Hypoplastic left heart syndrome

Summary

Hypoplastic left heart syndrome (MONDO:0004933) is a disease with 12 cohort genes and 53 clinical trials. The dominant Reactome pathway is Cardiogenesis (3 cohort genes). Top therapeutic interventions include ambrisentan, bosentan, and poractant alfa.

At a glance

• Prevalence: 1-5 / 10 000 (Europe) [Orphanet-validated]
• Cohort genes: 12
• ClinVar variants: 184
• Phenotypes (HPO): 8
• Clinical trials: 53

Clinical features

Epidemiology

Prevalence records

23 prevalence record(s), Orphanet, top 20 (validated / broadest geography first):

Type	Class	Value	Geography	Validation
Prevalence at birth	1-5 / 10 000	15.1	Europe	Validated
Prevalence at birth	1-5 / 10 000	16.2	United States	Validated
Prevalence at birth	1-5 / 10 000	49.1	Austria	Validated
Prevalence at birth	1-5 / 10 000	29.1	Belgium	Validated
Prevalence at birth	1-5 / 10 000	56.8	Croatia	Validated
Prevalence at birth	1-5 / 10 000	21.3	Denmark	Validated
Prevalence at birth	1-5 / 10 000	11.8	France	Validated
Prevalence at birth	1-5 / 10 000	23.8	Germany	Validated
Prevalence at birth	1-5 / 10 000	19.9	Hungary	Validated
Prevalence at birth	1-5 / 10 000	18.1	Ireland	Validated
Prevalence at birth	1-9 / 100 000	9.9	Italy	Validated
Prevalence at birth	1-5 / 10 000	49.8	Malta	Validated
Prevalence at birth	1-9 / 100 000	5.8	Netherlands	Validated
Prevalence at birth	1-5 / 10 000	16.4	Norway	Validated
Prevalence at birth	1-9 / 100 000	9.2	Poland	Validated
Prevalence at birth	1-9 / 100 000	5.5	Portugal	Validated
Prevalence at birth	1-5 / 10 000	12.5	Switzerland	Validated
Prevalence at birth	1-5 / 10 000	16.6	United Kingdom	Validated
Prevalence at birth	1-5 / 10 000	22.3	Ukraine	Validated
Prevalence at birth	1-9 / 100 000	1.9	Spain	Validated

Signs & symptoms

Clinical features (HPO)

8 HPO clinical features (Orphanet curated; top 8 by frequency):

HPO ID	Term	Frequency
HP:0004383	Hypoplastic left heart	Very frequent (80-99%)
HP:0012304	Hypoplastic aortic arch	Frequent (30-79%)
HP:0001643	Patent ductus arteriosus	Occasional (5-29%)
HP:0001718	Mitral stenosis	Occasional (5-29%)
HP:0009800	Maternal diabetes	Occasional (5-29%)
HP:0001631	Atrial septal defect	Occasional (5-29%)
HP:0002916	Abnormality of chromosome segregation	Occasional (5-29%)
HP:0011560	Mitral atresia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hypoplastic left heart syndrome
Mondo ID	MONDO:0004933
MeSH	D018636
OMIM	241550
Orphanet	2248
DOID	DOID:9955
ICD-10-CM	Q23.4
ICD-11	1811800027
NCIT	C98894
SNOMED CT	62067003
UMLS	C0152101
MedGen	57746
GARD	0006739
MedDRA	10021076
NORD	1277
Is cancer (heuristic)	no

Also known as: HLHS

Data availability: 184 ClinVar variants · 1 GenCC gene-disease record · 12 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › congenital anomaly of cardiovascular system › congenital heart malformation › congenital left-sided heart lesions › hypoplastic left heart syndrome

Subtypes (2): hypoplastic left heart syndrome 1, hypoplastic left heart syndrome 2

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

184 retrieved; paginated sample, class counts are floors:

112 uncertain significance, 51 likely benign, 8 likely pathogenic, 4 benign/likely benign, 3 pathogenic, 3 conflicting classifications of pathogenicity, 3 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1048548	GRCh37/hg19 9q34.3(chr9:139315643-139465759)x1	C9orf163	Pathogenic	no assertion criteria provided
438266	NM_001077653.2(TBX20):c.995del (p.Pro332fs)	TBX20	Pathogenic	no assertion criteria provided
638159	NM_001321120.2(TBX4):c.402G>A (p.Trp134Ter)	TBX4	Pathogenic	criteria provided, single submitter
267958	46;XY;inv(10)(q21.2q22.3)pat		Likely pathogenic	criteria provided, single submitter
1162783	NM_014209.4(ETV2):c.757G>T (p.Asp253Tyr)	ETV2	Likely pathogenic	no assertion criteria provided
1162784	NM_014209.4(ETV2):c.350del (p.Gly117fs)	ETV2	Likely pathogenic	no assertion criteria provided
2692441	NM_002471.4(MYH6):c.1223G>A (p.Gly408Asp)	MYH6	Likely pathogenic	criteria provided, single submitter
804230	NM_017617.5(NOTCH1):c.5385-1G>A	NOTCH1	Likely pathogenic	no assertion criteria provided
996736	NM_017617.5(NOTCH1):c.1077C>A (p.Cys359Ter)	NOTCH1	Likely pathogenic	no assertion criteria provided
996737	NM_017617.5(NOTCH1):c.1651dup (p.Thr551fs)	NOTCH1	Likely pathogenic	no assertion criteria provided
996738	NM_017617.5(NOTCH1):c.2741-1G>A	NOTCH1	Likely pathogenic	criteria provided, single submitter
1588630	NM_004821.3(HAND1):c.46C>A (p.Pro16Thr)	HAND1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1597432	NM_004821.3(HAND1):c.357G>C (p.Glu119Asp)	HAND1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
450338	NM_017617.5(NOTCH1):c.3853G>A (p.Val1285Met)	NOTCH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
974792	GRCh37/hg19 Xp22.33(chrX:2766830-2920785)x2	ARSD-AS1	Uncertain significance	no assertion criteria provided
560610	NM_145020.5(CFAP53):c.46C>T (p.Pro16Ser)	CFAP53	Uncertain significance	criteria provided, single submitter
1019101	NM_004821.3(HAND1):c.215A>G (p.Tyr72Cys)	HAND1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1023202	NM_004821.3(HAND1):c.551A>T (p.His184Leu)	HAND1	Uncertain significance	criteria provided, single submitter
1034420	NM_004821.3(HAND1):c.122A>G (p.Tyr41Cys)	HAND1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1369177	NM_004821.3(HAND1):c.62C>T (p.Pro21Leu)	HAND1	Uncertain significance	criteria provided, single submitter
1372110	NM_004821.3(HAND1):c.245C>T (p.Pro82Leu)	HAND1	Uncertain significance	criteria provided, single submitter
1379353	NM_004821.3(HAND1):c.117G>C (p.Arg39Ser)	HAND1	Uncertain significance	criteria provided, single submitter
1383106	NM_004821.3(HAND1):c.574G>A (p.Gly192Ser)	HAND1	Uncertain significance	criteria provided, single submitter
1394020	NM_004821.3(HAND1):c.400A>T (p.Lys134Ter)	HAND1	Uncertain significance	criteria provided, single submitter
1396928	NM_004821.3(HAND1):c.152A>T (p.Asp51Val)	HAND1	Uncertain significance	criteria provided, single submitter
1399711	NM_004821.3(HAND1):c.271C>A (p.Arg91Ser)	HAND1	Uncertain significance	criteria provided, single submitter
1400060	NM_004821.3(HAND1):c.128A>G (p.Gln43Arg)	HAND1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1404364	NM_004821.3(HAND1):c.202G>C (p.Ala68Pro)	HAND1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1406901	NM_004821.3(HAND1):c.161C>G (p.Pro54Arg)	HAND1	Uncertain significance	criteria provided, single submitter
1433570	NM_004821.3(HAND1):c.496C>T (p.Leu166Phe)	HAND1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 22 · 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
DENND5B	Limited	Autosomal dominant	hypoplastic left heart syndrome	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TBX1	Orphanet:1727	22q11.2 duplication syndrome
TBX1	Orphanet:3303	Tetralogy of Fallot
TBX1	Orphanet:567	22q11.2 deletion syndrome
TBX1	Orphanet:665044	Common arterial trunk with aortic dominance
TBX1	Orphanet:665058	Common arterial trunk with pulmonary dominance and interrupted aortic arch
TBX1	Orphanet:685017	Combined immunodeficiency due to TBX1 deficiency
TBX20	Orphanet:54260	Left ventricular noncompaction
TBX20	Orphanet:99103	Atrial septal defect, ostium secundum type
TBX4	Orphanet:1509	Coxopodopatellar syndrome
TBX4	Orphanet:238578	Familial clubfoot due to 17q23.1q23.2 microduplication
TBX4	Orphanet:261279	17q23.1q23.2 microdeletion syndrome
TBX4	Orphanet:275777	Heritable pulmonary arterial hypertension
TBX4	Orphanet:3301	Tetraamelia-multiple malformations syndrome
CFAP53	Orphanet:101063	Situs inversus totalis
CFAP53	Orphanet:157769	Situs ambiguus
MYH6	Orphanet:154	Familial isolated dilated cardiomyopathy
MYH6	Orphanet:166282	Hereditary sick sinus syndrome
MYH6	Orphanet:99103	Atrial septal defect, ostium secundum type
NOTCH1	Orphanet:402075	Familial bicuspid aortic valve
NOTCH1	Orphanet:974	Adams-Oliver syndrome
NOTCH2	Orphanet:261629	Alagille syndrome due to a NOTCH2 point mutation
NOTCH2	Orphanet:955	Hajdu-Cheney syndrome

Cohort genes → proteins

12 cohort genes, 11 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	12

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DENND5B	HGNC:28338	ENSG00000170456	Q6ZUT9	DENN domain-containing protein 5B	gencc
TBX1	HGNC:11592	ENSG00000184058	O43435	T-box transcription factor TBX1	clinvar
TBX20	HGNC:11598	ENSG00000164532	Q9UMR3	T-box transcription factor TBX20	clinvar
TBX4	HGNC:11603	ENSG00000121075	P57082	T-box transcription factor TBX4	clinvar
CFAP53	HGNC:26530	ENSG00000172361	Q96M91	Cilia- and flagella-associated protein 53	clinvar
C9orf163	HGNC:26718	ENSG00000196366	Q8N9P6	Uncharacterized protein C9orf163	clinvar
ETV2	HGNC:3491	ENSG00000105672	O00321	ETS translocation variant 2	clinvar
ARSD-AS1	HGNC:40085	ENSG00000229851		ARSD antisense RNA 1	clinvar
HAND1	HGNC:4807	ENSG00000113196	O96004	Heart- and neural crest derivatives-expressed protein 1	clinvar
MYH6	HGNC:7576	ENSG00000197616	P13533	Myosin-6	clinvar
NOTCH1	HGNC:7881	ENSG00000148400	P46531	Neurogenic locus notch homolog protein 1	clinvar
NOTCH2	HGNC:7882	ENSG00000134250	Q04721	Neurogenic locus notch homolog protein 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DENND5B	DENN domain-containing protein 5B	Guanine nucleotide exchange factor (GEF) which may activate RAB39A and/or RAB39B.
TBX1	T-box transcription factor TBX1	Transcription factor that plays a key role in cardiovascular development by promoting pharyngeal arch segmentation during embryonic development.
TBX20	T-box transcription factor TBX20	Acts as a transcriptional activator and repressor required for cardiac development and may have key roles in the maintenance of functional and structural phenotypes in adult heart.
TBX4	T-box transcription factor TBX4	Transcriptional regulator that has an essential role in the organogenesis of lungs, pelvis, and hindlimbs.
CFAP53	Cilia- and flagella-associated protein 53	Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme, which is required for motile cilia beating.
ETV2	ETS translocation variant 2	Binds to DNA sequences containing the consensus pentanucleotide 5’-CGGA[AT]-3'.
HAND1	Heart- and neural crest derivatives-expressed protein 1	Transcription factor that plays an essential role in both trophoblast giant cell differentiation and in cardiac morphogenesis.
MYH6	Myosin-6	Muscle contraction.
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.
NOTCH2	Neurogenic locus notch homolog protein 2	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: 0 · Difficult: 8 · Unknown: 4 · 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	5	3.4×	0.030
Scaffold/PPI	3	4.3×	0.043
Other/Unknown	4	0.6×	0.969

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DENND5B	Other/Unknown	no		PLAT/LH2_dom, cDENN_dom, Run_dom
TBX1	Transcription factor	no		TF_T-box, p53-like_TF_DNA-bd_sf, TF_T-box_CS
TBX20	Transcription factor	no		TF_T-box, p53-like_TF_DNA-bd_sf, TF_T-box_CS
TBX4	Transcription factor	no		TF_T-box, p53-like_TF_DNA-bd_sf, TF_T-box_CS
CFAP53	Transcription factor	no		CFAP53/TCHP, TPH_dom
C9orf163	Other/Unknown	no
ETV2	Other/Unknown	no		Ets_dom, WH-like_DNA-bd_sf, WH_DNA-bd_sf
ARSD-AS1	Other/Unknown	no
HAND1	Transcription factor	no		bHLH_dom, HLH_DNA-bd_sf, E-box_TF_Regulators
MYH6	Scaffold/PPI	no		Myosin_head_motor_dom-like, Myosin_tail, SH3_Myosin
NOTCH1	Scaffold/PPI	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Notch_dom
NOTCH2	Scaffold/PPI	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, Notch_dom

Expression context

Cohort genes with no expression data: 0.

7 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)	12
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cardiac atrium	2
left testis	2
male germ line stem cell (sensu Vertebrata) in testis	2
primordial germ cell in gonad	2
endothelial cell	1
lateral nuclear group of thalamus	1
pons	1
gastrocnemius	1
hindlimb stylopod muscle	1
muscle of leg	1
heart	1
right atrium auricular region	1
right lung	1
upper lobe of left lung	1
upper lobe of lung	1
bronchial epithelial cell	1
bronchus	1
myocardium	1
pituitary gland	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DENND5B	261	ubiquitous	marker	lateral nuclear group of thalamus, pons, endothelial cell
TBX1	220	broad	marker	hindlimb stylopod muscle, gastrocnemius, muscle of leg
TBX20	52	broad	marker	right atrium auricular region, cardiac atrium, heart
TBX4	116	tissue_specific	yes	right lung, upper lobe of left lung, upper lobe of lung
CFAP53	194	broad	marker	bronchial epithelial cell, bronchus, left testis
C9orf163	121	tissue_specific	yes	right uterine tube, myocardium, pituitary gland
ETV2	160	ubiquitous	yes	left testis, right testis, male germ line stem cell (sensu Vertebrata) in testis
ARSD-AS1	112		yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, liver
HAND1	74	broad	marker	muscle layer of sigmoid colon, primordial germ cell in gonad, apex of heart
MYH6	154	tissue_specific	yes	cardiac muscle of right atrium, cardiac atrium, vena cava
NOTCH1	272	ubiquitous	marker	ventricular zone, colonic epithelium, visceral pleura
NOTCH2	294	ubiquitous	marker	pigmented layer of retina, retina, skin of hip

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NOTCH1	7,411
NOTCH2	5,266
MYH6	3,119
CFAP53	1,448
TBX20	1,425
TBX1	1,256
TBX4	1,054
DENND5B	732
ETV2	690
HAND1	494

Intra-cohort edges

A	B	Sources
MYH6	TBX20	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 7 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NOTCH1	P46531	29
CFAP53	Q96M91	2
NOTCH2	Q04721	2
TBX1	O43435	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DENND5B	Q6ZUT9	77.12
MYH6	P13533	74.91
TBX20	Q9UMR3	67.87
HAND1	O96004	65.87
TBX4	P57082	60.96
ETV2	O00321	57.35
C9orf163	Q8N9P6	33.64

