Andersen-Tawil syndrome

Summary

Andersen-Tawil syndrome (MONDO:0008222) is a disease caused by KCNJ2 (GenCC Definitive), with 2 cohort genes and 4 clinical trials. Top therapeutic interventions include flecainide, acetazolamide, and potassium.

At a glance

• Prevalence: <1 / 1 000 000 (United Kingdom) [Orphanet-validated]
• Causal gene: KCNJ2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 546
• Phenotypes (HPO): 51
• Clinical trials: 4

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	<1 / 1 000 000	0.08	United Kingdom	Validated
Point prevalence	1-9 / 1 000 000	0.1	Netherlands	Validated
Annual incidence	1-9 / 1 000 000	0.1	Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

51 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0003768	Periodic paralysis	Obligate (100%)
HP:0001324	Muscle weakness	Obligate (100%)
HP:0003752	Episodic flaccid weakness	Very frequent (80-99%)
HP:0000164	Abnormality of the dentition	Frequent (30-79%)
HP:0000347	Micrognathia	Frequent (30-79%)
HP:0001657	Prolonged QT interval	Frequent (30-79%)
HP:0001999	Abnormal facial shape	Frequent (30-79%)
HP:0004308	Ventricular arrhythmia	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0008153	Periodic hypokalemic paresis	Frequent (30-79%)
HP:0001382	Joint hypermobility	Occasional (5-29%)
HP:0000218	High palate	Occasional (5-29%)
HP:0000219	Thin upper lip vermilion	Occasional (5-29%)
HP:0000316	Hypertelorism	Occasional (5-29%)
HP:0000324	Facial asymmetry	Occasional (5-29%)
HP:0000325	Triangular face	Occasional (5-29%)
HP:0000327	Hypoplasia of the maxilla	Occasional (5-29%)
HP:0000337	Broad forehead	Occasional (5-29%)
HP:0000369	Low-set ears	Occasional (5-29%)
HP:0000414	Bulbous nose	Occasional (5-29%)
HP:0000431	Wide nasal bridge	Occasional (5-29%)
HP:0000677	Oligodontia	Occasional (5-29%)
HP:0000678	Dental crowding	Occasional (5-29%)
HP:0000859	Hyperaldosteronism	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001328	Specific learning disability	Occasional (5-29%)
HP:0001510	Growth delay	Occasional (5-29%)
HP:0001644	Dilated cardiomyopathy	Occasional (5-29%)
HP:0001664	Torsade de pointes	Occasional (5-29%)
HP:0001773	Short foot	Occasional (5-29%)
HP:0001864	Clinodactyly of the 5th toe	Occasional (5-29%)
HP:0001962	Palpitations	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0004691	2-3 toe syndactyly	Occasional (5-29%)
HP:0005135	Abnormal T-wave	Occasional (5-29%)
HP:0005147	Bidirectional ventricular ectopy	Occasional (5-29%)
HP:0005184	Prolonged QTc interval	Occasional (5-29%)
HP:0006335	Persistence of primary teeth	Occasional (5-29%)
HP:0006682	Ventricular extrasystoles	Occasional (5-29%)
HP:0006696	Polymorphic and polytopic ventricular extrasystoles	Occasional (5-29%)
HP:0007215	Periodic hyperkalemic paralysis	Occasional (5-29%)
HP:0011073	Abnormality of dental color	Occasional (5-29%)
HP:0012745	Short palpebral fissure	Occasional (5-29%)
HP:0012758	Neurodevelopmental delay	Occasional (5-29%)
HP:0025072	Prominent U wave	Occasional (5-29%)
HP:0030799	Scaphocephaly	Occasional (5-29%)
HP:0031677	Polymorphic ventricular tachycardia	Occasional (5-29%)
HP:0200055	Small hand	Occasional (5-29%)
HP:0000089	Renal hypoplasia	Very rare (<1-4%)
HP:0000124	Renal tubular dysfunction	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Andersen-Tawil syndrome
Mondo ID	MONDO:0008222
MeSH	D050030
OMIM	170390
Orphanet	37553
DOID	DOID:0050434
NCIT	C84559
SNOMED CT	422348008
UMLS	C1563715
MedGen	327586
GARD	0009453
NORD	1883
Is cancer (heuristic)	no

Also known as: Andersen cardiodysrhythmic periodic paralysis · Andersen syndrome · Andersen-Tawil syndrome · ATS · long QT syndrome 7 · long QT syndrome type 7 · LQT7 · Potassium-sensitive periodic paralysis, ventricular ectopy, and dysmorphic features

Data availability: 546 ClinVar variants · 6 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn metal metabolism disorder › familial periodic paralysis › Andersen-Tawil syndrome

Related subtypes (5): hypokalemic periodic paralysis, hyperkalemic periodic paralysis, normokalemic periodic paralysis, periodic paralysis with later-onset distal motor neuropathy, thyrotoxic periodic paralysis

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

546 retrieved; paginated sample, class counts are floors:

261 uncertain significance, 123 likely benign, 65 conflicting classifications of pathogenicity, 38 pathogenic, 24 benign/likely benign, 14 benign, 12 likely pathogenic, 7 pathogenic/likely pathogenic, 2 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1480008	NM_000891.3(KCNJ2):c.636G>A (p.Trp212Ter)	KCNJ2	Pathogenic	criteria provided, single submitter
190820	NM_000891.3(KCNJ2):c.935G>A (p.Arg312His)	KCNJ2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2020840	NM_000891.3(KCNJ2):c.224C>A (p.Thr75Lys)	KCNJ2	Pathogenic	criteria provided, single submitter
2036326	NM_000891.3(KCNJ2):c.232G>A (p.Asp78Asn)	KCNJ2	Pathogenic	criteria provided, single submitter
30119	NM_000891.3(KCNJ2):c.161G>T (p.Cys54Phe)	KCNJ2	Pathogenic	no assertion criteria provided
30120	NM_000891.3(KCNJ2):c.913A>C (p.Thr305Pro)	KCNJ2	Pathogenic	no assertion criteria provided
3220886	NM_000891.3(KCNJ2):c.269T>G (p.Leu90Arg)	KCNJ2	Pathogenic	criteria provided, single submitter
3243061	NC_000017.10:g.(?68166871)(68171602_?)del	KCNJ2	Pathogenic	criteria provided, single submitter
3755832	NM_000891.3(KCNJ2):c.1044C>G (p.Tyr348Ter)	KCNJ2	Pathogenic	criteria provided, single submitter
403974	NM_000891.3(KCNJ2):c.682C>T (p.Arg228Ter)	KCNJ2	Pathogenic	criteria provided, single submitter
463523	NM_000891.3(KCNJ2):c.715G>T (p.Glu239Ter)	KCNJ2	Pathogenic	criteria provided, single submitter
4784294	NM_000891.3(KCNJ2):c.351del (p.Glu118fs)	KCNJ2	Pathogenic	criteria provided, single submitter
519476	NM_000891.3(KCNJ2):c.919A>G (p.Met307Val)	KCNJ2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
569363	NM_000891.3(KCNJ2):c.1102del (p.Leu368fs)	KCNJ2	Pathogenic	criteria provided, single submitter
638351	NM_000891.3(KCNJ2):c.1177G>T (p.Gly393Ter)	KCNJ2	Pathogenic	criteria provided, single submitter
67560	NM_000891.3(KCNJ2):c.200G>A (p.Arg67Gln)	KCNJ2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
67565	NM_000891.3(KCNJ2):c.224C>T (p.Thr75Met)	KCNJ2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
67566	NM_000891.3(KCNJ2):c.232G>T (p.Asp78Tyr)	KCNJ2	Pathogenic	criteria provided, single submitter
67567	NM_000891.3(KCNJ2):c.233A>G (p.Asp78Gly)	KCNJ2	Pathogenic	no assertion criteria provided
67568	NM_000891.3(KCNJ2):c.244C>T (p.Arg82Trp)	KCNJ2	Pathogenic	criteria provided, multiple submitters, no conflicts
67569	NM_000891.3(KCNJ2):c.245G>A (p.Arg82Gln)	KCNJ2	Pathogenic	criteria provided, multiple submitters, no conflicts
67573	NM_000891.3(KCNJ2):c.430G>A (p.Gly144Ser)	KCNJ2	Pathogenic	criteria provided, multiple submitters, no conflicts
67574	NM_000891.3(KCNJ2):c.431G>A (p.Gly144Asp)	KCNJ2	Pathogenic	criteria provided, multiple submitters, no conflicts
67575	NM_000891.3(KCNJ2):c.431G>C (p.Gly144Ala)	KCNJ2	Pathogenic	criteria provided, multiple submitters, no conflicts
67576	NM_000891.3(KCNJ2):c.436G>A (p.Gly146Ser)	KCNJ2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
67581	NM_000891.3(KCNJ2):c.574A>G (p.Thr192Ala)	KCNJ2	Pathogenic	criteria provided, single submitter
67583	NM_000891.3(KCNJ2):c.644G>A (p.Gly215Asp)	KCNJ2	Pathogenic	criteria provided, single submitter
67585	NM_000891.3(KCNJ2):c.653G>A (p.Arg218Gln)	KCNJ2	Pathogenic	criteria provided, multiple submitters, no conflicts
67588	NM_000891.3(KCNJ2):c.899G>A (p.Gly300Asp)	KCNJ2	Pathogenic	criteria provided, multiple submitters, no conflicts
67591	NM_000891.3(KCNJ2):c.913A>G (p.Thr305Ala)	KCNJ2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 23 · Orphanet: 7 · 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
KCNJ2	Definitive	Autosomal dominant	Andersen-Tawil syndrome	15
KCNJ5	Supportive	Autosomal dominant	Andersen-Tawil syndrome	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KCNJ2	Orphanet:334	Hereditary atrial fibrillation
KCNJ2	Orphanet:37553	Andersen-Tawil syndrome
KCNJ2	Orphanet:51083	Congenital short QT syndrome
KCNJ5	Orphanet:101016	Romano-Ward syndrome
KCNJ5	Orphanet:251274	Familial hyperaldosteronism type III
KCNJ5	Orphanet:334	Hereditary atrial fibrillation
KCNJ5	Orphanet:37553	Andersen-Tawil syndrome

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
KCNJ2	HGNC:6263	ENSG00000123700	P63252	Inward rectifier potassium channel 2	gencc,clinvar
KCNJ5	HGNC:6266	ENSG00000120457	P48544	G protein-activated inward rectifier potassium channel 4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
KCNJ5	G protein-activated inward rectifier potassium channel 4	Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Ion channel	2	111.5×	8e-05

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KCNJ2	Ion channel	yes		K_chnl_inward-rec_Kir2.1, K_chnl_inward-rec_Kir_cyto, K_chnl_inward-rec_Kir_N
KCNJ5	Ion channel	yes		K_chnl_inward-rec_Kir3.4, K_chnl_inward-rec_Kir_cyto, Ig_E-set

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
dorsal motor nucleus of vagus nerve	1
inferior vagus X ganglion	1
skeletal muscle tissue of rectus abdominis	1
adrenal cortex	1
buccal mucosa cell	1
endothelial cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KCNJ2	256	ubiquitous	marker	inferior vagus X ganglion, skeletal muscle tissue of rectus abdominis, dorsal motor nucleus of vagus nerve
KCNJ5	175	broad	marker	buccal mucosa cell, endothelial cell, adrenal cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KCNJ5	1,147
KCNJ2	65

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KCNJ2	P63252	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KCNJ5	P48544	82.01

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. 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
G protein gated Potassium channels	2	1142.0×	1e-05	KCNJ2, KCNJ5
Inwardly rectifying K+ channels	2	713.8×	1e-05	KCNJ2, KCNJ5
Activation of GABAB receptors	2	601.0×	1e-05	KCNJ2, KCNJ5
GABA B receptor activation	2	543.8×	1e-05	KCNJ2, KCNJ5
Activation of G protein gated Potassium channels	2	393.8×	2e-05	KCNJ2, KCNJ5
Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits	2	393.8×	2e-05	KCNJ2, KCNJ5
GABA receptor activation	2	317.2×	2e-05	KCNJ2, KCNJ5
Potassium Channels	2	134.3×	1e-04	KCNJ2, KCNJ5
Neurotransmitter receptors and postsynaptic signal transmission	2	100.2×	2e-04	KCNJ2, KCNJ5
Transmission across Chemical Synapses	2	76.1×	3e-04	KCNJ2, KCNJ5
Sensory perception of sour taste	1	2855.0×	6e-04	KCNJ2
Neuronal System	2	44.3×	8e-04	KCNJ2, KCNJ5
Classical Kir channels	1	1427.5×	1e-03	KCNJ2
Phase 4 - resting membrane potential	1	300.5×	0.004	KCNJ2
Sensory perception of taste	1	167.9×	0.007	KCNJ2
Cardiac conduction	1	54.4×	0.021	KCNJ2
Sensory Perception	1	47.6×	0.022	KCNJ2
Muscle contraction	1	38.6×	0.026	KCNJ2

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
regulation of monoatomic ion transmembrane transport	2	732.7×	4e-05	KCNJ2, KCNJ5
regulation of heart rate by cardiac conduction	2	374.5×	5e-05	KCNJ2, KCNJ5
potassium ion import across plasma membrane	2	366.4×	5e-05	KCNJ2, KCNJ5
potassium ion transport	2	191.5×	1e-04	KCNJ2, KCNJ5
potassium ion transmembrane transport	2	135.9×	2e-04	KCNJ2, KCNJ5
regulation of skeletal muscle contraction via regulation of action potential	1	8426.0×	4e-04	KCNJ2
relaxation of skeletal muscle	1	2808.7×	1e-03	KCNJ2
ventricular cardiac muscle cell membrane repolarization	1	2808.7×	1e-03	KCNJ5
membrane repolarization during atrial cardiac muscle cell action potential	1	1404.3×	0.002	KCNJ5
membrane repolarization during action potential	1	842.6×	0.002	KCNJ2
membrane repolarization during cardiac muscle cell action potential	1	842.6×	0.002	KCNJ2
membrane depolarization during cardiac muscle cell action potential	1	702.2×	0.002	KCNJ2
relaxation of cardiac muscle	1	648.1×	0.002	KCNJ2
regulation of resting membrane potential	1	648.1×	0.002	KCNJ2
regulation of membrane repolarization	1	648.1×	0.002	KCNJ2
magnesium ion transport	1	601.9×	0.002	KCNJ2
regulation of cardiac muscle cell contraction	1	561.7×	0.002	KCNJ2
intracellular potassium ion homeostasis	1	495.6×	0.002	KCNJ2
positive regulation of potassium ion transmembrane transport	1	495.6×	0.002	KCNJ2
cardiac muscle cell action potential involved in contraction	1	351.1×	0.003	KCNJ2
protein homotetramerization	1	118.7×	0.009	KCNJ2
cellular response to mechanical stimulus	1	108.0×	0.009	KCNJ2

Therapeutics

Drug target analysis

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

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
KCNJ2	0	0
KCNJ5	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
KCNJ5	32	Binding:32
KCNJ2	31	Binding:23, ADMET:8

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

0 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.

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	0
C	Druggable family + PDB, no drug	1	KCNJ2
D	Druggable family + AlphaFold only, no drug	1	KCNJ5
E	Difficult family or no structure, no drug	0

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	—
KCNJ5	32	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2
PHASE2	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06205550	PHASE2	NOT_YET_RECRUITING	N-of-1 in ATS and MEPPC
NCT00839501	PHASE1	TERMINATED	Effect of Potassium and Acetazolamide on People With Andersen-Tawil Syndrome
NCT00521794	Not specified	COMPLETED	Characteristics of Andersen-Tawil Syndrome
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
FLECAINIDE	4	3
ACETAZOLAMIDE	4	1
POTASSIUM	3	1