Holt-Oram syndrome

Summary

Holt-Oram syndrome (MONDO:0007732) is a disease caused by TBX5 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Causal gene: TBX5 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 230
• Phenotypes (HPO): 29

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 1 000 000	0.7	Europe	Validated
Prevalence at birth	1-9 / 1 000 000	0.95	Hungary	Validated

Signs & symptoms

Clinical features (HPO)

29 HPO clinical features (Orphanet curated; top 29 by frequency):

HPO ID	Term	Frequency
HP:0000889	Abnormality of the clavicle	Very frequent (80-99%)
HP:0001171	Split hand	Very frequent (80-99%)
HP:0001387	Joint stiffness	Very frequent (80-99%)
HP:0030680	Abnormal cardiovascular system morphology	Very frequent (80-99%)
HP:0001199	Triphalangeal thumb	Frequent (30-79%)
HP:0001629	Ventricular septal defect	Frequent (30-79%)
HP:0001631	Atrial septal defect	Frequent (30-79%)
HP:0001678	Atrioventricular block	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0002808	Kyphosis	Frequent (30-79%)
HP:0004757	Paroxysmal atrial fibrillation	Frequent (30-79%)
HP:0005916	Abnormal metacarpal morphology	Frequent (30-79%)
HP:0006501	Aplasia/Hypoplasia of the radius	Frequent (30-79%)
HP:0009777	Absent thumb	Frequent (30-79%)
HP:0011705	First degree atrioventricular block	Frequent (30-79%)
HP:0031095	Abnormal humerus morphology	Occasional (5-29%)
HP:0000767	Pectus excavatum	Occasional (5-29%)
HP:0000772	Abnormal rib morphology	Occasional (5-29%)
HP:0000912	Sprengel anomaly	Occasional (5-29%)
HP:0001643	Patent ductus arteriosus	Occasional (5-29%)
HP:0001679	Abnormal aortic morphology	Occasional (5-29%)
HP:0002974	Radioulnar synostosis	Occasional (5-29%)
HP:0004383	Hypoplastic left heart	Occasional (5-29%)
HP:0006101	Finger syndactyly	Occasional (5-29%)
HP:0006695	Atrioventricular canal defect	Occasional (5-29%)
HP:0009829	Phocomelia	Occasional (5-29%)
HP:0010772	Anomalous pulmonary venous return	Occasional (5-29%)
HP:0011304	Broad thumb	Occasional (5-29%)
HP:0200021	Down-sloping shoulders	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Holt-Oram syndrome
Mondo ID	MONDO:0007732
MeSH	C535326
OMIM	142900
Orphanet	392
DOID	DOID:0060468
ICD-11	1169240278
NCIT	C125592
SNOMED CT	19092004
UMLS	C0265264
MedGen	120524
GARD	0006666
MedDRA	10050469
NORD	1248
Is cancer (heuristic)	no

Also known as: atrio digital syndrome · atrio-digital syndrome · atriodigital dysplasia · atriodigital dysplasia type 1 · Cardiac-limb syndrome · heart-hand syndrome · heart-hand syndrome type 1 · heart-hand syndrome, type 1 · Holt Oram Syndrome · HOLT-Oram syndrome · Holt-Oram syndrome · HOS · HOS 1 · ventriculo-radial syndrome

Data availability: 230 ClinVar variants · 5 GenCC gene-disease records · 14 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 › Holt-Oram 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, 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, Marfan syndrome, 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): heart-hand syndrome type 3

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

230 retrieved; paginated sample, class counts are floors:

76 pathogenic, 61 uncertain significance, 32 benign, 19 benign/likely benign, 17 likely pathogenic, 14 conflicting classifications of pathogenicity, 6 pathogenic/likely pathogenic, 5 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1030662	NM_181486.4(TBX5):c.337A>T (p.Arg113Ter)	TBX5	Pathogenic	criteria provided, single submitter
1032248	NM_181486.4(TBX5):c.362+1G>A	TBX5	Pathogenic	criteria provided, single submitter
1175344	NM_181486.4(TBX5):c.262A>T (p.Lys88Ter)	TBX5	Pathogenic	no assertion criteria provided
1193170	NM_181486.4(TBX5):c.242+1G>A	TBX5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1299664	NM_181486.4(TBX5):c.166del (p.Val56fs)	TBX5	Pathogenic	no assertion criteria provided
213832	NM_181486.4(TBX5):c.835C>T (p.Arg279Ter)	TBX5	Pathogenic	criteria provided, multiple submitters, no conflicts
235885	NM_181486.4(TBX5):c.444G>A (p.Trp148Ter)	TBX5	Pathogenic	no assertion criteria provided
2444344	NM_181486.4(TBX5):c.261C>G (p.Tyr87Ter)	TBX5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2502300	NM_181486.4(TBX5):c.672del (p.Gln224fs)	TBX5	Pathogenic	criteria provided, single submitter
2573991	NM_181486.4(TBX5):c.694T>C (p.Phe232Leu)	TBX5	Pathogenic	criteria provided, single submitter
2575756	NM_181486.4(TBX5):c.873C>A (p.Tyr291Ter)	TBX5	Pathogenic	criteria provided, multiple submitters, no conflicts
2579689	NM_181486.4(TBX5):c.353A>G (p.Asp118Gly)	TBX5	Pathogenic	criteria provided, single submitter
2691618	NM_181486.4(TBX5):c.529del (p.His177fs)	TBX5	Pathogenic	criteria provided, single submitter
279906	NM_181486.4(TBX5):c.587C>A (p.Ser196Ter)	TBX5	Pathogenic	criteria provided, multiple submitters, no conflicts
3254820	NM_181486.4(TBX5):c.243-1G>T	TBX5	Pathogenic	criteria provided, single submitter
3382136	NM_181486.4(TBX5):c.242+1G>T	TBX5	Pathogenic	criteria provided, single submitter
369677	NM_181486.4(TBX5):c.105del (p.Ser36fs)	TBX5	Pathogenic	criteria provided, multiple submitters, no conflicts
374841	NC_000012.11:g.114795705_114844082dup	TBX5	Pathogenic	no assertion criteria provided
449105	NM_181486.4(TBX5):c.668C>T (p.Thr223Met)	TBX5	Pathogenic	criteria provided, multiple submitters, no conflicts
488620	NM_181486.4(TBX5):c.1158dup (p.Ser387fs)	TBX5	Pathogenic	criteria provided, single submitter
561217	NM_181486.4(TBX5):c.246_249del (p.Met83fs)	TBX5	Pathogenic	no assertion criteria provided
569967	NM_181486.4(TBX5):c.868C>T (p.Gln290Ter)	TBX5	Pathogenic	criteria provided, single submitter
620372	NM_181486.4(TBX5):c.408C>G (p.Tyr136Ter)	TBX5	Pathogenic	criteria provided, multiple submitters, no conflicts
625740	GRCh37/hg19 12q24.21(chr12:114791609-114793234)	TBX5	Pathogenic	criteria provided, single submitter
633719	NM_000192.3:c.(982+1_983-1)(*1602?)del	TBX5	Pathogenic	no assertion criteria provided
633722	NM_181486.4(TBX5):c.1269C>G (p.Tyr423Ter)	TBX5	Pathogenic	no assertion criteria provided
633723	NM_181486.4(TBX5):c.1303del (p.Leu435fs)	TBX5	Pathogenic	no assertion criteria provided
633724	NM_000192.3:c.(362+1_363-1)(*1602?)del	TBX5	Pathogenic	no assertion criteria provided
633725	NM_181486.4(TBX5):c.879T>A (p.Cys293Ter)	TBX5	Pathogenic	no assertion criteria provided
633726	NM_181486.4(TBX5):c.593dup (p.Asn198fs)	TBX5	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 4 · 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
TBX5	Definitive	Autosomal dominant	Holt-Oram syndrome	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TBX5	Orphanet:101016	Romano-Ward syndrome
TBX5	Orphanet:392	Holt-Oram syndrome
TGFB2	Orphanet:60030	Loeys-Dietz syndrome
TGFB2	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection

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
TBX5	HGNC:11604	ENSG00000089225	Q99593	T-box transcription factor TBX5	gencc,clinvar
TGFB2	HGNC:11768	ENSG00000092969	P61812	Transforming growth factor beta-2 proprotein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TBX5	T-box transcription factor TBX5	DNA-binding protein that regulates the transcription of several genes and is involved in heart development and limb pattern formation.
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.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TBX5	Transcription factor	no		TF_T-box, p53-like_TF_DNA-bd_sf, TF_T-box_CS
TGFB2	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGFb2

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
buccal mucosa cell	1
cardiac muscle of right atrium	1
tendon of biceps brachii	1
calcaneal tendon	1
cartilage tissue	1
tendon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TBX5	129	broad	marker	tendon of biceps brachii, cardiac muscle of right atrium, buccal mucosa cell
TGFB2	206	ubiquitous	marker	calcaneal tendon, tendon, cartilage tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TBX5	2,250
TGFB2	43

