Progressive familial heart block

Summary

Progressive familial heart block (MONDO:0019490) is a disease with 7 cohort genes. The dominant Reactome pathway is Cardiac conduction (4 cohort genes).

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Cohort genes: 7
• ClinVar variants: 4
• Phenotypes (HPO): 8

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		50	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0001279	Syncope	Frequent (30-79%)
HP:0001635	Congestive heart failure	Frequent (30-79%)
HP:0002027	Abdominal pain	Frequent (30-79%)
HP:0002094	Dyspnea	Frequent (30-79%)
HP:0002321	Vertigo	Frequent (30-79%)
HP:0011675	Arrhythmia	Frequent (30-79%)
HP:0011710	Bundle branch block	Frequent (30-79%)
HP:0012722	Heart block	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	progressive familial heart block
Mondo ID	MONDO:0019490
OMIM	113900
Orphanet	871
DOID	DOID:0111073
ICD-11	1762068981
SNOMED CT	698249005, 93130009
GARD	0010005
Is cancer (heuristic)	no

Also known as: familial Lenègre disease · familial Lev-Lenègre disease · familial progressive heart block · hereditary bundle branch defect

Data availability: 4 ClinVar variants · 3 GenCC gene-disease records.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › heart conduction disease › progressive familial heart block

Related subtypes (9): short QT syndrome, atrioventricular block, sinoatrial node disorder, Wolff-Parkinson-White syndrome, postural orthostatic tachycardia syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, sinoatrial block, NKX2.5-related congenital, conduction and myopathic heart disease

Subtypes (3): progressive familial heart block, type 1A, progressive familial heart block type II, progressive familial heart block type IB

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

4 retrieved; paginated sample, class counts are floors:

2 likely pathogenic, 1 conflicting classifications of pathogenicity, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
1332983	NM_001927.4(DES):c.1158_1160delinsTACCAGGACCTGCTG (p.Glu387delinsThrArgThrCysTrp)	DES	Likely pathogenic	criteria provided, single submitter
431487	NM_004415.4(DSP):c.5051A>G (p.His1684Arg)	DSP	Likely pathogenic	criteria provided, single submitter
191439	NM_001232.4(CASQ2):c.1186G>A (p.Asp396Asn)	CASQ2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
937283	NM_000238.4(KCNH2):c.523G>T (p.Ala175Ser)	KCNH2	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 49 · Orphanet: 34 · 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
SCN5A	Strong	Autosomal dominant	progressive familial heart block, type 1A	23
TRPM4	Strong	Autosomal dominant	progressive familial heart block type IB	11
SCN1B	Supportive	Autosomal dominant	progressive familial heart block	15

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SCN1B	Orphanet:130	Brugada syndrome
SCN1B	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
SCN1B	Orphanet:33069	Dravet syndrome
SCN1B	Orphanet:334	Hereditary atrial fibrillation
SCN1B	Orphanet:36387	Genetic epilepsy with febrile seizure plus
SCN1B	Orphanet:871	Hereditary progressive cardiac conduction defect
SCN5A	Orphanet:101016	Romano-Ward syndrome
SCN5A	Orphanet:130	Brugada syndrome
SCN5A	Orphanet:1344	Isolated atrial standstill
SCN5A	Orphanet:154	Familial isolated dilated cardiomyopathy
SCN5A	Orphanet:166282	Hereditary sick sinus syndrome
SCN5A	Orphanet:228140	Idiopathic ventricular fibrillation
SCN5A	Orphanet:334	Hereditary atrial fibrillation
SCN5A	Orphanet:871	Hereditary progressive cardiac conduction defect
TRPM4	Orphanet:130	Brugada syndrome
TRPM4	Orphanet:316	Progressive symmetric erythrokeratodermia
TRPM4	Orphanet:871	Hereditary progressive cardiac conduction defect
CASQ2	Orphanet:3286	Catecholaminergic polymorphic ventricular tachycardia
DES	Orphanet:154	Familial isolated dilated cardiomyopathy
DES	Orphanet:85146	Neurogenic scapuloperoneal syndrome, Kaeser type
DES	Orphanet:98909	Desminopathy
DSP	Orphanet:154	Familial isolated dilated cardiomyopathy
DSP	Orphanet:158687	Lethal acantholytic erosive disorder
DSP	Orphanet:2032	Idiopathic pulmonary fibrosis
DSP	Orphanet:293165	Skin fragility-woolly hair-palmoplantar keratoderma syndrome
DSP	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
DSP	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
DSP	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
DSP	Orphanet:369992	Severe dermatitis-multiple allergies-metabolic wasting syndrome
DSP	Orphanet:476096	Erythrokeratodermia-cardiomyopathy syndrome
DSP	Orphanet:50942	Striate palmoplantar keratoderma
DSP	Orphanet:65282	Carvajal syndrome
KCNH2	Orphanet:101016	Romano-Ward syndrome
KCNH2	Orphanet:51083	Congenital short QT syndrome

