Hereditary sensory and autonomic neuropathy

Summary

Hereditary sensory and autonomic neuropathy (MONDO:0015364) is a disease (an umbrella term covering 13 Mondo subtypes) caused by variants in PRDM12 and NGF, with 6 cohort genes and 4 clinical trials. Top therapeutic interventions include droxidopa.

At a glance

• Causal genes: PRDM12 (GenCC Definitive), NGF (GenCC Strong)
• Umbrella term: 13 Mondo subtypes
• Cohort genes: 6
• ClinVar variants: 7
• Clinical trials: 4

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary sensory and autonomic neuropathy
Mondo ID	MONDO:0015364
MeSH	D009477
OMIM	162400
Orphanet	140471
DOID	DOID:0050548
ICD-11	1091217288
NCIT	C125386
SNOMED CT	11442006
UMLS	C0027889
MedGen	14355
GARD	0012688
Is cancer (heuristic)	no

Also known as: CIP · congenital insensitivity to pain · congenital pain insensitivity · hereditary sensory and autonomic neuropathy · hereditary sensory autonomic neuropathy · hereditary sensory neuropathy · hereditary sensory peripheral neuropathy · HSAN · indifference to pain, Congenital, autosomal recessive

Data availability: 7 ClinVar variants · 3 GenCC gene-disease records.

Disease family

An umbrella term covering 13 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

Subtypes (13): 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, 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

7 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 2 conflicting classifications of pathogenicity, 1 benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
916537	NM_014053.4(FLVCR1):c.730G>A (p.Gly244Ser)	FLVCR1	Likely pathogenic	criteria provided, single submitter
364581	NM_003640.5(ELP1):c.209G>A (p.Arg70His)	ELP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
372384	NM_003640.5(ELP1):c.1213C>T (p.Arg405Trp)	ELP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
637913	NM_002529.4(NTRK1):c.717+1G>C	NTRK1	Uncertain significance	no assertion criteria provided
637914	NM_002529.4(NTRK1):c.2162T>C (p.Phe721Ser)	NTRK1	Uncertain significance	no assertion criteria provided
848087	NM_021619.3(PRDM12):c.1041CGC[17] (p.Ala355_Ala359dup)	PRDM12	Uncertain significance	criteria provided, multiple submitters, no conflicts
509943	NM_003640.5(ELP1):c.1721C>T (p.Ala574Val)	ELP1	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 8 · 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
PRDM12	Definitive	Autosomal recessive	hereditary sensory and autonomic neuropathy	5
NGF	Strong	Autosomal recessive	hereditary sensory and autonomic neuropathy	5
PLEKHN1	Limited	Autosomal recessive	hereditary sensory and autonomic neuropathy

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PRDM12	Orphanet:478664	Hereditary sensory and autonomic neuropathy type 8
NGF	Orphanet:64752	Hereditary sensory and autonomic neuropathy type 5
FLVCR1	Orphanet:88628	Posterior column ataxia-retinitis pigmentosa syndrome
ELP1	Orphanet:1764	Familial dysautonomia
NTRK1	Orphanet:146	Differentiated thyroid carcinoma
NTRK1	Orphanet:642	Hereditary sensory and autonomic neuropathy type 4
NTRK1	Orphanet:64752	Hereditary sensory and autonomic neuropathy type 5
NTRK1	Orphanet:99361	Isolated familial medullary thyroid carcinoma

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PRDM12	HGNC:13997	ENSG00000130711	Q9H4Q4	PR domain zinc finger protein 12	gencc,clinvar
PLEKHN1	HGNC:25284	ENSG00000187583	Q494U1	Pleckstrin homology domain-containing family N member 1	gencc
NGF	HGNC:7808	ENSG00000134259	P01138	Beta-nerve growth factor	gencc
FLVCR1	HGNC:24682	ENSG00000162769	Q9Y5Y0	Choline/ethanolamine transporter FLVCR1	clinvar
ELP1	HGNC:5959	ENSG00000070061	O95163	Elongator complex protein 1	clinvar
NTRK1	HGNC:8031	ENSG00000198400	P04629	High affinity nerve growth factor receptor	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PRDM12	PR domain zinc finger protein 12	Transcriptional regulator necessary for the development of nociceptive neurons, playing a key role in determining the nociceptive lineage from neural crest cell progenitors.
PLEKHN1	Pleckstrin homology domain-containing family N member 1	Controls the stability of the leptin mRNA harboring an AU-rich element (ARE) in its 3’ UTR, in cooperation with the RNA stabilizer ELAVL1.
NGF	Beta-nerve growth factor	Nerve growth factor is important for the development and maintenance of the sympathetic and sensory nervous systems.
FLVCR1	Choline/ethanolamine transporter FLVCR1	Uniporter that mediates the transport of extracellular choline and ethanolamine into cells, thereby playing a key role in phospholipid biosynthesis.
ELP1	Elongator complex protein 1	Component of the elongator complex which is required for multiple tRNA modifications, including mcm5U (5-methoxycarbonylmethyl uridine), mcm5s2U (5-methoxycarbonylmethyl-2-thiouridine), and ncm5U (5-carbamoylmethyl uridine).
NTRK1	High affinity nerve growth factor receptor	Receptor tyrosine kinase involved in the development and the maturation of the central and peripheral nervous systems through regulation of proliferation, differentiation and survival of sympathetic and nervous neurons.

Protein-family classification

Druggable: 2 · Difficult: 3 · Unknown: 1 · Druggable fraction: 0.33

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
Transporter	1	13.0×	0.187
Scaffold/PPI	2	5.8×	0.187
Kinase	1	4.6×	0.330
Transcription factor	1	1.4×	0.674
Other/Unknown	1	0.3×	0.993

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PRDM12	Transcription factor	no		SET_dom, Znf_C2H2_type, Znf_PRDM12
PLEKHN1	Scaffold/PPI	no		PH_domain, PH-like_dom_sf, PLEKHN1_PH
NGF	Other/Unknown	no		Nerve_growth_factor-rel, Nerve_growth_factor_CS, Nerve_growth_factor-like
FLVCR1	Transporter	yes		MFS, MFS_dom, MFS_trans_sf
ELP1	Scaffold/PPI	no		Elp1, WD40/YVTN_repeat-like_dom_sf, Beta-prop_ELP1_1st
NTRK1	Kinase	yes	2.7.10.1	Cys-rich_flank_reg_C, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom

Expression context

Cohort genes with no expression data: 0.

5 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
olfactory bulb	1
type B pancreatic cell	1
esophagus mucosa	1
lower esophagus mucosa	1
skin of abdomen	1
cartilage tissue	1
left uterine tube	1
right ovary	1
epithelial cell of pancreas	1
ileal mucosa	1
jejunal mucosa	1
adrenal tissue	1
right adrenal gland	1
right adrenal gland cortex	1
apex of heart	1
dorsal root ganglion	1
male germ line stem cell (sensu Vertebrata) in testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PRDM12	41		yes	type B pancreatic cell, buccal mucosa cell, olfactory bulb
PLEKHN1	146	ubiquitous	marker	lower esophagus mucosa, esophagus mucosa, skin of abdomen
NGF	158	broad	marker	cartilage tissue, left uterine tube, right ovary
FLVCR1	240	ubiquitous	marker	jejunal mucosa, ileal mucosa, epithelial cell of pancreas
ELP1	291	ubiquitous	marker	adrenal tissue, right adrenal gland cortex, right adrenal gland
NTRK1	160	broad	marker	dorsal root ganglion, apex of heart, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NTRK1	9,181
NGF	3,968
ELP1	2,733
FLVCR1	1,348
PLEKHN1	720
PRDM12	575

Intra-cohort edges

A	B	Sources
ELP1	PLEKHN1	intact
NGF	NTRK1	biogrid_interaction, intact, string_interaction

Structural data

PDB: 5 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NTRK1	P04629	65
NGF	P01138	10
FLVCR1	Q9Y5Y0	8
ELP1	O95163	5
PRDM12	Q9H4Q4	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PLEKHN1	Q494U1	54.31

