Hereditary sensory and autonomic neuropathy type 6

Summary

Hereditary sensory and autonomic neuropathy type 6 (MONDO:0013839) is a disease caused by DST (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: DST (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 3,404

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary sensory and autonomic neuropathy type 6
Mondo ID	MONDO:0013839
OMIM	614653
Orphanet	314381
DOID	DOID:0070151
UMLS	C3539003
MedGen	761278
GARD	0012987
Is cancer (heuristic)	no

Also known as: DST hereditary sensory and autonomic neuropathy · familial dysautonomia with contractures · hereditary sensory and autonomic neuropathy caused by mutation in DST · hereditary sensory and autonomic neuropathy type VI · HSAN6 · neuropathy, hereditary sensory and autonomic, type VI

Data availability: 3,404 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › peripheral nervous system disorder › peripheral neuropathy › sensory peripheral neuropathy › hereditary sensory and autonomic neuropathy › hereditary sensory and autonomic neuropathy type 6

Related subtypes (12): polyneuropathy-hand defect syndrome, hereditary sensory and autonomic neuropathy type 4, neuropathy, hereditary sensory, atypical, X-linked hereditary sensory and autonomic neuropathy with hearing loss, hereditary sensory neuropathy X-linked, hereditary sensory and autonomic neuropathy type 5, hereditary sensory and autonomic neuropathy type 7, congenital insensitivity to pain-hypohidrosis syndrome, congenital insensitivity to pain with hyperhidrosis, hereditary sensory and autonomic neuropathy type 1, cold-induced sweating syndrome - hyperthermia spectrum, hereditary sensory and autonomic neuropathy type 2

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:

312 likely benign, 270 uncertain significance, 5 conflicting classifications of pathogenicity, 4 pathogenic, 4 benign, 2 likely pathogenic, 2 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069200	NM_001723.7(DST):c.4534C>T (p.Arg1512Ter)	DST	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072927	NM_001374736.1(DST):c.4083_4086dup (p.Val1363Ter)	DST	Pathogenic	criteria provided, single submitter
1073401	NM_001374736.1(DST):c.16780C>T (p.Arg5594Ter)	DST	Pathogenic	criteria provided, single submitter
1074277	NM_001723.7(DST):c.4477del (p.Ala1493fs)	DST	Pathogenic	criteria provided, single submitter
1074760	NM_001374736.1(DST):c.3015C>A (p.Cys1005Ter)	DST	Pathogenic	criteria provided, single submitter
1067146	NM_001374736.1(DST):c.21048-1G>T	DST	Likely pathogenic	criteria provided, single submitter
1068243	NM_001374736.1(DST):c.20757+1G>A	DST	Likely pathogenic	criteria provided, single submitter
1013292	NM_001374736.1(DST):c.21538A>G (p.Met7180Val)	DST	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1089487	NM_001374736.1(DST):c.22195C>T (p.Arg7399Cys)	DST	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1091095	NM_001374736.1(DST):c.14441-7_14441-6del	DST	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1100057	NM_001374736.1(DST):c.11679T>C (p.Tyr3893=)	DST	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1132123	NM_001374736.1(DST):c.3585T>C (p.Asn1195=)	DST	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1000054	NM_001723.7(DST):c.11G>C (p.Ser4Thr)	DST	Uncertain significance	criteria provided, single submitter
1000055	NM_001374736.1(DST):c.21659G>A (p.Arg7220Gln)	DST	Uncertain significance	criteria provided, single submitter
1000158	NM_001374736.1(DST):c.14418G>C (p.Trp4806Cys)	DST	Uncertain significance	criteria provided, single submitter
1000373	NM_001723.7(DST):c.4351A>G (p.Lys1451Glu)	DST	Uncertain significance	criteria provided, single submitter
1000475	NM_001723.7(DST):c.7552C>T (p.Arg2518Ter)	DST	Uncertain significance	criteria provided, multiple submitters, no conflicts
1000845	NM_001374736.1(DST):c.18917T>C (p.Met6306Thr)	DST	Uncertain significance	criteria provided, single submitter
1001170	NM_001374736.1(DST):c.4306A>G (p.Lys1436Glu)	DST	Uncertain significance	criteria provided, single submitter
1001341	NM_001374736.1(DST):c.17783C>T (p.Ala5928Val)	DST	Uncertain significance	criteria provided, multiple submitters, no conflicts
1001539	NM_001374736.1(DST):c.17922+3A>G	DST	Uncertain significance	criteria provided, single submitter
1001642	NM_001723.7(DST):c.6887A>T (p.Asn2296Ile)	DST	Uncertain significance	criteria provided, single submitter
1001772	NM_001374736.1(DST):c.17593C>T (p.Arg5865Trp)	DST	Uncertain significance	criteria provided, single submitter
1001899	NM_001374736.1(DST):c.15898G>A (p.Asp5300Asn)	DST	Uncertain significance	criteria provided, multiple submitters, no conflicts
1001976	NM_001374736.1(DST):c.4876A>T (p.Thr1626Ser)	DST	Uncertain significance	criteria provided, multiple submitters, no conflicts
1002331	NM_001374736.1(DST):c.17443C>A (p.Leu5815Ile)	DST	Uncertain significance	criteria provided, multiple submitters, no conflicts
1002591	NM_001723.7(DST):c.4613A>G (p.His1538Arg)	DST	Uncertain significance	criteria provided, single submitter
1002603	NM_001374736.1(DST):c.3838A>G (p.Ile1280Val)	DST	Uncertain significance	criteria provided, multiple submitters, no conflicts
1002647	NM_001723.7(DST):c.7219A>G (p.Ile2407Val)	DST	Uncertain significance	criteria provided, multiple submitters, no conflicts
1002797	NM_001374736.1(DST):c.14297T>C (p.Val4766Ala)	DST	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · 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
DST	Strong	Autosomal recessive	hereditary sensory and autonomic neuropathy type 6	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DST	Orphanet:314381	Hereditary sensory and autonomic neuropathy type 6
DST	Orphanet:412181	Epidermolysis bullosa simplex due to BP230 deficiency

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DST	HGNC:1090	ENSG00000151914	Q03001	Dystonin	gencc,clinvar
DST-AS1	HGNC:40098	ENSG00000231441		DST antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DST	Dystonin	Cytoskeletal linker protein.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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	8.6×	0.225
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DST	Scaffold/PPI	no		Plectin_repeat, SH3_domain, Actinin_actin-bd_CS
DST-AS1	Other/Unknown	no

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
corpus callosum	1
medial globus pallidus	1
cortical plate	1
male germ line stem cell (sensu Vertebrata) in testis	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DST	305	ubiquitous	marker	corpus callosum, calcaneal tendon, medial globus pallidus
DST-AS1	115		yes	male germ line stem cell (sensu Vertebrata) in testis, cortical plate, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DST	2,009
DST-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DST	Q03001	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
Type I hemidesmosome assembly	1	1038.2×	0.004	DST
RHOV GTPase cycle	1	285.5×	0.004	DST
RHOU GTPase cycle	1	278.5×	0.004	DST
RND1 GTPase cycle	1	265.6×	0.004	DST
RND3 GTPase cycle	1	259.6×	0.004	DST
RND2 GTPase cycle	1	259.6×	0.004	DST
Assembly of collagen fibrils and other multimeric structures	1	200.3×	0.005	DST

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
maintenance of cell polarity	1	2407.4×	0.002	DST
hemidesmosome assembly	1	2407.4×	0.002	DST
retrograde axonal transport	1	1532.0×	0.002	DST
intermediate filament cytoskeleton organization	1	936.2×	0.003	DST
cell motility	1	401.2×	0.005	DST
wound healing	1	227.7×	0.007	DST
response to wounding	1	221.7×	0.007	DST
integrin-mediated signaling pathway	1	160.5×	0.009	DST
cytoskeleton organization	1	132.7×	0.009	DST
microtubule cytoskeleton organization	1	121.2×	0.009	DST
cell adhesion	1	37.5×	0.027	DST

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DST	0	0
DST-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	DST, DST-AS1

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)
DST	0	—
DST-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.