren vs Negative Controls on Aortic Stiffness in Patients With MFS
NCT00593710	PHASE2	COMPLETED	Losartan Versus Atenolol for the Treatment of Marfan Syndrome
NCT00651235	PHASE2	UNKNOWN	A Randomized, Open-label, LOSARTAN Therapy on the Progression of Aortic Root Dilation in Patients With Marfan Syndrome
NCT01949233	PHASE2	UNKNOWN	The Oxford Marfan Trial
NCT02050113	Not specified	RECRUITING	Complex Aortic Aneurysm Repair Using Physician Modified Endografts and Custom Made Devices
NCT03440697	Not specified	ACTIVE_NOT_RECRUITING	Pathogenetic Basis of Aortopathy and Aortic Valve Disease
NCT04194619	Not specified	RECRUITING	Pregnancy in Women With Rare Multisystemic Vascular Diseases: COGRare5 Study
NCT04970459	Not specified	RECRUITING	Biological Collection for Marfan and Related Syndromes
NCT05389865	Not specified	ACTIVE_NOT_RECRUITING	Proximal Aortopathy in Scotland - Epidemiology and Surgical Outcomes
NCT05700175	Not specified	RECRUITING	Transcriptomic Study of Adult Population With Marfan Syndrome
NCT05702476	Not specified	RECRUITING	Marfan Syndrome (MFS) and Facial Dysmorphism: Non-invasive 3D Assessment
NCT05720923	Not specified	ACTIVE_NOT_RECRUITING	Analysis of Muscular Properties in Patients With MFS and EDS
NCT05809323	Not specified	RECRUITING	Marfan Syndrome Moderate Exercise Trial II
NCT05838235	Not specified	RECRUITING	Adapted Physical Activity Program (APA) for Effort Rehabilitation of Children and Teenagers With Marfan Syndrome
NCT06546137	Not specified	RECRUITING	National Network for Cardiovascular Genomics: Advancing Cardiovascular Healthcare for Hereditary Diseases in Brazil’s Unified Health System Through a Multicenter Registry
NCT06786754	Not specified	ENROLLING_BY_INVITATION	Fibroblasts and Thoracic Aortic Aneurysms: in Vitro Characterization in With Marfan Syndrome and Genetic Aortic Diseases
NCT07169669	Not specified	NOT_YET_RECRUITING	Multicentre Longitudinal Study of Bone Mineralisation Characteristics in Marfan Syndrome and Ehlers-Danlos Syndrome
NCT07419386	Not specified	NOT_YET_RECRUITING	Clinical and Psychosocial Factors Associated With Physical Activity Level in Adults With Marfan Syndrome
NCT07495267	Not specified	NOT_YET_RECRUITING	Nutritional Ketosis Marfan
NCT00001641	Not specified	COMPLETED	Study of Heritable Connective Tissue Disorders
NCT00270686	Not specified	COMPLETED	Studies of Heritable Disorders of Connective Tissue
NCT01322165	Not specified	COMPLETED	National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions
NCT01707563	Not specified	COMPLETED	Clinical Variability in Marfan Syndrome
NCT01760668	Not specified	COMPLETED	Aortopathy in Persons With Bicuspid Aortic Valve, Turner and Marfan Syndrome
NCT02111668	Not specified	COMPLETED	Thoracic Aortic Dilatation Syndromes
NCT02148900	Not specified	UNKNOWN	Development of a Blood Test for Marfan Syndrome
NCT02213484	Not specified	COMPLETED	Micro RNAs as a Marker of Aortic Aneurysm in Hereditary Aortopathy Syndromes
NCT02815072	Not specified	UNKNOWN	Generation of Marfan Syndrome and Fontan Cardiovascular Models Using Patient-specific Induced Pluripotent Stem Cells
NCT03236571	Not specified	COMPLETED	Cardiorespiratory and Muscular Rehabilitation of Children and Young Adults With Marfan Syndrome.
NCT03567460	Not specified	COMPLETED	Children and Adolescents With Marfan Syndrome: 10,000 Healthy Steps and Beyond
NCT03581682	Not specified	COMPLETED	Tele-Clinic Visits in Pediatric Marfan Patients Using Parental Echo: The Future?

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
LOSARTAN	4	13
ATENOLOL	4	6
PERINDOPRIL	4	4
NEBIVOLOL	4	1
VERAPAMIL	4	1
ESATENOLOL	2	6
DEXVERAPAMIL	2	1
CHEMBL1230004	0	6
CHEMBL2365658	0	1
CHEMBL3526436	0	1