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 23. Enrichment computed across 6 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
TRKA activation by NGF	2	2855.0×	2e-06	NGF, NTRK1
PLC-gamma1 signalling	2	1903.3×	2e-06	NGF, NTRK1
Signalling to STAT3	2	1903.3×	2e-06	NGF, NTRK1
Signalling to p38 via RIT and RIN	2	1142.0×	5e-06	NGF, NTRK1
ARMS-mediated activation	2	815.7×	9e-06	NGF, NTRK1
PI3K/AKT activation	2	634.4×	1e-05	NGF, NTRK1
Frs2-mediated activation	2	475.8×	2e-05	NGF, NTRK1
Retrograde neurotrophin signalling	2	407.9×	2e-05	NGF, NTRK1
Signalling to RAS	2	335.9×	3e-05	NGF, NTRK1
NFG and proNGF binds to p75NTR	1	1427.5×	0.002	NGF
Ceramide signalling	1	951.7×	0.002	NGF
NGF processing	1	713.8×	0.002	NGF
Axonal growth stimulation	1	713.8×	0.002	NGF
NGF-independant TRKA activation	1	571.0×	0.003	NTRK1
p75NTR negatively regulates cell cycle via SC1	1	475.8×	0.003	NGF
NADE modulates death signalling	1	475.8×	0.003	NGF
p75NTR recruits signalling complexes	1	219.6×	0.006	NGF
NF-kB is activated and signals survival	1	219.6×	0.006	NGF
Heme biosynthesis	1	190.3×	0.006	FLVCR1
NRIF signals cell death from the nucleus	1	178.4×	0.006	NGF
Iron uptake and transport	1	86.5×	0.013	FLVCR1
NRAGE signals death through JNK	1	46.0×	0.023	NGF
HATs acetylate histones	1	19.8×	0.049	ELP1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
nerve growth factor signaling pathway	2	432.1×	4e-04	NGF, NTRK1
neurotrophin TRK receptor signaling pathway	2	351.1×	4e-04	NGF, NTRK1
positive regulation of Ras protein signal transduction	2	295.6×	4e-04	NGF, NTRK1
detection of temperature stimulus involved in sensory perception of pain	2	280.9×	4e-04	PRDM12, NTRK1
sensory perception of pain	2	124.8×	0.002	PRDM12, NGF
circadian rhythm	2	81.4×	0.004	NGF, NTRK1
neuron apoptotic process	2	61.7×	0.005	NGF, NTRK1
cell surface receptor protein tyrosine kinase signaling pathway	2	57.9×	0.005	NGF, NTRK1
programmed cell death involved in cell development	1	1404.3×	0.006	NTRK1
tRNA wobble base 5-methoxycarbonylmethyl-2-thiouridinylation	1	936.2×	0.006	ELP1
positive regulation of neuron maturation	1	936.2×	0.006	NGF
olfactory nerve development	1	936.2×	0.006	NTRK1
behavioral response to formalin induced pain	1	936.2×	0.006	NTRK1
heme export	1	936.2×	0.006	FLVCR1
positive regulation of neuron projection development	2	45.7×	0.006	NGF, NTRK1
neuron projection development	2	40.7×	0.006	PRDM12, NTRK1
negative regulation of neuron apoptotic process	2	37.0×	0.006	NGF, NTRK1
heme transport	1	702.2×	0.007	FLVCR1
response to hydrostatic pressure	1	702.2×	0.007	NTRK1
mechanoreceptor differentiation	1	561.7×	0.008	NTRK1
positive regulation of ERK1 and ERK2 cascade	2	28.4×	0.008	NGF, NTRK1
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	2	26.1×	0.009	NGF, NTRK1
regulation of organ growth	1	351.1×	0.010	FLVCR1
head morphogenesis	1	351.1×	0.010	FLVCR1
cellular response to nicotine	1	351.1×	0.010	NTRK1
peptidyl-tyrosine autophosphorylation	1	312.1×	0.010	NTRK1
positive regulation of collateral sprouting	1	312.1×	0.010	NGF
axonogenesis involved in innervation	1	280.9×	0.011	NTRK1
choline transport	1	255.3×	0.012	FLVCR1
tRNA wobble uridine modification	1	200.6×	0.014	ELP1

Therapeutics

Drugs indicated for this disease

No approved or late-stage (phase ≥3) drug is indicated for this disease; the following are in earlier-phase trials only.

