Hereditary sensory neuropathy-deafness-dementia syndrome

Summary

Hereditary sensory neuropathy-deafness-dementia syndrome (MONDO:0013584) is a disease caused by DNMT1 (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DNMT1 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 1,436

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		6	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary sensory neuropathy-deafness-dementia syndrome
Mondo ID	MONDO:0013584
MeSH	C580162
OMIM	614116
Orphanet	456318
DOID	DOID:0070158
UMLS	C3279885
MedGen	481515
GARD	0011927
NORD	1903
Is cancer (heuristic)	no

Also known as: DNMT1-related dementia, deafness, and sensory neuropathy · Hereditary Sensory and Autonomic Neuropathy Type 1E · hereditary sensory and autonomic neuropathy type 1E · hereditary sensory neuropathy with hearing loss and dementia · hereditary sensory neuropathy-sensorineural hearing loss-dementia syndrome · HSAN1E · HSN1E · HSNIE · neuropathy, hereditary sensory, type IE

Data availability: 1,436 ClinVar variants · 3 GenCC gene-disease records · 3 cell lines.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › sleep disorder › sleep-wake disorder › hereditary sensory neuropathy-deafness-dementia syndrome

Related subtypes (11): bruxism, recurrent hypersomnia, sleep apnea syndrome, hypersomnia, periodic limb movement disorder, REM sleep behavior disorder, autosomal dominant cerebellar ataxia, deafness and narcolepsy, 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

600 retrieved; paginated sample, class counts are floors:

326 likely benign, 218 uncertain significance, 26 conflicting classifications of pathogenicity, 18 benign, 9 benign/likely benign, 2 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
162188	NM_001130823.3(DNMT1):c.1531T>C (p.Tyr511His)	DNMT1	Pathogenic	criteria provided, single submitter
1072609	NM_001130823.3(DNMT1):c.4490-1G>C	LOC126862853	Pathogenic	criteria provided, single submitter
1067356	NM_001130823.3(DNMT1):c.1619A>C (p.Tyr540Ser)	DNMT1	Likely pathogenic	criteria provided, single submitter
1010647	NM_001130823.3(DNMT1):c.769-4T>G	DNMT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1057276	NM_001130823.3(DNMT1):c.4061C>T (p.Ala1354Val)	DNMT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1107736	NM_001130823.3(DNMT1):c.3117-5C>T	DNMT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1311680	NM_001130823.3(DNMT1):c.3139A>G (p.Thr1047Ala)	DNMT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1380193	NM_001130823.3(DNMT1):c.736C>T (p.Arg246Cys)	DNMT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1403380	NM_001130823.3(DNMT1):c.3163A>G (p.Ile1055Val)	DNMT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1419464	NM_001130823.3(DNMT1):c.317G>A (p.Arg106His)	DNMT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1466174	NM_001130823.3(DNMT1):c.2788C>T (p.Leu930Phe)	DNMT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1483302	NM_001130823.3(DNMT1):c.4445G>A (p.Arg1482His)	DNMT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1562239	NM_001130823.3(DNMT1):c.3294C>T (p.Arg1098=)	DNMT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1656796	NM_001130823.3(DNMT1):c.3949-5C>A	DNMT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
196315	NM_001130823.3(DNMT1):c.150C>T (p.His50=)	DNMT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
196614	NM_001130823.3(DNMT1):c.3156C>T (p.His1052=)	DNMT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1984472	NM_001130823.3(DNMT1):c.4884A>T (p.Glu1628Asp)	DNMT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2037613	NM_001130823.3(DNMT1):c.4489+17G>T	DNMT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
234461	NM_001130823.3(DNMT1):c.406C>T (p.Arg136Cys)	DNMT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
234681	NM_001130823.3(DNMT1):c.919A>G (p.Lys307Glu)	DNMT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2440975	NM_001130823.3(DNMT1):c.3255C>T (p.Pro1085=)	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
246059	NM_001130823.3(DNMT1):c.868G>A (p.Glu290Lys)	DNMT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
246060	NM_001130823.3(DNMT1):c.4876G>A (p.Glu1626Lys)	DNMT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
246280	NM_001130823.3(DNMT1):c.575C>T (p.Ala192Val)	DNMT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
246583	NM_001130823.3(DNMT1):c.382C>A (p.Pro128Thr)	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
257540	NM_001130823.3(DNMT1):c.3117-8G>A	DNMT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2580396	NM_001130823.3(DNMT1):c.3678G>A (p.Arg1226=)	DNMT1	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

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 3 · 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
ANKRD17	Orphanet:528084	Non-specific syndromic intellectual disability

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
DNMT1	HGNC:2976	ENSG00000130816	P26358	DNA (cytosine-5)-methyltransferase 1	gencc,clinvar
ANKRD17	HGNC:23575	ENSG00000132466	O75179	Ankyrin repeat domain-containing protein 17	clinvar
SHFL	HGNC:25649	ENSG00000130813	Q9NUL5	Shiftless antiviral inhibitor of ribosomal frameshifting protein	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.
ANKRD17	Ankyrin repeat domain-containing protein 17	Could play pivotal roles in cell cycle and DNA regulation.
SHFL	Shiftless antiviral inhibitor of ribosomal frameshifting protein	Inhibits programmed -1 ribosomal frameshifting (-1PRF) of a variety of mRNAs from viruses, such as HIV1, and cellular genes, such as PEG10.

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 1 · 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
Scaffold/PPI	1	5.8×	0.482
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DNMT1	Transcription factor	no	2.1.1.37	BAH_dom, C5_MeTfrase, Znf_CXXC
ANKRD17	Scaffold/PPI	no		Ankyrin_rpt, KH_dom, KH_dom_type_1
SHFL	Other/Unknown	no		SHFL

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
secondary oocyte	2
sural nerve	2
oocyte	1
visceral pleura	1
granulocyte	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DNMT1	266	ubiquitous	marker	oocyte, secondary oocyte, sural nerve
ANKRD17	292	ubiquitous	marker	secondary oocyte, sural nerve, visceral pleura
SHFL	278	ubiquitous	marker	right lobe of liver, granulocyte, liver

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DNMT1	7,179
ANKRD17	2,536
SHFL	762

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DNMT1	P26358	27
SHFL	Q9NUL5	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ANKRD17	O75179	53.73

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 3 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 3 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	5617.3×	0.003	DNMT1
obsolete negative regulation of vascular associated smooth muscle cell differentiation involved in phenotypic switching	1	2808.7×	0.003	DNMT1
negative regulation of translational frameshifting	1	2808.7×	0.003	SHFL
response to type III interferon	1	1872.4×	0.003	SHFL
negative regulation of vascular associated smooth muscle cell apoptotic process	1	1872.4×	0.003	DNMT1
chromosomal DNA methylation maintenance following DNA replication	1	1404.3×	0.003	DNMT1
positive regulation of MDA-5 signaling pathway	1	1404.3×	0.003	ANKRD17
cellular response to bisphenol A	1	1123.5×	0.003	DNMT1
regulation of translational termination	1	936.2×	0.003	SHFL
viral translational frameshifting	1	936.2×	0.003	SHFL
response to type I interferon	1	624.1×	0.005	SHFL
response to interferon-beta	1	510.7×	0.005	SHFL
positive regulation of RIG-I signaling pathway	1	510.7×	0.005	ANKRD17
innate immune response	2	22.4×	0.006	ANKRD17, SHFL
negative regulation of gene expression via chromosomal CpG island methylation	1	351.1×	0.006	DNMT1
DNA methylation-dependent constitutive heterochromatin formation	1	181.2×	0.010	DNMT1
response to type II interferon	1	175.5×	0.010	SHFL
positive regulation of cell cycle	1	147.8×	0.011	ANKRD17
positive regulation of vascular associated smooth muscle cell proliferation	1	144.0×	0.011	DNMT1
positive regulation of G1/S transition of mitotic cell cycle	1	133.8×	0.012	ANKRD17
negative regulation of viral genome replication	1	124.8×	0.012	SHFL
regulation of DNA replication	1	122.1×	0.012	ANKRD17
cellular response to amino acid stimulus	1	102.1×	0.013	DNMT1
DNA-templated transcription	1	74.9×	0.017	DNMT1
methylation	1	56.7×	0.022	DNMT1
defense response to bacterium	1	36.0×	0.033	ANKRD17
positive regulation of canonical NF-kappaB signal transduction	1	24.2×	0.046	ANKRD17
defense response to virus	1	23.1×	0.046	SHFL
negative regulation of gene expression	1	23.0×	0.046	DNMT1
positive regulation of gene expression	1	12.9×	0.078	DNMT1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) 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
ANKRD17	0	0
SHFL	0	0

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: 3; 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	2	ANKRD17, SHFL

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)
ANKRD17	0	—
SHFL	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.