Cohort genes → proteins

7 cohort genes, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SCN1B	HGNC:10586	ENSG00000105711	Q07699	Sodium channel regulatory subunit beta-1	gencc
SCN5A	HGNC:10593	ENSG00000183873	Q14524	Sodium channel protein type 5 subunit alpha	gencc
TRPM4	HGNC:17993	ENSG00000130529	Q8TD43	Transient receptor potential cation channel subfamily M member 4	gencc
CASQ2	HGNC:1513	ENSG00000118729	O14958	Calsequestrin-2	clinvar
DES	HGNC:2770	ENSG00000175084	P17661	Desmin	clinvar
DSP	HGNC:3052	ENSG00000096696	P15924	Desmoplakin	clinvar
KCNH2	HGNC:6251	ENSG00000055118	Q12809	Voltage-gated inwardly rectifying potassium channel KCNH2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SCN1B	Sodium channel regulatory subunit beta-1	Regulatory subunit of multiple voltage-gated sodium (Nav) channels directly mediating the depolarization of excitable membranes.
SCN5A	Sodium channel protein type 5 subunit alpha	Pore-forming subunit of Nav1.5, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes.
TRPM4	Transient receptor potential cation channel subfamily M member 4	Calcium-activated selective cation channel that mediates membrane depolarization.
CASQ2	Calsequestrin-2	Calsequestrin is a high-capacity, moderate affinity, calcium-binding protein and thus acts as an internal calcium store in muscle.
DES	Desmin	Muscle-specific type III intermediate filament essential for proper muscular structure and function.
DSP	Desmoplakin	A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion.
KCNH2	Voltage-gated inwardly rectifying potassium channel KCNH2	Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel.

Protein-family classification

Druggable: 4 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.57

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
Ion channel	3	47.8×	1e-04
Antibody/Immunoglobulin	1	4.2×	0.433
Scaffold/PPI	1	2.5×	0.455
Other/Unknown	2	0.5×	0.968

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCN1B	Antibody/Immunoglobulin	yes		Ig_V-set, Ig-like_fold, Na_channel_b1/b3
SCN5A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a5su
TRPM4	Ion channel	yes		Ion_trans_dom, TRPM_SLOG, TRPM
CASQ2	Other/Unknown	no		Calsequestrin, Calsequestrin_CS, Thioredoxin-like_sf
DES	Other/Unknown	no		Intermed_filament_DNA-bd, IF_conserved, IF_rod_dom
DSP	Scaffold/PPI	no		Plectin_repeat, SH3_domain, Spectrin/alpha-actinin
KCNH2	Ion channel	yes		PAS, cNMP-bd_dom, PAS-assoc_C

Expression context

Cohort genes with no expression data: 0.

6 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)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	4
cerebellum	1
primary visual cortex	1
right hemisphere of cerebellum	1
cardiac ventricle	1
heart left ventricle	1
mucosa of transverse colon	1
rectum	1
heart right ventricle	1
left ventricle myocardium	1
myocardium	1
gastrocnemius	1
saphenous vein	1
hair follicle	1
skin of hip	1
upper leg skin	1
cardiac atrium	1
right atrium auricular region	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SCN1B	133	ubiquitous	marker	primary visual cortex, right hemisphere of cerebellum, cerebellum
SCN5A	161	broad	yes	apex of heart, heart left ventricle, cardiac ventricle
TRPM4	201	ubiquitous	marker	mucosa of transverse colon, rectum, apex of heart
CASQ2	213	broad	marker	heart right ventricle, left ventricle myocardium, myocardium
DES	280	broad	marker	apex of heart, saphenous vein, gastrocnemius
DSP	253	ubiquitous	marker	skin of hip, upper leg skin, hair follicle
KCNH2	211	broad	marker	apex of heart, right atrium auricular region, cardiac atrium

Protein interactions among cohort

Intra-cohort edges: 6.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DSP	2,897
DES	2,486
SCN5A	2,090
CASQ2	1,977
KCNH2	1,932
SCN1B	1,328
TRPM4	1,217

Intra-cohort edges

A	B	Sources
CASQ2	KCNH2	string_interaction
CASQ2	SCN5A	string_interaction
DES	DSP	string_interaction
KCNH2	SCN5A	string_interaction
SCN1B	SCN5A	string_interaction
SCN5A	TRPM4	string_interaction

Structural data

PDB: 6 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SCN1B	Q07699	39
TRPM4	Q8TD43	29
KCNH2	Q12809	24
SCN5A	Q14524	16
CASQ2	O14958	4
DSP	P15924	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DES	P17661	77.73