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 30. Enrichment computed across 12 evidence-associated genes (7 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 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Cardiogenesis	3	181.3×	1e-05	TBX1, TBX20, HAND1
Defective LFNG causes SCDO3	2	652.6×	5e-05	NOTCH1, NOTCH2
Pre-NOTCH Processing in the Endoplasmic Reticulum	2	543.8×	5e-05	NOTCH1, NOTCH2
Pre-NOTCH Processing in Golgi	2	181.3×	4e-04	NOTCH1, NOTCH2
NOTCH4 Intracellular Domain Regulates Transcription	2	163.1×	4e-04	NOTCH1, NOTCH2
Notch-HLH transcription pathway	2	116.5×	6e-04	NOTCH1, NOTCH2
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	2	41.8×	0.004	NOTCH1, NOTCH2
Pre-NOTCH Transcription and Translation	2	35.1×	0.005	NOTCH1, NOTCH2
Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling	1	326.3×	0.010	NOTCH1
Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant	1	233.1×	0.013	NOTCH1
Regulation of NFE2L2 gene expression	1	203.9×	0.013	NOTCH1
NOTCH2 intracellular domain regulates transcription	1	135.9×	0.017	NOTCH2
NFE2L2 regulating tumorigenic genes	1	135.9×	0.017	NOTCH1
RUNX3 regulates NOTCH signaling	1	116.5×	0.018	NOTCH1
Constitutive Signaling by NOTCH1 HD Domain Mutants	1	108.8×	0.018	NOTCH1
Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells	1	102.0×	0.018	NOTCH1
MECP2 regulates neuronal receptors and channels	1	85.9×	0.020	NOTCH1
NOTCH2 Activation and Transmission of Signal to the Nucleus	1	62.8×	0.025	NOTCH2
NOTCH3 Intracellular Domain Regulates Transcription	1	62.8×	0.025	NOTCH1
Formation of paraxial mesoderm	1	58.3×	0.026	NOTCH1
Activated NOTCH1 Transmits Signal to the Nucleus	1	51.0×	0.028	NOTCH1
Nuclear events stimulated by ALK signaling in cancer	1	46.6×	0.029	NOTCH1
Striated Muscle Contraction	1	44.1×	0.029	MYH6
NOTCH1 Intracellular Domain Regulates Transcription	1	34.0×	0.036	NOTCH1
Somitogenesis	1	33.3×	0.036	NOTCH1
Constitutive Signaling by NOTCH1 PEST Domain Mutants	1	28.1×	0.039	NOTCH1
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	1	28.1×	0.039	NOTCH1
RAB GEFs exchange GTP for GDP on RABs	1	17.7×	0.059	DENND5B
Developmental Biology	2	4.1×	0.082	TBX1, TBX20
Muscle contraction	1	11.0×	0.087	MYH6

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 10 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
heart looping	4	107.0×	1e-05	TBX20, HAND1, NOTCH1, NOTCH2
cardiac chamber formation	2	1123.5×	9e-05	TBX20, NOTCH1
cell fate specification	3	158.0×	9e-05	TBX1, TBX20, TBX4
positive regulation of BMP signaling pathway	3	136.6×	9e-05	TBX20, NOTCH1, NOTCH2
cardiac right ventricle formation	2	842.6×	1e-04	HAND1, NOTCH1
cellular response to tumor cell	2	842.6×	1e-04	NOTCH1, NOTCH2
atrioventricular node development	2	561.7×	2e-04	NOTCH1, NOTCH2
mesenchymal cell development	2	481.5×	2e-04	TBX20, NOTCH1
determination of left/right symmetry	3	76.6×	2e-04	TBX1, CFAP53, NOTCH1
pericardium morphogenesis	2	421.3×	3e-04	TBX20, NOTCH1
positive regulation of smooth muscle cell differentiation	2	374.5×	3e-04	NOTCH1, NOTCH2
coronary artery morphogenesis	2	374.5×	3e-04	TBX1, NOTCH1
positive regulation of endothelial cell differentiation	2	306.4×	4e-04	ETV2, NOTCH1
cardiac muscle tissue morphogenesis	2	280.9×	5e-04	TBX20, NOTCH1
atrial septum morphogenesis	2	259.3×	5e-04	TBX20, NOTCH2
cardiac septum morphogenesis	2	240.7×	5e-04	HAND1, NOTCH1
left/right axis specification	2	240.7×	5e-04	NOTCH1, NOTCH2
Notch signaling pathway	3	42.5×	7e-04	ETV2, NOTCH1, NOTCH2
inflammatory response to antigenic stimulus	2	187.2×	7e-04	NOTCH1, NOTCH2
pulmonary valve morphogenesis	2	187.2×	7e-04	NOTCH1, NOTCH2
positive regulation of Ras protein signal transduction	2	177.4×	8e-04	NOTCH1, NOTCH2
endocardial cushion morphogenesis	2	168.5×	8e-04	TBX20, NOTCH1
regulation of transcription by RNA polymerase II	6	7.0×	8e-04	TBX1, TBX20, TBX4, ETV2, HAND1, NOTCH1
blood vessel morphogenesis	2	160.5×	8e-04	TBX1, ETV2
ventricular cardiac muscle tissue morphogenesis	2	140.4×	0.001	HAND1, MYH6
blastocyst development	2	134.8×	0.001	ETV2, HAND1
outflow tract septum morphogenesis	2	129.6×	0.001	TBX1, TBX20
positive regulation of cardiac muscle cell proliferation	2	124.8×	0.001	TBX20, NOTCH1
embryonic hindlimb morphogenesis	2	116.2×	0.001	TBX4, NOTCH1
aortic valve morphogenesis	2	86.4×	0.002	TBX20, NOTCH1

Therapeutics

Drugs indicated for this disease

No approved or late-stage (phase ≥3) drug is indicated for this disease; the following are in earlier-phase trials only.

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Ambrisentan, Bosentan, Sildenafil.

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 11

Druggability breadth: 3 of 12 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NOTCH1	1	2
DENND5B	0	0
TBX1	0	0
TBX20	0	0
TBX4	0	0
CFAP53	0	0
C9orf163	0	0
ETV2	0	0
ARSD-AS1	0	0
HAND1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VAREGACESTAT	2	NOTCH1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NOTCH1	23	Binding:19, ADMET:4
NOTCH2	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 11; 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)
VAREGACESTAT	2	NOTCH1

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	NOTCH1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	11	DENND5B, TBX1, TBX20, TBX4, CFAP53, C9orf163, ETV2, ARSD-AS1, HAND1, MYH6 (+1 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DENND5B	0	—
TBX1	0	—
TBX20	0	—
TBX4	0	—
CFAP53	0	—
C9orf163	0	—
ETV2	0	—
ARSD-AS1	0	—
HAND1	0	—
MYH6	0	—
NOTCH2	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 53.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	34
PHASE1	8
PHASE2	6
PHASE1/PHASE2	4
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02781922	PHASE3	RECRUITING	Cardiac Stem/Progenitor Cell Infusion in Univentricular Physiology (APOLLON Trial)
NCT03779711	PHASE2	ACTIVE_NOT_RECRUITING	Intramyocardial Injection of Autologous Umbilical Cord Blood Derived Mononuclear Cells During Surgical Repair of Hypoplastic Left Heart Syndrome
NCT04925024	PHASE2	ACTIVE_NOT_RECRUITING	Evaluation of Lomecel-B™ Injection in Patients With Hypoplastic Left Heart Syndrome (HLHS): A Phase IIb Clinical Trial.
NCT00507819	PHASE2	COMPLETED	Sildenafil After the Fontan Operation
NCT00513240	PHASE1/PHASE2	COMPLETED	Erythropoetin Neuroprotection for Neonatal Cardiac Surgery
NCT01292551	PHASE2	COMPLETED	Study of Placebo or Bosentan to Treat Patients With Single Ventricle Physiology.
NCT01829750	PHASE2	COMPLETED	Cardiac Progenitor Cell Infusion to Treat Univentricular Heart Disease (PERSEUS)
NCT02080637	PHASE2	COMPLETED	Ambrisentan in Single Ventricle
NCT03079401	PHASE1/PHASE2	UNKNOWN	Mesoblast Stem Cell Therapy for Patients With Single Ventricle and Borderline Left Ventricle
NCT03136835	PHASE1/PHASE2	COMPLETED	Maternal Hyperoxygenation in Congenital Heart Disease
NCT03525418	PHASE1/PHASE2	UNKNOWN	Lomecel-B Delivered During Stage II Surgery for Hypoplastic Left Heart Syndrome (ELPIS)
NCT06461676	PHASE1	NOT_YET_RECRUITING	Study of Intramyocardial Injection of Ventrix Bio Extracellular Matrix (VentriGel) to Assess the Safety and Feasibility in Pediatric Patients with Hypoplastic Left Heart Syndrome (HLHS)
NCT01273857	PHASE1	COMPLETED	Transcoronary Infusion of Cardiac Progenitor Cells in Patients With Single Ventricle Physiology
NCT01445041	PHASE1	TERMINATED	Safety and Feasibility Study of Umbilical Cord Blood Cells for Infants With Hypoplastic Left Heart Syndrome
