Aldosterone-producing adenoma with seizures and neurological abnormalities

Summary

Aldosterone-producing adenoma with seizures and neurological abnormalities (MONDO:0014200) is a cancer caused by CACNA1D (GenCC Definitive), with 1 cohort gene (1 CIViC-evidence somatic driver; 90 ClinVar predisposition records).

At a glance

• Classification: Cancer
• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CACNA1D (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 90
• Phenotypes (HPO): 30

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

30 HPO clinical features (Orphanet curated; top 30 by frequency):

HPO ID	Term	Frequency
HP:0000822	Hypertension	Obligate (100%)
HP:0000859	Hyperaldosteronism	Obligate (100%)
HP:0040084	Abnormal circulating renin	Obligate (100%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001714	Ventricular hypertrophy	Very frequent (80-99%)
HP:0002900	Hypokalemia	Very frequent (80-99%)
HP:0100021	Cerebral palsy	Very frequent (80-99%)
HP:0001258	Spastic paraplegia	Frequent (30-79%)
HP:0001959	Polydipsia	Frequent (30-79%)
HP:0002069	Bilateral tonic-clonic seizure	Frequent (30-79%)
HP:0002092	Pulmonary arterial hypertension	Frequent (30-79%)
HP:0002305	Athetosis	Frequent (30-79%)
HP:0002384	Focal impaired awareness seizure	Frequent (30-79%)
HP:0010864	Intellectual disability, severe	Frequent (30-79%)
HP:0011166	Focal myoclonic seizure	Frequent (30-79%)
HP:0011410	Caesarian section	Frequent (30-79%)
HP:0011706	Second degree atrioventricular block	Frequent (30-79%)
HP:0100285	EMG: impaired neuromuscular transmission	Frequent (30-79%)
HP:0100704	Cerebral visual impairment	Frequent (30-79%)
HP:0200114	Metabolic alkalosis	Frequent (30-79%)
HP:0000360	Tinnitus	Occasional (5-29%)
HP:0000421	Epistaxis	Occasional (5-29%)
HP:0000787	Nephrolithiasis	Occasional (5-29%)
HP:0001629	Ventricular septal defect	Occasional (5-29%)
HP:0002018	Nausea	Occasional (5-29%)
HP:0002170	Intracranial hemorrhage	Occasional (5-29%)
HP:0002315	Headache	Occasional (5-29%)
HP:0011739	Dexamethasone-suppresible primary hyperaldosteronism	Excluded (0%)
HP:0008221	Adrenal hyperplasia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	aldosterone-producing adenoma with seizures and neurological abnormalities
Mondo ID	MONDO:0014200
OMIM	615474
Orphanet	369929
UMLS	C3809609
MedGen	815939
GARD	0017591
Is cancer (heuristic)	yes

Also known as: aldosterone-secreting adenoma with seizures and neurological abnormalities · APA with seizures and neurological abnormalities · complex neurodevelopmental disorder with or without aldosteronism · Conn adenoma with seizures and neurological abnormalities · PASNA · primary aldosteronism, seizures, and neurologic abnormalities

Data availability: 90 ClinVar variants · 4 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › endocrine system disorder › adrenal gland disorder › adrenal cortex disorder › adrenal gland hyperfunction › hyperaldosteronism › primary aldosteronism › familial hyperaldosteronism › aldosterone-producing adenoma with seizures and neurological abnormalities

Related subtypes (4): glucocorticoid-remediable aldosteronism, familial hyperaldosteronism type II, familial hyperaldosteronism type III, hyperaldosteronism, familial, type IV

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

90 retrieved; paginated sample, class counts are floors:

50 uncertain significance, 16 benign, 9 benign/likely benign, 7 conflicting classifications of pathogenicity, 3 likely benign, 2 pathogenic, 2 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1710231	NM_001128840.3(CACNA1D):c.2222-1G>A	CACNA1D	Pathogenic	no assertion criteria provided
66072	NM_000720.4(CACNA1D):c.1208G>A (p.Gly403Asp)	CACNA1D	Pathogenic	criteria provided, multiple submitters, no conflicts
66073	NM_001128840.3(CACNA1D):c.2250C>G (p.Ile750Met)	CACNA1D	Pathogenic/Likely pathogenic	no assertion criteria provided
4686615	NM_001128840.3(CACNA1D):c.2241C>G (p.Phe747Leu)	CACNA1D	Likely pathogenic	criteria provided, single submitter
4796565	NM_001128840.3(CACNA1D):c.698G>A (p.Gly233Asp)	CACNA1D	Likely pathogenic	criteria provided, single submitter
1032455	NM_001128840.3(CACNA1D):c.4924-6A>G	CACNA1D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1338143	NM_001128840.3(CACNA1D):c.6100C>T (p.Arg2034Trp)	CACNA1D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1445557	NM_001128840.3(CACNA1D):c.6217C>T (p.Arg2073Cys)	CACNA1D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1445626	NM_001128840.3(CACNA1D):c.5971C>T (p.Arg1991Trp)	CACNA1D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1959088	NM_001128840.3(CACNA1D):c.2744G>A (p.Arg915Gln)	CACNA1D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3382634	NM_001128840.3(CACNA1D):c.4370A>G (p.Asn1457Ser)	CACNA1D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3681226	NM_001128840.3(CACNA1D):c.5644C>T (p.Arg1882Ter)	CACNA1D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1030884	NM_001128840.3(CACNA1D):c.5492A>G (p.His1831Arg)	CACNA1D	Uncertain significance	criteria provided, single submitter
1032456	NM_001128840.3(CACNA1D):c.658G>C (p.Glu220Gln)	CACNA1D	Uncertain significance	criteria provided, single submitter
1065579	NM_001128840.3(CACNA1D):c.971G>A (p.Arg324His)	CACNA1D	Uncertain significance	criteria provided, multiple submitters, no conflicts
1098648	NM_001128840.3(CACNA1D):c.2569A>C (p.Ile857Leu)	CACNA1D	Uncertain significance	criteria provided, single submitter
1184426	NM_001128840.3(CACNA1D):c.2473G>A (p.Val825Ile)	CACNA1D	Uncertain significance	criteria provided, single submitter
1333734	NM_001128840.3(CACNA1D):c.4863A>T (p.Lys1621Asn)	CACNA1D	Uncertain significance	criteria provided, single submitter
1333735	NM_001128840.3(CACNA1D):c.5587C>T (p.Gln1863Ter)	CACNA1D	Uncertain significance	criteria provided, single submitter
1346650	NM_001128840.3(CACNA1D):c.2143A>G (p.Ile715Val)	CACNA1D	Uncertain significance	criteria provided, multiple submitters, no conflicts
1358582	NM_001128840.3(CACNA1D):c.2423A>G (p.Tyr808Cys)	CACNA1D	Uncertain significance	criteria provided, single submitter
1385600	NM_001128840.3(CACNA1D):c.3571A>C (p.Lys1191Gln)	CACNA1D	Uncertain significance	criteria provided, multiple submitters, no conflicts
1391972	NM_001128840.3(CACNA1D):c.1678A>G (p.Lys560Glu)	CACNA1D	Uncertain significance	criteria provided, multiple submitters, no conflicts
1398504	NM_000720.4(CACNA1D):c.1528C>T (p.Arg510Trp)	CACNA1D	Uncertain significance	criteria provided, multiple submitters, no conflicts
1405751	NM_001128840.3(CACNA1D):c.6076A>G (p.Thr2026Ala)	CACNA1D	Uncertain significance	criteria provided, multiple submitters, no conflicts
1417392	NM_001128840.3(CACNA1D):c.2146A>G (p.Met716Val)	CACNA1D	Uncertain significance	criteria provided, multiple submitters, no conflicts
1421329	NM_001128840.3(CACNA1D):c.149T>C (p.Val50Ala)	CACNA1D	Uncertain significance	criteria provided, multiple submitters, no conflicts
1426310	NM_001128840.3(CACNA1D):c.3413T>C (p.Ile1138Thr)	CACNA1D	Uncertain significance	criteria provided, multiple submitters, no conflicts
1438559	NM_001128840.3(CACNA1D):c.6349G>A (p.Gly2117Arg)	CACNA1D	Uncertain significance	criteria provided, multiple submitters, no conflicts
1443910	NM_001128840.3(CACNA1D):c.3038G>A (p.Arg1013Gln)	CACNA1D	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
CACNA1D	Act	BRCA,CCRCC,HCC,SARCNOS,STAD

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
CACNA1D	Definitive	Autosomal dominant	aldosterone-producing adenoma with seizures and neurological abnormalities	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CACNA1D	Orphanet:324321	Sinoatrial node dysfunction and deafness
CACNA1D	Orphanet:369929	Primary hyperaldosteronism-seizures-neurological abnormalities syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CACNA1D	HGNC:1391	ENSG00000157388	Q01668	Voltage-dependent L-type calcium channel subunit alpha-1D	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CACNA1D	Voltage-dependent L-type calcium channel subunit alpha-1D	Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene exp…

Protein-family classification

Druggable: 1 · 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	1	111.5×	0.009

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CACNA1D	Ion channel	yes		VDCCAlpha1, VDCC_L_a1su, LVDCC_a1dsu

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	1
buccal mucosa cell	1
right lung	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CACNA1D	219	broad	marker	buccal mucosa cell, adrenal tissue, right lung