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TGFB2	P61812	11
TBX5	Q99593	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 23. 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
TGFBR3 regulates TGF-beta signaling	1	713.8×	0.019	TGFB2
YAP1- and WWTR1 (TAZ)-stimulated gene expression	1	380.7×	0.019	TBX5
Physiological factors	1	335.9×	0.019	TBX5
Cardiogenesis	1	211.5×	0.019	TBX5
Signaling by TGFBR3	1	184.2×	0.019	TGFB2
Elastic fibre formation	1	167.9×	0.019	TGFB2
TGF-beta receptor signaling activates SMADs	1	163.1×	0.019	TGFB2
Molecules associated with elastic fibres	1	154.3×	0.019	TGFB2
Signaling by TGF-beta Receptor Complex	1	100.2×	0.025	TGFB2
Response to elevated platelet cytosolic Ca2+	1	81.6×	0.028	TGFB2
ECM proteoglycans	1	75.1×	0.028	TGFB2
Signaling by TGFB family members	1	57.7×	0.031	TGFB2
Cardiac conduction	1	54.4×	0.031	TBX5
Platelet activation, signaling and aggregation	1	52.9×	0.031	TGFB2
Platelet degranulation	1	43.9×	0.035	TGFB2
Muscle contraction	1	38.6×	0.037	TBX5
Extracellular matrix organization	1	31.6×	0.043	TGFB2
Hemostasis	1	18.0×	0.070	TGFB2
RNA Polymerase II Transcription	1	11.3×	0.105	TBX5
Gene expression (Transcription)	1	8.9×	0.125	TBX5
Generic Transcription Pathway	1	7.5×	0.140	TBX5
Developmental Biology	1	7.2×	0.140	TBX5
Signal Transduction	1	5.1×	0.187	TGFB2

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 cardioblast differentiation	2	4213.0×	6e-06	TBX5, TGFB2
atrial septum morphogenesis	2	1296.3×	3e-05	TBX5, TGFB2
atrioventricular valve morphogenesis	2	1203.7×	3e-05	TBX5, TGFB2
cardiac muscle cell proliferation	2	581.1×	1e-04	TBX5, TGFB2
embryonic limb morphogenesis	2	401.2×	2e-04	TBX5, TGFB2
regulation of timing of catagen	1	8426.0×	0.001	TGFB2
cell migration involved in coronary vasculogenesis	1	8426.0×	0.001	TBX5
positive regulation of activation-induced cell death of T cells	1	8426.0×	0.001	TGFB2
regulation of apoptotic process involved in outflow tract morphogenesis	1	8426.0×	0.001	TGFB2
positive regulation of cardiac conduction	1	8426.0×	0.001	TBX5
negative regulation of epithelial to mesenchymal transition involved in endocardial cushion formation	1	8426.0×	0.001	TGFB2
cardiac left ventricle formation	1	4213.0×	0.002	TBX5
cardioblast differentiation	1	4213.0×	0.002	TGFB2
uterine wall breakdown	1	4213.0×	0.002	TGFB2
atrioventricular node cell fate commitment	1	4213.0×	0.002	TBX5
bundle of His cell to Purkinje myocyte communication by electrical coupling	1	4213.0×	0.002	TBX5
positive regulation of cell communication by electrical coupling involved in cardiac conduction	1	4213.0×	0.002	TBX5
substantia propria of cornea development	1	4213.0×	0.002	TGFB2
heart development	2	78.8×	0.002	TBX5, TGFB2
atrioventricular bundle cell differentiation	1	2808.7×	0.002	TBX5
positive regulation of integrin biosynthetic process	1	2808.7×	0.002	TGFB2
positive regulation of timing of catagen	1	2808.7×	0.002	TGFB2
positive regulation of secondary heart field cardioblast proliferation	1	2808.7×	0.002	TBX5
bundle of His development	1	2106.5×	0.002	TBX5
regulation of transforming growth factor beta2 production	1	2106.5×	0.002	TGFB2
ascending aorta morphogenesis	1	2106.5×	0.002	TGFB2
atrioventricular node cell development	1	2106.5×	0.002	TBX5
positive regulation of epithelial to mesenchymal transition involved in endocardial cushion formation	1	2106.5×	0.002	TGFB2
endocardial cushion fusion	1	1685.2×	0.003	TGFB2
atrial septum primum morphogenesis	1	1685.2×	0.003	TGFB2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · 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).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TGFB2	1	2
TBX5	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
GALUNISERTIB	2	TGFB2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TGFB2	3	Binding:3
TBX5	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

1 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)
GALUNISERTIB	2	TGFB2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	TGFB2
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	TBX5

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)
TBX5	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.