Hereditary neuropathy with liability to pressure palsies

Summary

Hereditary neuropathy with liability to pressure palsies (MONDO:0008087) is a disease caused by PMP22 (GenCC Definitive), with 10 cohort genes and 2 clinical trials.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Causal gene: PMP22 (GenCC Definitive)
• Cohort genes: 10
• ClinVar variants: 74
• Phenotypes (HPO): 18
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	3.5	Europe	Validated
Point prevalence	1-5 / 10 000	16	Finland	Validated

Signs & symptoms

Clinical features (HPO)

18 HPO clinical features (Orphanet curated; top 18 by frequency):

HPO ID	Term	Frequency
HP:0003431	Decreased motor nerve conduction velocity	Very frequent (80-99%)
HP:0009830	Peripheral neuropathy	Very frequent (80-99%)
HP:0001324	Muscle weakness	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0003401	Paresthesia	Frequent (30-79%)
HP:0007141	Sensorimotor neuropathy	Frequent (30-79%)
HP:0200101	Decreased/absent ankle reflexes	Frequent (30-79%)
HP:0000407	Sensorineural hearing impairment	Occasional (5-29%)
HP:0001265	Hyporeflexia	Occasional (5-29%)
HP:0001605	Vocal cord paralysis	Occasional (5-29%)
HP:0001608	Abnormality of the voice	Occasional (5-29%)
HP:0001761	Pes cavus	Occasional (5-29%)
HP:0002093	Respiratory insufficiency	Occasional (5-29%)
HP:0003394	Muscle spasm	Occasional (5-29%)
HP:0003693	Distal amyotrophy	Occasional (5-29%)
HP:0003704	Scapuloperoneal weakness	Occasional (5-29%)
HP:0003738	Exercise-induced myalgia	Occasional (5-29%)
HP:0006824	Cranial nerve paralysis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary neuropathy with liability to pressure palsies
Mondo ID	MONDO:0008087
MeSH	C536965
OMIM	162500
Orphanet	640
DOID	DOID:0060843
ICD-11	2126843932
SNOMED CT	230558006
UMLS	C0393814
MedGen	98291
GARD	0005221
MedDRA	10069382
Is cancer (heuristic)	no

Also known as: current pressure-sensitive neuropathy · hereditary liability to pressure palsies · hereditary neuropathy with liability to pressure palsies · hereditary neuropathy with liability to pressure palsy · heterozygous microdeletion 17p11.2p12 · HNPP · neuropathy, hereditary, with liability to pressure palsies · neuropathy, recurrent, with pressure palsies · potato-grubbing palsy · Tomaculous neuropathy · tomaculous neuropathy · tulip-bulb digger’s palsy

Data availability: 74 ClinVar variants · 5 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › peripheral nervous system disorder › peripheral neuropathy › hereditary peripheral neuropathy › hereditary neuropathy with liability to pressure palsies

Related subtypes (64): giant axonal neuropathy, Finnish type amyloidosis, familial amyloid neuropathy, carpal tunnel syndrome, congenital trigeminal anesthesia, familial recurrent peripheral facial palsy, meralgia paraesthetica, familial, amyotrophic neuralgia, abetalipoproteinemia, VPS13A-related neurodegenerative disease, mitochondrial DNA depletion syndrome 4a, oxoglutaricaciduria, cerebrotendinous xanthomatosis, Chediak-Higashi syndrome, homocystinuria due to methylene tetrahydrofolate reductase deficiency, Krabbe disease, beta-mannosidosis, biotinidase deficiency, Leigh syndrome, hereditary sensory and autonomic neuropathy with spastic paraplegia, ornithine aminotransferase deficiency, adult polyglucosan body disease, Sandhoff disease, Tay-Sachs disease, methylmalonic aciduria and homocystinuria type cblC, familial isolated deficiency of vitamin E, Kearns-Sayre syndrome, NARP syndrome, Charcot-Marie-Tooth disease type 5, hereditary motor and sensory neuropathy, Okinawa type, fumaric aciduria, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1, sensory ataxic neuropathy, dysarthria, and ophthalmoparesis, Niemann-Pick disease type B, long chain 3-hydroxyacyl-CoA dehydrogenase deficiency, primary CD59 deficiency, PHARC syndrome, progressive demyelinating neuropathy with bilateral striatal necrosis, cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome, ataxia - oculomotor apraxia type 4, adrenomyeloneuropathy, neuropathy with hearing impairment, hereditary motor and sensory neuropathy, hereditary sensory and autonomic neuropathy, Charcot-Marie-Tooth disease, infantile axonal neuropathy, mitochondrial neurogastrointestinal encephalomyopathy, attenuated Chédiak-Higashi syndrome, coenzyme Q10 deficiency, familial episodic pain syndrome, non-progressive predominantly posterior cavitating leukoencephalopathy with peripheral neuropathy, metachromatic leukodystrophy, distal hereditary motor neuropathy, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2, proximal spinal muscular atrophy, pyruvate dehydrogenase deficiency, peroxisome biogenesis disorder, neurodegeneration with brain iron accumulation 2A, neuropathy, congenital hypomelinating, optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome, EMILIN-1-related connective tissue disease, PRPS1 deficiency disorder, neuropathy, hereditary sensory and autonomic, type IId, peripheral motor neuropathy, childhood-onset, biotin-responsive

