Sinoatrial node dysfunction and deafness

Summary

Sinoatrial node dysfunction and deafness (MONDO:0013960) is a disease caused by CACNA1D (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CACNA1D (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 63

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		8	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	sinoatrial node dysfunction and deafness
Mondo ID	MONDO:0013960
OMIM	614896
Orphanet	324321
UMLS	C3554018
MedGen	766932
GARD	0017484
Is cancer (heuristic)	no

Also known as: SANDD · sinoatrial node dysfunction and deafness

Data availability: 63 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › cardiac rhythm disease › sinoatrial node dysfunction and deafness

Related subtypes (16): ventricular fibrillation, cardiac arrest, atrial fibrillation, ventricular tachycardia, atrial tachycardia, torsade-de-pointes syndrome with short coupling interval, sino-auricular heart block, multifocal atrial tachycardia, His bundle tachycardia, incessant infant ventricular tachycardia, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, sudden arrhythmia death syndrome, cardiac conduction defect, sudden cardiac arrest, cardiac conduction disease with or without cardiomyoopathy, cardiogenetic rhythm disorder

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

63 retrieved; paginated sample, class counts are floors:

31 uncertain significance, 11 benign, 9 conflicting classifications of pathogenicity, 4 likely benign, 4 benign/likely benign, 3 likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
39709	NM_000720.4(CACNA1D):c.1208_1209insGGG (p.Gly403dup)	CACNA1D	Pathogenic	criteria provided, multiple submitters, no conflicts
3376718	NM_001128840.3(CACNA1D):c.2907del (p.Phe970fs)	CACNA1D	Likely pathogenic	criteria provided, single submitter
4796565	NM_001128840.3(CACNA1D):c.698G>A (p.Gly233Asp)	CACNA1D	Likely pathogenic	criteria provided, single submitter
801978	NM_001128840.3(CACNA1D):c.2248A>T (p.Ile750Phe)	CACNA1D	Likely pathogenic	criteria provided, single submitter
1201900	NM_001128840.3(CACNA1D):c.6101G>A (p.Arg2034Gln)	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
1500556	NM_001128840.3(CACNA1D):c.2629G>A (p.Val877Ile)	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
402284	NM_000720.4(CACNA1D):c.1127C>T (p.Ala376Val)	CACNA1D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
417905	NM_001128840.3(CACNA1D):c.2250C>A (p.Ile750=)	CACNA1D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
504766	NM_001128840.3(CACNA1D):c.1998G>A (p.Leu666=)	CACNA1D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
801977	NM_001128840.3(CACNA1D):c.1722G>A (p.Met574Ile)	CACNA1D	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3778976	NC_000012.12:g.53440593_53440595del		Uncertain significance	criteria provided, single submitter
1284712	NM_001128840.3(CACNA1D):c.5936G>C (p.Arg1979Pro)	CACNA1D	Uncertain significance	criteria provided, multiple submitters, no conflicts
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
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
1449169	NM_001128840.3(CACNA1D):c.3786+5G>A	CACNA1D	Uncertain significance	criteria provided, multiple submitters, no conflicts
1483527	NM_001128840.3(CACNA1D):c.5218C>T (p.His1740Tyr)	CACNA1D	Uncertain significance	criteria provided, multiple submitters, no conflicts
2052507	NM_001128840.3(CACNA1D):c.1520G>A (p.Arg507His)	CACNA1D	Uncertain significance	criteria provided, multiple submitters, no conflicts
2378579	NM_001128840.3(CACNA1D):c.1105G>A (p.Val369Met)	CACNA1D	Uncertain significance	criteria provided, multiple submitters, no conflicts
3064421	NM_001128840.3(CACNA1D):c.814C>T (p.Leu272Phe)	CACNA1D	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 5 · 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
CACNA1D	Strong	Autosomal recessive	sinoatrial node dysfunction and deafness	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
DNAH9	Orphanet:101063	Situs inversus totalis
DNAH9	Orphanet:157769	Situs ambiguus
DNAH9	Orphanet:244	Primary ciliary dyskinesia

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
CACNA1D	HGNC:1391	ENSG00000157388	Q01668	Voltage-dependent L-type calcium channel subunit alpha-1D	gencc,clinvar
DNAH9	HGNC:2953	ENSG00000007174	Q9NYC9	Dynein axonemal heavy chain 9	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…
DNAH9	Dynein axonemal heavy chain 9	Force generating protein required for cilia beating in respiratory epithelia.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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	55.8×	0.036
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CACNA1D	Ion channel	yes		VDCCAlpha1, VDCC_L_a1su, LVDCC_a1dsu
DNAH9	Other/Unknown	no		AAA+_ATPase, Dhc_D6_P-loop, Dynein_heavy_tail

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
adrenal tissue	1
buccal mucosa cell	1
right lung	1
bronchial epithelial cell	1
epithelium of bronchus	1
right uterine tube	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
DNAH9	184	broad	marker	right uterine tube, bronchial epithelial cell, epithelium of bronchus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CACNA1D	2,318
DNAH9	1,841

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CACNA1D	Q01668	6
DNAH9	Q9NYC9	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 2 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 2 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	1685.2×	0.006	CACNA1D
membrane depolarization during SA node cell action potential	1	1685.2×	0.006	CACNA1D
regulation of atrial cardiac muscle cell membrane repolarization	1	1203.7×	0.006	CACNA1D
membrane depolarization during cardiac muscle cell action potential	1	702.2×	0.006	CACNA1D
mucociliary clearance	1	648.1×	0.006	DNAH9
cerebrospinal fluid circulation	1	443.5×	0.006	DNAH9
calcium ion import	1	401.2×	0.006	CACNA1D
cardiac muscle cell action potential involved in contraction	1	351.1×	0.006	CACNA1D
cilium movement involved in cell motility	1	337.0×	0.006	DNAH9
regulation of potassium ion transmembrane transport	1	312.1×	0.006	CACNA1D
positive regulation of calcium ion transport	1	290.6×	0.006	CACNA1D
calcium ion import across plasma membrane	1	271.8×	0.006	CACNA1D
cilium movement	1	195.9×	0.007	DNAH9
cell projection organization	1	187.2×	0.007	DNAH9
regulation of heart rate by cardiac conduction	1	187.2×	0.007	CACNA1D
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1	168.5×	0.007	CACNA1D
calcium ion transmembrane transport	1	105.3×	0.011	CACNA1D
calcium ion transport	1	90.6×	0.012	CACNA1D
establishment of localization in cell	1	80.2×	0.013	DNAH9
sensory perception of sound	1	50.5×	0.020	CACNA1D

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 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
CACNA1D	BEPRIDIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CACNA1D	48	4
DNAH9	0	0

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: 2; 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	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	1	DNAH9

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
DNAH9	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.