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Serine.

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 5

Druggability breadth: 4 of 6 evidence-associated genes (67%) 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
NTRK1	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NTRK1	66	4
PRDM12	0	0
PLEKHN1	0	0
NGF	0	0
FLVCR1	0	0
ELP1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	NTRK1
FEDRATINIB	4	NTRK1
AXITINIB	4	NTRK1
SORAFENIB	4	NTRK1
RUXOLITINIB	4	NTRK1
ENTRECTINIB	4	NTRK1
CABOZANTINIB	4	NTRK1
CERITINIB	4	NTRK1
BOSUTINIB	4	NTRK1
LORLATINIB	4	NTRK1
ABEMACICLIB	4	NTRK1
LAROTRECTINIB	4	NTRK1
LAROTRECTINIB SULFATE	4	NTRK1
REPOTRECTINIB	4	NTRK1
NINTEDANIB	4	NTRK1
SUNITINIB	4	NTRK1
QUIZARTINIB	4	NTRK1
CRIZOTINIB	4	NTRK1
MIDOSTAURIN	4	NTRK1
AMITRIPTYLINE	4	NTRK1
CRENOLANIB	3	NTRK1
LINIFANIB	3	NTRK1
DEFACTINIB	3	NTRK1
ENTOSPLETINIB	3	NTRK1
SITRAVATINIB	3	NTRK1
ALISERTIB	3	NTRK1
DOVITINIB	3	NTRK1
LESTAURTINIB	3	NTRK1
DORAMAPIMOD	2	NTRK1
FORETINIB	2	NTRK1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
NTRK1	1,194	Binding:1182, ADMET:7, Functional:5
NGF	4	Binding:4
PRDM12	1	Binding:1
ELP1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NTRK1	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
NTRK1	1,194

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; 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)
PONATINIB	4	NTRK1
FEDRATINIB	4	NTRK1
AXITINIB	4	NTRK1
SORAFENIB	4	NTRK1
RUXOLITINIB	4	NTRK1
ENTRECTINIB	4	NTRK1
CABOZANTINIB	4	NTRK1
CERITINIB	4	NTRK1
BOSUTINIB	4	NTRK1
LORLATINIB	4	NTRK1
ABEMACICLIB	4	NTRK1
LAROTRECTINIB	4	NTRK1
LAROTRECTINIB SULFATE	4	NTRK1
REPOTRECTINIB	4	NTRK1
NINTEDANIB	4	NTRK1
SUNITINIB	4	NTRK1
QUIZARTINIB	4	NTRK1
CRIZOTINIB	4	NTRK1
MIDOSTAURIN	4	NTRK1
AMITRIPTYLINE	4	NTRK1
CRENOLANIB	3	NTRK1
LINIFANIB	3	NTRK1
DEFACTINIB	3	NTRK1
ENTOSPLETINIB	3	NTRK1
SITRAVATINIB	3	NTRK1
ALISERTIB	3	NTRK1
DOVITINIB	3	NTRK1
LESTAURTINIB	3	NTRK1
DORAMAPIMOD	2	NTRK1
FORETINIB	2	NTRK1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	NTRK1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	FLVCR1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	PRDM12, PLEKHN1, NGF, ELP1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NGF	4	NTRK1
PRDM12	1	—
PLEKHN1	0	—
FLVCR1	0	—
ELP1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02624310	PHASE2	WITHDRAWN	A Study of Norepinephrine in Patients With Congenital Insensitivity to Pain and Anhidrosis
NCT03920774	Not specified	RECRUITING	The Natural History of Familial Dysautonomia
NCT02696746	Not specified	UNKNOWN	Painful Channelopathies Study
NCT05527379	Not specified	COMPLETED	Interest of Virtual Reality to Reduce Patient Anxiety During the Placement of a Percutaneous Implantable Port Catheter

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DROXIDOPA	4	1