NCT01883076	PHASE1	COMPLETED	Safety Study of Autologous Umbilical Cord Blood Cells for Treatment of Hypoplastic Left Heart Syndrome
NCT02398604	PHASE1	TERMINATED	Allogeneic hMSC Injection in Patients With Hypoplastic Left Heart Syndrome
NCT03406884	PHASE1	COMPLETED	The CHILD Trial: Hypoplastic Left Heart Syndrome Study.
NCT03431480	PHASE1	COMPLETED	Safety of Autologous Cord Blood Cells in HLHS Patients During Norwood Heart Surgery
NCT04181255	PHASE1	TERMINATED	Cold Heart Study: A Randomized Pilot Trial of Surfactant Therapy
NCT02852031	Not specified	RECRUITING	National Collaborative to Improve Care of Children With Complex Congenital Heart Disease
NCT05386173	Not specified	RECRUITING	Effect of Fetal Aortic Valvuloplasty on Outcomes
NCT06342999	Not specified	ENROLLING_BY_INVITATION	Fetal Aortic Valvuloplasty for Evolving Hypoplastic Left Heart Syndrome
NCT06711666	Not specified	RECRUITING	Prenatal Maternal Mental Health and Neurodevelopment in Congenital Heart Disease
NCT06768008	Not specified	RECRUITING	An Integrated Prenatal and Postnatal Treatment Model for the Treatment of Newborns With Critical Congenital Heart Disease
NCT06853054	Not specified	NOT_YET_RECRUITING	Seeking for Perfected Aortic Arch Reconstruction Using a Graphically Designed Patient-specific Surgical Patch
NCT00156455	Not specified	WITHDRAWN	Sleep Disordered Breathing in Children With Single Ventricle Physiology
NCT00308217	Not specified	COMPLETED	Single Ventricle Outcome
NCT00464100	Not specified	COMPLETED	Near-infrared Spectroscopy (NIRS) Neurodevelopmental Outcomes
NCT00571233	Not specified	COMPLETED	Biomarker Study for Heart Failure in Children With Single Ventricle Physiology
NCT00734643	Not specified	COMPLETED	Family Adaptation Study Following the Diagnosis of Hypoplastic Left Heart Syndrome in a Newborn
NCT00860327	Not specified	TERMINATED	Examining Developmental Changes in Heart Contractions of Children With Congenital Heart Defects
NCT00974025	Not specified	COMPLETED	Impact of Vitamin C on Endothelial Function and Exercise Capacity in Fontan-Palliated Patients
NCT01032876	Not specified	COMPLETED	Cerebral Perfusion During Neonatal Cardiac Surgery
NCT01107990	Not specified	TERMINATED	Global and Regional Myocardial Strain and Power Output In Patients With Single Ventricles Using Novel MRI Techniques
NCT01215240	Not specified	COMPLETED	Prophylactic Peritoneal Dialysis Decreases Time to Achieve a Negative Fluid Balance After the Norwood Procedure
NCT01582529	Not specified	COMPLETED	SVRII Family Factors Study
NCT01656941	Not specified	COMPLETED	Genetic Determinants of Congenital Heart Disease Outcomes
NCT01708863	Not specified	COMPLETED	A Prospective Study of Patients With Hypoplastic Left Heart Syndrome (HLHS) Following Stage II Surgical Palliation
NCT01736956	Not specified	COMPLETED	Fetal Intervention for Aortic Stenosis and Evolving Hypoplastic Left Heart Syndrome
NCT01856049	Not specified	COMPLETED	Umbilical Cord Blood Collection and Processing for Hypoplastic Left Heart Syndrome Patients

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
AMBRISENTAN	4	1
BOSENTAN	4	1
PORACTANT ALFA	4	1
SILDENAFIL	4	1
AUTOLOGOUS CORD BLOOD	3	1
REXLEMESTROCEL-L	3	1
CHEMBL302753	0	1