Hypoplastic left heart syndrome 1

Summary

Hypoplastic left heart syndrome 1 (MONDO:0009433) is a disease with 4 cohort genes and 1 clinical trial.

At a glance

• Cohort genes: 4
• ClinVar variants: 62
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypoplastic left heart syndrome 1
Mondo ID	MONDO:0009433
OMIM	241550
UMLS	C4551854
MedGen	1646779
GARD	0024671
Is cancer (heuristic)	no

Also known as: GJA1 hypoplastic left heart syndrome · HLHS · HLHS1 · hypoplastic left heart syndrome 1 · hypoplastic left heart syndrome caused by mutation in GJA1 · hypoplastic left heart syndrome type 1

Data availability: 62 ClinVar variants.

Disease family

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 › hypoplastic left heart syndrome 1

Related subtypes (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

62 retrieved; paginated sample, class counts are floors:

38 uncertain significance, 15 conflicting classifications of pathogenicity, 4 benign/likely benign, 3 benign, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1703529	GRCh37/hg19 1q21.1-21.2(chr1:145792051-148001265)	ACP6	Pathogenic	no assertion criteria provided
435323	NM_000165.5(GJA1):c.119C>T (p.Ala40Val)	GJA1	Pathogenic	criteria provided, multiple submitters, no conflicts
16990	NM_000165.5(GJA1):c.1085G>A (p.Arg362Gln)	GJA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
16991	NM_000165.5(GJA1):c.1127G>A (p.Arg376Gln)	GJA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
355156	NM_000165.5(GJA1):c.-135C>T	GJA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
355157	NM_000165.5(GJA1):c.-67C>G	GJA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
355158	NM_000165.5(GJA1):c.-16-12T>A	GJA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
355159	NM_000165.5(GJA1):c.270C>G (p.Leu90=)	GJA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
355160	NM_000165.5(GJA1):c.456G>A (p.Leu152=)	GJA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
355163	NM_000165.5(GJA1):c.1128G>A (p.Arg376=)	GJA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
355165	NM_000165.5(GJA1):c.*119T>C	GJA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
355170	NM_000165.5(GJA1):c.*243A>G	GJA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
580391	NM_000165.5(GJA1):c.814T>C (p.Ser272Pro)	GJA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
904919	NM_000165.5(GJA1):c.706G>A (p.Val236Ile)	GJA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
906627	NM_000165.5(GJA1):c.*498G>A	GJA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
907523	NM_000165.5(GJA1):c.717G>C (p.Arg239=)	GJA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
907524	NM_000165.5(GJA1):c.764G>A (p.Ser255Asn)	GJA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1703530	GRCh37/hg19 15q11.2(chr15:22770421-23282799)	CYFIP1	Uncertain significance	no assertion criteria provided
1050474	NM_000165.5(GJA1):c.932del (p.Ala311fs)	GJA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1206770	NM_000165.5(GJA1):c.1039C>A (p.Leu347Ile)	GJA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
355154	NM_000165.5(GJA1):c.-188G>T	GJA1	Uncertain significance	criteria provided, single submitter
355155	NM_000165.5(GJA1):c.-161G>T	GJA1	Uncertain significance	criteria provided, single submitter
355162	NM_000165.5(GJA1):c.1015G>A (p.Asp339Asn)	GJA1	Uncertain significance	criteria provided, multiple submitters, no conflicts
355164	NM_000165.5(GJA1):c.*47A>G	GJA1	Uncertain significance	criteria provided, single submitter
355166	NM_000165.5(GJA1):c.*163G>A	GJA1	Uncertain significance	criteria provided, single submitter
355168	NM_000165.5(GJA1):c.*191G>A	GJA1	Uncertain significance	criteria provided, single submitter
355169	NM_000165.5(GJA1):c.*214G>A	GJA1	Uncertain significance	criteria provided, single submitter
355171	NM_000165.5(GJA1):c.*285A>T	GJA1	Uncertain significance	criteria provided, single submitter
355172	NM_000165.5(GJA1):c.*529C>G	GJA1	Uncertain significance	criteria provided, single submitter
355173	NM_000165.5(GJA1):c.*538G>A	GJA1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 10 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FOXP1	Orphanet:391372	FOXP1 Syndrome
FOXP1	Orphanet:52417	MALT lymphoma
FOXP1	Orphanet:585877	B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormality
GJA1	Orphanet:1010	Autosomal dominant palmoplantar keratoderma and congenital alopecia
GJA1	Orphanet:1522	Craniometaphyseal dysplasia
GJA1	Orphanet:2248	Hypoplastic left heart syndrome
GJA1	Orphanet:2710	Oculodentodigital dysplasia
GJA1	Orphanet:317	Erythrokeratodermia variabilis
GJA1	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
GJA1	Orphanet:93404	Syndactyly type 3

