Autosomal dominant cerebellar ataxia, deafness and narcolepsy

Summary

Autosomal dominant cerebellar ataxia, deafness and narcolepsy (MONDO:0011397) is a disease caused by DNMT1 (GenCC Definitive), with 1 cohort gene and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DNMT1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 55
• Phenotypes (HPO): 28
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		80	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

28 HPO clinical features (Orphanet curated; top 28 by frequency):

HPO ID	Term	Frequency
HP:0000407	Sensorineural hearing impairment	Very frequent (80-99%)
HP:0030050	Narcolepsy	Very frequent (80-99%)
HP:0000648	Optic atrophy	Frequent (30-79%)
HP:0003287	Abnormality of mitochondrial metabolism	Frequent (30-79%)
HP:0000020	Urinary incontinence	Occasional (5-29%)
HP:0000518	Cataract	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000716	Depression	Occasional (5-29%)
HP:0000763	Sensory neuropathy	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001257	Spasticity	Occasional (5-29%)
HP:0001268	Mental deterioration	Occasional (5-29%)
HP:0001272	Cerebellar atrophy	Occasional (5-29%)
HP:0001347	Hyperreflexia	Occasional (5-29%)
HP:0002059	Cerebral atrophy	Occasional (5-29%)
HP:0002200	Pseudobulbar signs	Occasional (5-29%)
HP:0002322	Resting tremor	Occasional (5-29%)
HP:0002346	Head tremor	Occasional (5-29%)
HP:0002354	Memory impairment	Occasional (5-29%)
HP:0002476	Primitive reflex	Occasional (5-29%)
HP:0002500	Abnormal cerebral white matter morphology	Occasional (5-29%)
HP:0002529	Neuronal loss in central nervous system	Occasional (5-29%)
HP:0002921	Abnormality of the cerebrospinal fluid	Occasional (5-29%)
HP:0003487	Babinski sign	Occasional (5-29%)
HP:0003550	Predominantly lower limb lymphedema	Occasional (5-29%)
HP:0007082	Dilated third ventricle	Occasional (5-29%)
HP:0007366	Atrophy/Degeneration affecting the brainstem	Occasional (5-29%)
HP:0009830	Peripheral neuropathy	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant cerebellar ataxia, deafness and narcolepsy
Mondo ID	MONDO:0011397
OMIM	604121
Orphanet	314404
DOID	DOID:0050968
UMLS	C4302668
MedGen	928337
GARD	0012372
Is cancer (heuristic)	no

Also known as: ADCA-DN · ADCA-DN syndrome · ADCADN · autosomal dominant cerebellar ataxia, deafness and narcolepsy · autosomal dominant cerebellar ataxia, deafness, and narcolepsy · autosomal dominant cerebellar ataxia-deafness-narcolepsy syndrome · cerebellar ataxia, deafness, and narcolepsy, autosomal dominant

Data availability: 55 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › sleep disorder › sleep-wake disorder › autosomal dominant cerebellar ataxia, deafness and narcolepsy

Related subtypes (11): bruxism, recurrent hypersomnia, sleep apnea syndrome, hypersomnia, periodic limb movement disorder, REM sleep behavior disorder, hereditary sensory neuropathy-deafness-dementia syndrome, autoimmune encephalopathy with parasomnia and obstructive sleep apnea, narcolepsy, circadian rhythm sleep disorder, sleep disorder, initiating and maintaining sleep

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

55 retrieved; paginated sample, class counts are floors:

22 uncertain significance, 13 conflicting classifications of pathogenicity, 6 benign, 4 likely benign, 4 likely pathogenic, 4 benign/likely benign, 1 pathogenic/likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
29682	NM_001130823.3(DNMT1):c.1532A>G (p.Tyr511Cys)	DNMT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
50920	NM_001130823.3(DNMT1):c.1709C>T (p.Ala570Val)	DNMT1	Pathogenic	criteria provided, multiple submitters, no conflicts
50919	NM_001130823.3(DNMT1):c.1816G>T (p.Val606Phe)	DNMT1	Likely pathogenic	criteria provided, single submitter
50921	NM_001130823.3(DNMT1):c.1814G>C (p.Gly605Ala)	DNMT1	Likely pathogenic	criteria provided, single submitter
976693	NM_001130823.3(DNMT1):c.1823T>G (p.Leu608Arg)	DNMT1	Likely pathogenic	criteria provided, single submitter
1685301	NM_001130823.3(DNMT1):c.4641G>T (p.Glu1547Asp)	LOC126862853	Likely pathogenic	criteria provided, single submitter
1027465	NM_001130823.3(DNMT1):c.3311C>T (p.Ala1104Val)	DNMT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
245911	NM_001130823.3(DNMT1):c.4001C>T (p.Ala1334Val)	DNMT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
246584	NM_001130823.3(DNMT1):c.2315C>A (p.Thr772Asn)	DNMT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
472269	NM_001130823.3(DNMT1):c.3262G>A (p.Val1088Ile)	DNMT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
472277	NM_001130823.3(DNMT1):c.4483G>A (p.Val1495Met)	DNMT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
498104	NM_001130823.3(DNMT1):c.3196G>A (p.Val1066Met)	DNMT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
539606	NM_001130823.3(DNMT1):c.382C>T (p.Pro128Ser)	DNMT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
565384	NM_001130823.3(DNMT1):c.3498G>T (p.Gly1166=)	DNMT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
807592	NM_001130823.3(DNMT1):c.4298T>C (p.Met1433Thr)	DNMT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
852192	NM_001130823.3(DNMT1):c.855C>T (p.Gly285=)	DNMT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
859966	NM_001130823.3(DNMT1):c.901A>C (p.Lys301Gln)	DNMT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
952729	NM_001130823.3(DNMT1):c.1678C>T (p.Arg560Cys)	DNMT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
547912	NM_001130823.3(DNMT1):c.4636C>G (p.Pro1546Ala)	LOC126862853	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1002749	NM_001130823.3(DNMT1):c.910A>C (p.Ser304Arg)	DNMT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1061265	NM_001130823.3(DNMT1):c.1008G>A (p.Lys336=)	DNMT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1254310	NM_001130823.3(DNMT1):c.3157G>A (p.Ala1053Thr)	DNMT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1305834	NM_001130823.3(DNMT1):c.859C>G (p.Gln287Glu)	DNMT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1678080	NM_001130823.3(DNMT1):c.2493C>G (p.Phe831Leu)	DNMT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1679751	NM_001130823.3(DNMT1):c.4136G>A (p.Arg1379Gln)	DNMT1	Uncertain significance	criteria provided, single submitter
246040	NM_001130823.3(DNMT1):c.3353A>G (p.His1118Arg)	DNMT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3254757	NM_001130823.3(DNMT1):c.4711C>T (p.Arg1571Cys)	DNMT1	Uncertain significance	criteria provided, single submitter
3362343	NM_001130823.3(DNMT1):c.616G>A (p.Asp206Asn)	DNMT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3777093	NM_001130823.3(DNMT1):c.1756A>G (p.Ser586Gly)	DNMT1	Uncertain significance	criteria provided, single submitter
569266	NM_001130823.3(DNMT1):c.695C>T (p.Pro232Leu)	DNMT1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 2 · 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
DNMT1	Definitive	Unknown	autosomal dominant cerebellar ataxia, deafness and narcolepsy	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DNMT1	Orphanet:314404	Autosomal dominant cerebellar ataxia-deafness-narcolepsy syndrome
DNMT1	Orphanet:456318	Hereditary sensory neuropathy-deafness-dementia 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
DNMT1	HGNC:2976	ENSG00000130816	P26358	DNA (cytosine-5)-methyltransferase 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DNMT1	DNA (cytosine-5)-methyltransferase 1	DNA methyltransferase that methylates CpG residues.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.0

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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DNMT1	Transcription factor	no	2.1.1.37	BAH_dom, C5_MeTfrase, Znf_CXXC

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
oocyte	1
secondary oocyte	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DNMT1	266	ubiquitous	marker	oocyte, secondary oocyte, sural nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DNMT1	7,179

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DNMT1	P26358	27

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
STAT3 nuclear events downstream of ALK signaling	1	1038.2×	0.005	DNMT1
SUMOylation of DNA methylation proteins	1	671.8×	0.005	DNMT1
Nuclear events stimulated by ALK signaling in cancer	1	326.3×	0.007	DNMT1
DNA methylation	1	178.4×	0.008	DNMT1
Defective pyroptosis	1	156.4×	0.008	DNMT1
PRC2 methylates histones and DNA	1	152.3×	0.008	DNMT1
NoRC negatively regulates rRNA expression	1	104.8×	0.010	DNMT1

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
epigenetic programming of gene expression	1	16852.0×	8e-04	DNMT1
obsolete negative regulation of vascular associated smooth muscle cell differentiation involved in phenotypic switching	1	8426.0×	8e-04	DNMT1
negative regulation of vascular associated smooth muscle cell apoptotic process	1	5617.3×	8e-04	DNMT1
chromosomal DNA methylation maintenance following DNA replication	1	4213.0×	8e-04	DNMT1
cellular response to bisphenol A	1	3370.4×	8e-04	DNMT1
negative regulation of gene expression via chromosomal CpG island methylation	1	1053.2×	0.002	DNMT1
DNA methylation-dependent constitutive heterochromatin formation	1	543.6×	0.004	DNMT1
positive regulation of vascular associated smooth muscle cell proliferation	1	432.1×	0.004	DNMT1
cellular response to amino acid stimulus	1	306.4×	0.005	DNMT1
DNA-templated transcription	1	224.7×	0.006	DNMT1
methylation	1	170.2×	0.007	DNMT1
negative regulation of gene expression	1	69.1×	0.017	DNMT1
positive regulation of gene expression	1	38.7×	0.028	DNMT1
negative regulation of transcription by RNA polymerase II	1	17.7×	0.056	DNMT1

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
DNMT1	DECITABINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DNMT1	6	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
DECITABINE	4	DNMT1
AZACITIDINE	4	DNMT1
CEPHALOTHIN	4	DNMT1
EPIGALOCATECHIN GALLATE	3	DNMT1
MOLIBRESIB	2	DNMT1
GENISTEIN	2	DNMT1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
DNMT1	233	Binding:229, Functional:3, ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DNMT1	2.1.1.37	DNA (cytosine-5-)-methyltransferase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
DNMT1	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).

Chemical tractability of cohort targets

6 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)
DECITABINE	4	DNMT1
AZACITIDINE	4	DNMT1
CEPHALOTHIN	4	DNMT1
EPIGALOCATECHIN GALLATE	3	DNMT1
MOLIBRESIB	2	DNMT1
GENISTEIN	2	DNMT1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	DNMT1
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: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford