Hereditary sensory and autonomic neuropathy type 2

Summary

Hereditary sensory and autonomic neuropathy type 2 (MONDO:0019941) is a disease with 4 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 4
• ClinVar variants: 5
• Phenotypes (HPO): 15

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		35	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

15 HPO clinical features (Orphanet curated; top 15 by frequency):

HPO ID	Term	Frequency
HP:0000975	Hyperhidrosis	Very frequent (80-99%)
HP:0001182	Tapered finger	Very frequent (80-99%)
HP:0001810	Dystrophic toenail	Very frequent (80-99%)
HP:0001842	Acroosteolysis (feet)	Very frequent (80-99%)
HP:0002645	Wormian bones	Very frequent (80-99%)
HP:0002797	Osteolysis	Very frequent (80-99%)
HP:0002815	Abnormality of the knee	Very frequent (80-99%)
HP:0003028	Abnormality of the ankles	Very frequent (80-99%)
HP:0003103	Abnormal cortical bone morphology	Very frequent (80-99%)
HP:0003202	Skeletal muscle atrophy	Very frequent (80-99%)
HP:0003272	Abnormality of the hip bone	Very frequent (80-99%)
HP:0003307	Hyperlordosis	Very frequent (80-99%)
HP:0004349	Reduced bone mineral density	Very frequent (80-99%)
HP:0005930	Abnormality of epiphysis morphology	Very frequent (80-99%)
HP:0008391	Dystrophic fingernails	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary sensory and autonomic neuropathy type 2
Mondo ID	MONDO:0019941
Orphanet	970
DOID	DOID:0070161
SNOMED CT	398148000
UMLS	C0020072
MedGen	42513
GARD	0003976
NORD	1235
Is cancer (heuristic)	no

Also known as: autosomal recessive sensory radicular neuropathy · Giaccai type acroosteolysis · Hereditary Sensory and Autonomic Neuropathy Type II · hereditary sensory and autonomic neuropathy type II · hereditary sensory neuropathy type 2 · hereditary sensory radicular neuropathy, recessive form · HSAN2 · neurogenic acroosteolysis

Data availability: 5 ClinVar variants · 4 GenCC gene-disease records.

Disease family

An umbrella term covering 3 Mondo subtypes.

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 2

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 6, 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

Subtypes (3): neuropathy, hereditary sensory and autonomic, type 2B, neuropathy, hereditary sensory, type 2C, neuropathy, hereditary sensory and autonomic, type 2A

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

5 retrieved; paginated sample, class counts are floors:

4 pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
21257	NM_001034850.3(RETREG1):c.18_19del (p.Pro7fs)	LOC129993734	Pathogenic	criteria provided, multiple submitters, no conflicts
21259	NM_001034850.3(RETREG1):c.873+2T>C	RETREG1	Pathogenic	criteria provided, single submitter
328	NM_001034850.3(RETREG1):c.926C>G (p.Ser309Ter)	RETREG1	Pathogenic	criteria provided, multiple submitters, no conflicts
330	NM_001034850.3(RETREG1):c.433C>T (p.Gln145Ter)	RETREG1	Pathogenic	criteria provided, multiple submitters, no conflicts
203444	NM_001034850.3(RETREG1):c.826del (p.Ser276fs)	RETREG1	Conflicting classifications of pathogenicity	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 47 · Orphanet: 13 · 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
KIF1A	Definitive	Autosomal recessive	neuropathy, hereditary sensory, type 2C	19
RETREG1	Definitive	Autosomal recessive	neuropathy, hereditary sensory and autonomic, type 2B	3
WNK1	Definitive	Autosomal recessive	neuropathy, hereditary sensory and autonomic, type 2A	9
SCN9A	Strong	Semidominant	hereditary peripheral neuropathy	16

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RETREG1	Orphanet:970	Hereditary sensory and autonomic neuropathy type 2
SCN9A	Orphanet:306577	Hereditary sodium channelopathy-related small fibers neuropathy
SCN9A	Orphanet:33069	Dravet syndrome
SCN9A	Orphanet:36387	Genetic epilepsy with febrile seizure plus
SCN9A	Orphanet:46348	Paroxysmal extreme pain disorder
SCN9A	Orphanet:88642	Congenital insensitivity to pain-anosmia-neuropathic arthropathy
SCN9A	Orphanet:90026	Primary erythromelalgia
SCN9A	Orphanet:970	Hereditary sensory and autonomic neuropathy type 2
WNK1	Orphanet:88940	Pseudohypoaldosteronism type 2C
WNK1	Orphanet:970	Hereditary sensory and autonomic neuropathy type 2
KIF1A	Orphanet:101010	Autosomal spastic paraplegia type 30
KIF1A	Orphanet:662367	NESCAV syndrome
KIF1A	Orphanet:970	Hereditary sensory and autonomic neuropathy type 2

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RETREG1	HGNC:25964	ENSG00000154153	Q9H6L5	Reticulophagy regulator 1	gencc,clinvar
SCN9A	HGNC:10597	ENSG00000169432	Q15858	Sodium channel protein type 9 subunit alpha	gencc
WNK1	HGNC:14540	ENSG00000060237	Q9H4A3	Serine/threonine-protein kinase WNK1	gencc
KIF1A	HGNC:888	ENSG00000130294	Q12756	Kinesin-like protein KIF1A	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RETREG1	Reticulophagy regulator 1	Endoplasmic reticulum (ER)-anchored autophagy regulator which mediates ER delivery into lysosomes through sequestration into autophagosomes.
SCN9A	Sodium channel protein type 9 subunit alpha	Pore-forming subunit of Nav1.7, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes.
WNK1	Serine/threonine-protein kinase WNK1	Serine/threonine-protein kinase component of the WNK1-SPAK/OSR1 kinase cascade, which acts as a key regulator of blood pressure and regulatory volume increase by promoting ion influx.
KIF1A	Kinesin-like protein KIF1A	Kinesin motor with a plus-end-directed microtubule motor activity.

Protein-family classification

Druggable: 2 · Difficult: 1 · 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	27.9×	0.142
Kinase	1	6.9×	0.273
Scaffold/PPI	1	4.3×	0.283
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RETREG1	Other/Unknown	no		RETREG1/3, RETR1_RHD, RETREG1-3-like_RHD
SCN9A	Ion channel	yes		IQ_motif_EF-hand-BS, Na_channel_asu, Ion_trans_dom
WNK1	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
KIF1A	Scaffold/PPI	no	5.6.1.3	FHA_dom, Kinesin_motor_dom, PH_domain

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
diaphragm	1
heart right ventricle	1
skeletal muscle tissue of rectus abdominis	1
dorsal root ganglion	1
stromal cell of endometrium	1
sural nerve	1
globus pallidus	1
inferior vagus X ganglion	1
medial globus pallidus	1
parietal lobe	1
postcentral gyrus	1
right frontal lobe	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RETREG1	283	ubiquitous	marker	skeletal muscle tissue of rectus abdominis, diaphragm, heart right ventricle
SCN9A	187	ubiquitous	marker	sural nerve, dorsal root ganglion, stromal cell of endometrium
WNK1	297	ubiquitous	marker	medial globus pallidus, globus pallidus, inferior vagus X ganglion
KIF1A	198	broad	marker	right frontal lobe, postcentral gyrus, parietal lobe

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KIF1A	2,833
RETREG1	1,899
SCN9A	1,575
WNK1	371

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SCN9A	Q15858	43
KIF1A	Q12756	21
WNK1	Q9H4A3	5
RETREG1	Q9H6L5	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 21. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Dengue virus modulates apoptosis	1	178.4×	0.060	RETREG1
Interaction between L1 and Ankyrins	1	92.1×	0.060	SCN9A
Phase 0 - rapid depolarisation	1	86.5×	0.060	SCN9A
Sensory perception of taste	1	84.0×	0.060	SCN9A
Sensory perception of sweet, bitter, and umami (glutamate) taste	1	69.6×	0.060	SCN9A
Kinesins	1	44.6×	0.066	KIF1A
Stimuli-sensing channels	1	34.0×	0.066	WNK1
Golgi-to-ER retrograde transport	1	33.2×	0.066	KIF1A
L1CAM interactions	1	30.1×	0.066	SCN9A
COPI-dependent Golgi-to-ER retrograde traffic	1	27.7×	0.066	KIF1A
Cardiac conduction	1	27.2×	0.066	SCN9A
Intra-Golgi and retrograde Golgi-to-ER traffic	1	26.2×	0.066	KIF1A
Sensory Perception	1	23.8×	0.067	SCN9A
Muscle contraction	1	19.3×	0.076	SCN9A
Factors involved in megakaryocyte development and platelet production	1	16.6×	0.082	KIF1A
Axon guidance	1	11.3×	0.111	SCN9A
Nervous system development	1	10.7×	0.111	SCN9A
Membrane Trafficking	1	9.3×	0.116	KIF1A
Hemostasis	1	9.0×	0.116	KIF1A
Vesicle-mediated transport	1	8.7×	0.116	KIF1A
Developmental Biology	1	3.6×	0.249	SCN9A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
sensory perception of pain	2	187.2×	0.003	RETREG1, SCN9A
action potential propagation	1	4213.0×	0.004	SCN9A
positive regulation of termination of RNA polymerase II transcription	1	4213.0×	0.004	WNK1
sodium ion transmembrane transport	2	101.5×	0.004	SCN9A, WNK1
negative regulation of cell-cell adhesion mediated by integrin	1	2106.5×	0.005	WNK1
monoatomic cation homeostasis	1	2106.5×	0.005	WNK1
chemokine (C-C motif) ligand 21 signaling pathway	1	1053.2×	0.006	WNK1
lymphocyte migration into lymph node	1	1053.2×	0.006	WNK1
dense core granule cytoskeletal transport	1	1053.2×	0.006	KIF1A
anterograde neuronal dense core vesicle transport	1	1053.2×	0.006	KIF1A
negative regulation of pancreatic juice secretion	1	842.6×	0.006	WNK1
retrograde neuronal dense core vesicle transport	1	842.6×	0.006	KIF1A
negative regulation of sodium ion transport	1	702.2×	0.006	WNK1
detection of mechanical stimulus involved in sensory perception	1	702.2×	0.006	SCN9A
negative regulation of leukocyte cell-cell adhesion	1	702.2×	0.006	WNK1
positive regulation of mitotic cytokinesis	1	702.2×	0.006	WNK1
regulation of mRNA export from nucleus	1	526.6×	0.007	WNK1
regulation of monoatomic cation transmembrane transport	1	526.6×	0.007	WNK1
negative regulation of heterotypic cell-cell adhesion	1	468.1×	0.007	WNK1
intracellular chloride ion homeostasis	1	421.3×	0.007	WNK1
regulation of dendritic spine development	1	421.3×	0.007	KIF1A
protein insertion into ER membrane by stop-transfer membrane-anchor sequence	1	383.0×	0.007	WNK1
positive regulation of systemic arterial blood pressure	1	351.1×	0.008	WNK1
negative regulation of small GTPase mediated signal transduction	1	300.9×	0.008	WNK1
cellular hyperosmotic response	1	300.9×	0.008	WNK1
positive regulation of T cell chemotaxis	1	280.9×	0.008	WNK1
membraneless organelle assembly	1	280.9×	0.008	WNK1
regulation of sodium ion transmembrane transport	1	263.3×	0.008	WNK1
cellular response to chemokine	1	247.8×	0.009	WNK1
regulation of sodium ion transport	1	234.1×	0.009	WNK1

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 4 evidence-associated genes (75%) 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
SCN9A	IMIPRAMINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN9A	36	4
RETREG1	0	0
WNK1	0	0
KIF1A	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IMIPRAMINE	4	SCN9A
SERTINDOLE	4	SCN9A
PIMOZIDE	4	SCN9A
NIFEDIPINE	4	SCN9A
DILTIAZEM	4	SCN9A
MIBEFRADIL	4	SCN9A
HALOPERIDOL	4	SCN9A
MEXILETINE	4	SCN9A
AMITRIPTYLINE	4	SCN9A
AMIODARONE	4	SCN9A
CHLORPROMAZINE	4	SCN9A
CARBAMAZEPINE	4	SCN9A
MEXILETINE HYDROCHLORIDE	4	SCN9A
CANNABIDIOL	4	SCN9A
SAFINAMIDE	4	SCN9A
LACOSAMIDE	4	SCN9A
TETRACAINE	4	SCN9A
LAMOTRIGINE	4	SCN9A
RILUZOLE	4	SCN9A
LIDOCAINE	4	SCN9A
TEDISAMIL	3	SCN9A
NITRENDIPINE	3	SCN9A
AJMALINE	3	SCN9A
RALFINAMIDE	3	SCN9A
VIXOTRIGINE	3	SCN9A
ELECLAZINE	3	SCN9A
TETRODOTOXIN	3	SCN9A
CIFENLINE	2	SCN9A
PF-05089771	2	SCN9A
PF-04531083	2	SCN9A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
SCN9A	428	Binding:395, Functional:29, ADMET:3, Toxicity:1
WNK1	165	Binding:165
KIF1A	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
KIF1A	5.6.1.3	plus-end-directed kinesin ATPase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SCN9A	428
WNK1	165

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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)
IMIPRAMINE	4	SCN9A
SERTINDOLE	4	SCN9A
PIMOZIDE	4	SCN9A
NIFEDIPINE	4	SCN9A
DILTIAZEM	4	SCN9A
MIBEFRADIL	4	SCN9A
HALOPERIDOL	4	SCN9A
MEXILETINE	4	SCN9A
AMITRIPTYLINE	4	SCN9A
AMIODARONE	4	SCN9A
CHLORPROMAZINE	4	SCN9A
CARBAMAZEPINE	4	SCN9A
MEXILETINE HYDROCHLORIDE	4	SCN9A
CANNABIDIOL	4	SCN9A
SAFINAMIDE	4	SCN9A
LACOSAMIDE	4	SCN9A
TETRACAINE	4	SCN9A
LAMOTRIGINE	4	SCN9A
RILUZOLE	4	SCN9A
LIDOCAINE	4	SCN9A
TEDISAMIL	3	SCN9A
NITRENDIPINE	3	SCN9A
AJMALINE	3	SCN9A
RALFINAMIDE	3	SCN9A
VIXOTRIGINE	3	SCN9A
ELECLAZINE	3	SCN9A
TETRODOTOXIN	3	SCN9A
CIFENLINE	2	SCN9A
PF-05089771	2	SCN9A
PF-04531083	2	SCN9A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SCN9A
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	WNK1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	RETREG1, KIF1A

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
WNK1	165	—
RETREG1	0	—
KIF1A	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.