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CACNA1D	2,318

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CACNA1D	Q01668	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Adrenaline,noradrenaline inhibits insulin secretion	1	393.8×	0.011	CACNA1D
Sensory processing of sound	1	308.6×	0.011	CACNA1D
NCAM signaling for neurite out-growth	1	271.9×	0.011	CACNA1D
NCAM1 interactions	1	248.3×	0.011	CACNA1D
Regulation of insulin secretion	1	219.6×	0.011	CACNA1D
Integration of energy metabolism	1	175.7×	0.011	CACNA1D
Sensory processing of sound by inner hair cells of the cochlea	1	163.1×	0.011	CACNA1D
Sensory Perception	1	95.2×	0.016	CACNA1D
Axon guidance	1	45.1×	0.028	CACNA1D
Nervous system development	1	42.9×	0.028	CACNA1D
Developmental Biology	1	14.5×	0.075	CACNA1D
Metabolism	1	11.6×	0.086	CACNA1D

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of adenylate cyclase activity	1	3370.4×	0.002	CACNA1D
membrane depolarization during SA node cell action potential	1	3370.4×	0.002	CACNA1D
regulation of atrial cardiac muscle cell membrane repolarization	1	2407.4×	0.002	CACNA1D
membrane depolarization during cardiac muscle cell action potential	1	1404.3×	0.002	CACNA1D
calcium ion import	1	802.5×	0.003	CACNA1D
cardiac muscle cell action potential involved in contraction	1	702.2×	0.003	CACNA1D
regulation of potassium ion transmembrane transport	1	624.1×	0.003	CACNA1D
positive regulation of calcium ion transport	1	581.1×	0.003	CACNA1D
calcium ion import across plasma membrane	1	543.6×	0.003	CACNA1D
regulation of heart rate by cardiac conduction	1	374.5×	0.004	CACNA1D
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1	337.0×	0.004	CACNA1D
calcium ion transmembrane transport	1	210.7×	0.006	CACNA1D
calcium ion transport	1	181.2×	0.006	CACNA1D
sensory perception of sound	1	100.9×	0.010	CACNA1D

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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
CACNA1D	BEPRIDIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CACNA1D	48	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	CACNA1D
IMIPRAMINE	4	CACNA1D
HALOFANTRINE	4	CACNA1D
DROPERIDOL	4	CACNA1D
SAQUINAVIR	4	CACNA1D
DULOXETINE	4	CACNA1D
DIAZEPAM	4	CACNA1D
SERTINDOLE	4	CACNA1D
QUINIDINE	4	CACNA1D
LAMIVUDINE	4	CACNA1D
PIMOZIDE	4	CACNA1D
PHENYTOIN	4	CACNA1D
TERFENADINE	4	CACNA1D
CISAPRIDE	4	CACNA1D
SOLIFENACIN	4	CACNA1D
NIFEDIPINE	4	CACNA1D
DILTIAZEM	4	CACNA1D
NILOTINIB	4	CACNA1D
ASTEMIZOLE	4	CACNA1D
TERODILINE	4	CACNA1D
CLOZAPINE	4	CACNA1D
MIBEFRADIL	4	CACNA1D
DOFETILIDE	4	CACNA1D
THIORIDAZINE	4	CACNA1D
PAROXETINE	4	CACNA1D
DONEPEZIL	4	CACNA1D
IBUTILIDE	4	CACNA1D
SUNITINIB	4	CACNA1D
HALOPERIDOL	4	CACNA1D
DASATINIB	4	CACNA1D

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CACNA1D	233	Binding:145, Functional:81, Toxicity:5, ADMET:2

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CACNA1D	233

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Drug repurposing candidates

30 approved/phased drugs hit cohort targets but don’t yet appear in disease-level clinical trials. Target-inhibition rationale is strongest for cancer driver genes; a bioactivity hit is a screening signal, not a treatment claim.

Compound	Max phase	Cohort target (bioactivity)
BEPRIDIL	4	CACNA1D
IMIPRAMINE	4	CACNA1D
HALOFANTRINE	4	CACNA1D
DROPERIDOL	4	CACNA1D
SAQUINAVIR	4	CACNA1D
DULOXETINE	4	CACNA1D
DIAZEPAM	4	CACNA1D
SERTINDOLE	4	CACNA1D
QUINIDINE	4	CACNA1D
LAMIVUDINE	4	CACNA1D
PIMOZIDE	4	CACNA1D
PHENYTOIN	4	CACNA1D
TERFENADINE	4	CACNA1D
CISAPRIDE	4	CACNA1D
SOLIFENACIN	4	CACNA1D
NIFEDIPINE	4	CACNA1D
DILTIAZEM	4	CACNA1D
NILOTINIB	4	CACNA1D
ASTEMIZOLE	4	CACNA1D
TERODILINE	4	CACNA1D
CLOZAPINE	4	CACNA1D
MIBEFRADIL	4	CACNA1D
DOFETILIDE	4	CACNA1D
THIORIDAZINE	4	CACNA1D
PAROXETINE	4	CACNA1D
DONEPEZIL	4	CACNA1D
IBUTILIDE	4	CACNA1D
SUNITINIB	4	CACNA1D
HALOPERIDOL	4	CACNA1D
DASATINIB	4	CACNA1D

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CACNA1D
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.