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CYFIP1	HGNC:13759	ENSG00000273749	Q7L576	Cytoplasmic FMR1-interacting protein 1	clinvar
ACP6	HGNC:29609	ENSG00000162836	Q9NPH0	Lysophosphatidic acid phosphatase type 6	clinvar
FOXP1	HGNC:3823	ENSG00000114861	Q9H334	Forkhead box protein P1	clinvar
GJA1	HGNC:4274	ENSG00000152661	P17302	Gap junction alpha-1 protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CYFIP1	Cytoplasmic FMR1-interacting protein 1	Component of the CYFIP1-EIF4E-FMR1 complex which binds to the mRNA cap and mediates translational repression.
ACP6	Lysophosphatidic acid phosphatase type 6	Hydrolyzes lysophosphatidic acid (LPA) containing a medium length fatty acid chain to the corresponding monoacylglycerol.
FOXP1	Forkhead box protein P1	Transcriptional repressor.
GJA1	Gap junction alpha-1 protein	Structural component of the gap junction, a specialized intercellular structure consisting of a cluster of closely packed pairs of transmembrane channels, the connexons, that allow passage of small molecules and electrical signals between…

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.25

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
Phosphatase	1	21.0×	0.141
Transcription factor	1	2.1×	0.605
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CYFIP1	Other/Unknown	no		Cytoplasmic_FMR1-int, CYRIA/CYRIB_Rac1-bd
ACP6	Phosphatase	yes	3.1.3.106	His_Pase_clade-2, His_PPase_superfam, Acid_Pase_AS
FOXP1	Transcription factor	no		Fork_head_dom, TF_fork_head_CS_2, FOXP-CC
GJA1	Other/Unknown	no		Connexin, Connexin43, Connexin_N

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
pancreatic ductal cell	2
epithelium of esophagus	1
esophagus squamous epithelium	1
germinal epithelium of ovary	1
mucosa of stomach	1
right uterine tube	1
cardia of stomach	1
oviduct epithelium	1
dorsal motor nucleus of vagus nerve	1
hair follicle	1
lateral globus pallidus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CYFIP1	295	ubiquitous	marker	esophagus squamous epithelium, germinal epithelium of ovary, epithelium of esophagus
ACP6	257	ubiquitous	marker	right uterine tube, pancreatic ductal cell, mucosa of stomach
FOXP1	256	ubiquitous	marker	pancreatic ductal cell, oviduct epithelium, cardia of stomach
GJA1	292	ubiquitous	marker	lateral globus pallidus, dorsal motor nucleus of vagus nerve, hair follicle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GJA1	4,942
FOXP1	2,939
CYFIP1	2,156
ACP6	785