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 27. Enrichment computed across 7 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
Cardiac conduction	4	62.1×	6e-06	SCN1B, SCN5A, CASQ2, KCNH2
Muscle contraction	4	44.1×	1e-05	SCN1B, SCN5A, CASQ2, KCNH2
Interaction between L1 and Ankyrins	2	105.2×	0.001	SCN1B, SCN5A
Phase 0 - rapid depolarisation	2	98.9×	0.001	SCN1B, SCN5A
Sensory perception of sweet, bitter, and umami (glutamate) taste	2	79.6×	0.001	SCN1B, TRPM4
L1CAM interactions	2	34.4×	0.006	SCN1B, SCN5A
Phase 3 - rapid repolarisation	1	163.1×	0.023	KCNH2
Apoptotic cleavage of cell adhesion proteins	1	148.3×	0.023	DSP
Axon guidance	2	12.9×	0.028	SCN1B, SCN5A
Nervous system development	2	12.3×	0.028	SCN1B, SCN5A
TRP channels	1	58.3×	0.042	TRPM4
Sensory perception of taste	1	48.0×	0.046	SCN1B
Striated Muscle Contraction	1	44.1×	0.047	DES
RND1 GTPase cycle	1	37.9×	0.048	DSP
RND3 GTPase cycle	1	37.1×	0.048	DSP
Voltage gated Potassium channels	1	34.7×	0.048	KCNH2
Ion homeostasis	1	29.1×	0.054	CASQ2
Stimuli-sensing channels	1	19.4×	0.072	CASQ2
Potassium Channels	1	19.2×	0.072	KCNH2
Ion channel transport	1	13.7×	0.092	CASQ2
Sensory Perception	1	13.6×	0.092	SCN1B
Formation of the cornified envelope	1	12.6×	0.093	DSP
Developmental Biology	2	4.1×	0.093	SCN1B, SCN5A
Keratinization	1	8.0×	0.134	DSP
Neuronal System	1	6.3×	0.160	KCNH2
Transport of small molecules	1	3.6×	0.257	CASQ2
Neutrophil degranulation	1	3.3×	0.267	DSP

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of heart rate by cardiac conduction	5	267.5×	3e-10	SCN1B, SCN5A, TRPM4, DSP, KCNH2
membrane depolarization during Purkinje myocyte cell action potential	3	2407.4×	3e-09	SCN1B, SCN5A, TRPM4
cardiac muscle contraction	4	229.3×	5e-08	SCN1B, SCN5A, CASQ2, KCNH2
membrane depolarization during action potential	3	722.2×	2e-07	SCN1B, SCN5A, KCNH2
regulation of ventricular cardiac muscle cell membrane repolarization	3	361.1×	1e-06	SCN1B, SCN5A, KCNH2
membrane depolarization during bundle of His cell action potential	2	1605.0×	9e-06	SCN5A, TRPM4
membrane depolarization during AV node cell action potential	2	963.0×	3e-05	SCN5A, TRPM4
regulation of atrial cardiac muscle cell membrane depolarization	2	535.0×	8e-05	SCN1B, SCN5A
membrane depolarization during cardiac muscle cell action potential	2	401.2×	1e-04	SCN1B, SCN5A
regulation of ventricular cardiac muscle cell action potential	2	401.2×	1e-04	TRPM4, DSP
regulation of membrane repolarization	2	370.4×	1e-04	CASQ2, KCNH2
regulation of sodium ion transmembrane transport	2	300.9×	2e-04	SCN1B, SCN5A
ventricular cardiac muscle cell action potential	2	283.2×	2e-04	SCN5A, KCNH2
positive regulation of sodium ion transport	2	240.7×	2e-04	SCN1B, SCN5A
cardiac muscle cell action potential involved in contraction	2	200.6×	3e-04	SCN1B, SCN5A
membrane depolarization	2	145.9×	6e-04	SCN1B, SCN5A
regulation of heart rate	2	133.8×	6e-04	SCN5A, CASQ2
corticospinal neuron axon guidance	1	2407.4×	0.002	SCN1B
positive regulation of atrial cardiac muscle cell action potential	1	2407.4×	0.002	TRPM4
positive regulation of regulation of vascular associated smooth muscle cell membrane depolarization	1	2407.4×	0.002	TRPM4
regulation of membrane repolarization during ventricular cardiac muscle cell action potential	1	2407.4×	0.002	CASQ2
intermediate filament organization	2	68.8×	0.002	DES, DSP
sodium ion transmembrane transport	2	58.0×	0.003	SCN1B, SCN5A
regulation of heart rate by hormone	1	1203.7×	0.004	KCNH2
Purkinje myocyte to ventricular cardiac muscle cell signaling	1	1203.7×	0.004	CASQ2
bundle of His cell action potential	1	1203.7×	0.004	SCN5A
AV node cell to bundle of His cell communication	1	1203.7×	0.004	SCN5A
membrane depolarization during atrial cardiac muscle cell action potential	1	802.5×	0.005	SCN5A
positive regulation of voltage-gated sodium channel activity	1	802.5×	0.005	SCN1B
regulation of T cell cytokine production	1	601.9×	0.006	TRPM4

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 3 · Undrugged: 4

Druggability breadth: 5 of 7 evidence-associated genes (71%) 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
SCN5A	BEPRIDIL
KCNH2	CETIRIZINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCNH2	706	4
SCN5A	108	4
SCN1B	2	2
TRPM4	0	0
CASQ2	0	0
DES	0	0
DSP	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	KCNH2, SCN5A
CANDESARTAN CILEXETIL	4	SCN5A
TELMISARTAN	4	SCN5A
CARBAMAZEPINE	4	SCN5A
DIBUCAINE	4	KCNH2, SCN5A
IMIPRAMINE	4	KCNH2, SCN5A
DROPERIDOL	4	KCNH2, SCN5A
PONATINIB	4	KCNH2, SCN5A
DULOXETINE	4	KCNH2, SCN5A
PALONOSETRON	4	KCNH2, SCN5A
VILANTEROL	4	SCN5A
MEXILETINE HYDROCHLORIDE	4	SCN5A
UNOPROSTONE ISOPROPYL	4	SCN5A
LURASIDONE	4	KCNH2, SCN5A
LETERMOVIR	4	SCN5A
SERTINDOLE	4	KCNH2, SCN5A
FEDRATINIB	4	KCNH2, SCN5A
QUINIDINE	4	KCNH2, SCN5A
DARUNAVIR	4	KCNH2, SCN5A
DARIFENACIN	4	KCNH2, SCN5A
BENZONATATE	4	SCN5A
TOLTERODINE	4	KCNH2, SCN5A
RANOLAZINE	4	KCNH2, SCN5A
PIMOZIDE	4	KCNH2, SCN5A
NIMODIPINE	4	SCN5A
FELODIPINE	4	SCN5A
NICARDIPINE	4	KCNH2, SCN5A
AMLODIPINE	4	KCNH2, SCN5A
PHENYTOIN	4	KCNH2, SCN5A
PALIPERIDONE	4	KCNH2, SCN5A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
KCNH2	4,851	Binding:3558, Toxicity:1071, Functional:169, ADMET:53
SCN5A	594	Binding:380, Functional:98, ADMET:72, Toxicity:43, Unclassified:1
SCN1B	15	Binding:7, ADMET:6, Toxicity:2
TRPM4	14	Binding:13, Functional:1
DSP	2	Binding:2

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SCN5A	594
KCNH2	4,851

Pharmacogenomics

Cohort genes with a PharmGKB record: 7; 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)
BEPRIDIL	4	KCNH2, SCN5A
CANDESARTAN CILEXETIL	4	SCN5A
TELMISARTAN	4	SCN5A
CARBAMAZEPINE	4	SCN5A
DIBUCAINE	4	KCNH2, SCN5A
IMIPRAMINE	4	KCNH2, SCN5A
DROPERIDOL	4	KCNH2, SCN5A
PONATINIB	4	KCNH2, SCN5A
DULOXETINE	4	KCNH2, SCN5A
PALONOSETRON	4	KCNH2, SCN5A
VILANTEROL	4	SCN5A
MEXILETINE HYDROCHLORIDE	4	SCN5A
UNOPROSTONE ISOPROPYL	4	SCN5A
LURASIDONE	4	KCNH2, SCN5A
LETERMOVIR	4	SCN5A
SERTINDOLE	4	KCNH2, SCN5A
FEDRATINIB	4	KCNH2, SCN5A
QUINIDINE	4	KCNH2, SCN5A
DARUNAVIR	4	KCNH2, SCN5A
DARIFENACIN	4	KCNH2, SCN5A
BENZONATATE	4	SCN5A
TOLTERODINE	4	KCNH2, SCN5A
RANOLAZINE	4	KCNH2, SCN5A
PIMOZIDE	4	KCNH2, SCN5A
NIMODIPINE	4	SCN5A
FELODIPINE	4	SCN5A
NICARDIPINE	4	KCNH2, SCN5A
AMLODIPINE	4	KCNH2, SCN5A
PHENYTOIN	4	KCNH2, SCN5A
PALIPERIDONE	4	KCNH2, SCN5A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	SCN5A, KCNH2
B	Phased (≥1) drug, not yet approved	1	SCN1B
C	Druggable family + PDB, no drug	1	TRPM4
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	CASQ2, DES, DSP

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TRPM4	14	—
CASQ2	0	—
DES	0	—
DSP	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.