Atrial fibrillation, familial, 1

Summary

Atrial fibrillation, familial, 1 (MONDO:0012066) is a disease with 3 cohort genes.

At a glance

• Cohort genes: 3
• ClinVar variants: 3

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	atrial fibrillation, familial, 1
Mondo ID	MONDO:0012066
MeSH	C538261
OMIM	608583
UMLS	C1843687
MedGen	334469
GARD	0024840
Is cancer (heuristic)	no

Also known as: ATFB1 · atrial fibrillation, autosomal dominant · atrial fibrillation, familial, 1

Data availability: 3 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › cardiac rhythm disease › atrial fibrillation › familial atrial fibrillation › atrial fibrillation, familial, 1

Related subtypes (17): atrial fibrillation, familial, 3, atrial fibrillation, familial, 2, atrial fibrillation, familial, 4, atrial fibrillation, familial, 5, atrial fibrillation, familial, 6, atrial fibrillation, familial, 7, atrial fibrillation, familial, 8, atrial fibrillation, familial, 9, atrial fibrillation, familial, 10, atrial fibrillation, familial, 11, atrial fibrillation, familial, 12, atrial fibrillation, familial, 13, atrial fibrillation, familial, 14, atrial fibrillation, familial, 15, atrial fibrillation, familial, 18, atrial fibrillation, familial, 17, atrial fibrillation, familial, 16

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

3 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
67574	NM_000891.3(KCNJ2):c.431G>A (p.Gly144Asp)	KCNJ2	Pathogenic	criteria provided, multiple submitters, no conflicts
559593	NM_000325.6(PITX2):c.619A>G (p.Met207Val)	PITX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
864391	NM_001037.5(SCN1B):c.388G>A (p.Glu130Lys)	SCN1B	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 15 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

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
KCNJ2	Orphanet:334	Hereditary atrial fibrillation
KCNJ2	Orphanet:37553	Andersen-Tawil syndrome
KCNJ2	Orphanet:51083	Congenital short QT syndrome
PITX2	Orphanet:334	Hereditary atrial fibrillation
PITX2	Orphanet:708	Peters anomaly
PITX2	Orphanet:782	Axenfeld-Rieger syndrome
PITX2	Orphanet:91481	Ring dermoid of cornea
PITX2	Orphanet:91483	Rieger anomaly
PITX2	Orphanet:98978	Axenfeld anomaly

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SCN1B	HGNC:10586	ENSG00000105711	Q07699	Sodium channel regulatory subunit beta-1	clinvar
KCNJ2	HGNC:6263	ENSG00000123700	P63252	Inward rectifier potassium channel 2	clinvar
PITX2	HGNC:9005	ENSG00000164093	Q99697	Pituitary homeobox 2	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.
KCNJ2	Inward rectifier potassium channel 2	Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it.
PITX2	Pituitary homeobox 2	May play a role in myoblast differentiation.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.67

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	1	37.2×	0.080
Antibody/Immunoglobulin	1	9.7×	0.149
Transcription factor	1	2.8×	0.321

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCN1B	Antibody/Immunoglobulin	yes		Ig_V-set, Ig-like_fold, Na_channel_b1/b3
KCNJ2	Ion channel	yes		K_chnl_inward-rec_Kir2.1, K_chnl_inward-rec_Kir_cyto, K_chnl_inward-rec_Kir_N
PITX2	Transcription factor	no		HD, OAR_dom, Homeodomain-like_sf

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellum	1
primary visual cortex	1
right hemisphere of cerebellum	1
dorsal motor nucleus of vagus nerve	1
inferior vagus X ganglion	1
skeletal muscle tissue of rectus abdominis	1
biceps brachii	1
gingiva	1
gingival epithelium	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
KCNJ2	256	ubiquitous	marker	inferior vagus X ganglion, skeletal muscle tissue of rectus abdominis, dorsal motor nucleus of vagus nerve
PITX2	166	broad	marker	gingiva, biceps brachii, gingival epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PITX2	2,389
SCN1B	1,328
KCNJ2	65

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SCN1B	Q07699	39
KCNJ2	P63252	3
PITX2	Q99697	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 26. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Sensory perception of taste	2	223.9×	7e-04	SCN1B, KCNJ2
Sensory perception of sour taste	1	1903.3×	0.003	KCNJ2
Cardiac conduction	2	72.5×	0.003	SCN1B, KCNJ2
Sensory Perception	2	63.4×	0.003	SCN1B, KCNJ2
Muscle contraction	2	51.4×	0.003	SCN1B, KCNJ2
Classical Kir channels	1	951.7×	0.004	KCNJ2
TFAP2 (AP-2) family regulates transcription of other transcription factors	1	951.7×	0.004	PITX2
G protein gated Potassium channels	1	380.7×	0.009	KCNJ2
Inwardly rectifying K+ channels	1	237.9×	0.012	KCNJ2
Phase 4 - resting membrane potential	1	200.3×	0.012	KCNJ2
Activation of GABAB receptors	1	200.3×	0.012	KCNJ2
GABA B receptor activation	1	181.3×	0.012	KCNJ2
Activation of G protein gated Potassium channels	1	131.3×	0.014	KCNJ2
Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits	1	131.3×	0.014	KCNJ2
Interaction between L1 and Ankyrins	1	122.8×	0.014	SCN1B
Phase 0 - rapid depolarisation	1	115.3×	0.014	SCN1B
GABA receptor activation	1	105.7×	0.014	KCNJ2
Sensory perception of sweet, bitter, and umami (glutamate) taste	1	92.8×	0.016	SCN1B
Potassium Channels	1	44.8×	0.030	KCNJ2
L1CAM interactions	1	40.1×	0.032	SCN1B
Neurotransmitter receptors and postsynaptic signal transmission	1	33.4×	0.037	KCNJ2
Transmission across Chemical Synapses	1	25.4×	0.046	KCNJ2
Axon guidance	1	15.1×	0.071	SCN1B
Neuronal System	1	14.8×	0.071	KCNJ2
Nervous system development	1	14.3×	0.071	SCN1B
Developmental Biology	1	4.8×	0.194	SCN1B

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
membrane depolarization during cardiac muscle cell action potential	2	936.2×	1e-04	SCN1B, KCNJ2
cardiac muscle cell action potential involved in contraction	2	468.1×	2e-04	SCN1B, KCNJ2
regulation of heart rate by cardiac conduction	2	249.7×	5e-04	SCN1B, KCNJ2
regulation of skeletal muscle contraction via regulation of action potential	1	5617.3×	0.002	KCNJ2
subthalamic nucleus development	1	5617.3×	0.002	PITX2
corticospinal neuron axon guidance	1	5617.3×	0.002	SCN1B
superior vena cava morphogenesis	1	5617.3×	0.002	PITX2
hypothalamus cell migration	1	2808.7×	0.002	PITX2
prolactin secreting cell differentiation	1	2808.7×	0.002	PITX2
left lung morphogenesis	1	2808.7×	0.002	PITX2
pulmonary vein morphogenesis	1	2808.7×	0.002	PITX2
cell proliferation involved in outflow tract morphogenesis	1	2808.7×	0.002	PITX2
pulmonary myocardium development	1	1872.4×	0.002	PITX2
vascular associated smooth muscle cell differentiation	1	1872.4×	0.002	PITX2
deltoid tuberosity development	1	1872.4×	0.002	PITX2
endodermal digestive tract morphogenesis	1	1872.4×	0.002	PITX2
membrane depolarization during Purkinje myocyte cell action potential	1	1872.4×	0.002	SCN1B
relaxation of skeletal muscle	1	1872.4×	0.002	KCNJ2
positive regulation of voltage-gated sodium channel activity	1	1872.4×	0.002	SCN1B
atrioventricular valve development	1	1404.3×	0.003	PITX2
somatotropin secreting cell differentiation	1	1404.3×	0.003	PITX2
extraocular skeletal muscle development	1	936.2×	0.004	PITX2
embryonic heart tube left/right pattern formation	1	936.2×	0.004	PITX2
cardiac neural crest cell migration involved in outflow tract morphogenesis	1	802.5×	0.004	PITX2
atrial cardiac muscle tissue morphogenesis	1	802.5×	0.004	PITX2
hair cell differentiation	1	702.2×	0.004	PITX2
regulation of atrial cardiac muscle cell membrane depolarization	1	624.1×	0.004	SCN1B
iris morphogenesis	1	624.1×	0.004	PITX2
cardiac conduction	1	561.7×	0.004	SCN1B
membrane depolarization during action potential	1	561.7×	0.004	SCN1B

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN1B	2	2
KCNJ2	0	0
PITX2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
DS-1971	2	SCN1B
PF-05089771	2	SCN1B

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
KCNJ2	31	Binding:23, ADMET:8
SCN1B	15	Binding:7, ADMET:6, Toxicity:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

2 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)
DS-1971	2	SCN1B
PF-05089771	2	SCN1B

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	SCN1B
C	Druggable family + PDB, no drug	1	KCNJ2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	PITX2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
KCNJ2	31	—
PITX2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.