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GJA1	P17302	19
CYFIP1	Q7L576	5
ACP6	Q9NPH0	3
FOXP1	Q9H334	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 22. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Oligomerization of connexins into connexons	1	951.7×	0.008	GJA1
Transport of connexins along the secretory pathway	1	951.7×	0.008	GJA1
Regulation of gap junction activity	1	951.7×	0.008	GJA1
SARS-CoV-2 targets PDZ proteins in cell-cell junction	1	571.0×	0.010	GJA1
Formation of annular gap junctions	1	259.6×	0.015	GJA1
Gap junction degradation	1	237.9×	0.015	GJA1
Mechanical load activates signaling by PIEZO1 and integrins in osteocytes	1	167.9×	0.018	GJA1
Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane	1	135.9×	0.018	GJA1
Transcriptional regulation of pluripotent stem cells	1	135.9×	0.018	FOXP1
RHO GTPases Activate WASPs and WAVEs	1	79.3×	0.025	CYFIP1
Synthesis of PA	1	73.2×	0.025	ACP6
Gap junction assembly	1	73.2×	0.025	GJA1
RHOJ GTPase cycle	1	50.1×	0.030	GJA1
FCGR3A-mediated phagocytosis	1	46.8×	0.030	CYFIP1
Regulation of actin dynamics for phagocytic cup formation	1	46.0×	0.030	CYFIP1
RHOQ GTPase cycle	1	45.3×	0.030	GJA1
RHOG GTPase cycle	1	37.1×	0.035	CYFIP1
VEGFA-VEGFR2 Pathway	1	34.8×	0.035	CYFIP1
RAC2 GTPase cycle	1	31.7×	0.036	CYFIP1
RAC3 GTPase cycle	1	29.7×	0.037	CYFIP1
RAC1 GTPase cycle	1	15.3×	0.067	CYFIP1
Neutrophil degranulation	1	5.8×	0.162	CYFIP1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
microtubule-based transport	1	4213.0×	0.005	GJA1
regulation of macrophage colony-stimulating factor production	1	4213.0×	0.005	FOXP1
positive regulation of mesodermal cell differentiation	1	4213.0×	0.005	GJA1
negative regulation of gonadotropin secretion	1	2106.5×	0.005	GJA1
regulation of monocyte differentiation	1	2106.5×	0.005	FOXP1
regulation of defense response to bacterium	1	2106.5×	0.005	FOXP1
lysobisphosphatidic acid metabolic process	1	2106.5×	0.005	ACP6
positive regulation of interleukin-21 production	1	1404.3×	0.005	FOXP1
regulation of translation at postsynapse, modulating synaptic transmission	1	1404.3×	0.005	CYFIP1
positive regulation of morphogenesis of an epithelium	1	1404.3×	0.005	GJA1
regulation of chemokine (C-X-C motif) ligand 2 production	1	1404.3×	0.005	FOXP1
cell communication by electrical coupling	1	1053.2×	0.006	GJA1
regulation of interleukin-12 production	1	1053.2×	0.006	FOXP1
positive regulation of hydrogen peroxide-mediated programmed cell death	1	1053.2×	0.006	FOXP1
positive regulation of neurotrophin TRK receptor signaling pathway	1	842.6×	0.006	CYFIP1
regulation of endothelial tube morphogenesis	1	842.6×	0.006	FOXP1
positive regulation of B cell receptor signaling pathway	1	601.9×	0.006	FOXP1
negative regulation of trophoblast cell migration	1	601.9×	0.006	GJA1
regulation of modification of postsynaptic actin cytoskeleton	1	601.9×	0.006	CYFIP1
gap junction assembly	1	526.6×	0.006	GJA1
regulation of interleukin-1 beta production	1	526.6×	0.006	FOXP1
osteoclast development	1	526.6×	0.006	FOXP1
positive regulation of Arp2/3 complex-mediated actin nucleation	1	526.6×	0.006	CYFIP1
monocyte activation	1	468.1×	0.006	FOXP1
glutamate secretion	1	421.3×	0.006	GJA1
regulation of tumor necrosis factor production	1	421.3×	0.006	FOXP1
endothelial cell activation	1	421.3×	0.006	FOXP1
atrial cardiac muscle cell action potential	1	421.3×	0.006	GJA1
dendrite extension	1	421.3×	0.006	CYFIP1
export across plasma membrane	1	421.3×	0.006	GJA1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 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
GJA1	KANAMYCIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GJA1	1	4
CYFIP1	0	0
ACP6	0	0
FOXP1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
KANAMYCIN	4	GJA1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CYFIP1	7	Binding:7
GJA1	4	Binding:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ACP6	3.1.3.106	2-lysophosphatidate phosphatase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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)
KANAMYCIN	4	GJA1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GJA1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	ACP6
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	CYFIP1, FOXP1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CYFIP1	7	—
ACP6	0	—
FOXP1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03525418	PHASE1/PHASE2	UNKNOWN	Lomecel-B Delivered During Stage II Surgery for Hypoplastic Left Heart Syndrome (ELPIS)