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

74 retrieved; paginated sample, class counts are floors:

29 uncertain significance, 18 pathogenic, 7 benign/likely benign, 6 conflicting classifications of pathogenicity, 5 benign, 3 pathogenic/likely pathogenic, 3 likely pathogenic, 2 not provided, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2580333	GRCh37/hg19 17p12(chr17:14095256-15477547)x1	CDRT15	Pathogenic	criteria provided, single submitter
3392523	NC_000017.11:g.14193766_15590127del	CDRT15	Pathogenic	criteria provided, single submitter
4071497	NC_000017.10:g.14095309_15455610del	CDRT15	Pathogenic	no assertion criteria provided
4081902	NC_000017.11:g.14236562_15569040del	CDRT15	Pathogenic	no assertion criteria provided
625678	GRCh37/hg19 17p12(chr17:14128550-15422557)	CDRT15	Pathogenic	criteria provided, single submitter
625725	GRCh37/hg19 17p12(chr17:14101029-15449627)	CDRT15	Pathogenic	criteria provided, single submitter
625727	GRCh37/hg19 17p12(chr17:14104012-15551814)	CDRT15	Pathogenic	criteria provided, single submitter
625729	GRCh37/hg19 17p12(chr17:14110451-15449097)	CDRT15	Pathogenic	criteria provided, single submitter
3899836	Single allele	HS3ST3B1	Pathogenic	criteria provided, single submitter
8430	NC_000017.11:g.(14170534_14194724)_(15567585_15591587)del	LOC126862513	Pathogenic	no assertion criteria provided
625547	GRCh37/hg19 2q13(chr2:110824957-110983703)	MALL	Pathogenic	criteria provided, single submitter
8446	NR_039884.1(MIR4731):n.(?-9031)(1_70)del	MIR4731	Pathogenic	no assertion criteria provided
217238	NM_000304.4(PMP22):c.434del (p.Leu145fs)	PMP22	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
531680	NM_000304.4(PMP22):c.83G>A (p.Trp28Ter)	PMP22	Pathogenic	criteria provided, multiple submitters, no conflicts
568922	NM_000304.4(PMP22):c.261_262del (p.Phe88fs)	PMP22	Pathogenic	criteria provided, single submitter
637713	NM_000304.4(PMP22):c.372G>A (p.Trp124Ter)	PMP22	Pathogenic	criteria provided, single submitter
8437	NM_000304.4(PMP22):c.281dup (p.Arg95fs)	PMP22	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8444	NM_000304.4(PMP22):c.469C>T (p.Arg157Trp)	PMP22	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8445	NM_000304.4(PMP22):c.65C>T (p.Ser22Phe)	PMP22	Pathogenic	no assertion criteria provided
1703548	GRCh37/hg19 17p12(chr17:14076989-15473312)	TVP23C-CDRT4	Pathogenic	no assertion criteria provided
4083496	GRCh37/hg19 17p12(chr17:14110127-15477497)x1	TVP23C-CDRT4	Pathogenic	criteria provided, single submitter
3896952	NM_000304.4(PMP22):c.201del (p.Thr68fs)	PMP22	Likely pathogenic	criteria provided, single submitter
637842	NM_000304.4(PMP22):c.418T>A (p.Trp140Arg)	PMP22	Likely pathogenic	criteria provided, multiple submitters, no conflicts
803325	NM_000304.4(PMP22):c.78+3G>T	PMP22	Likely pathogenic	criteria provided, single submitter
321861	NM_000304.4(PMP22):c.*3C>T	PMP22	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
321863	NM_000304.4(PMP22):c.-34-5C>T	PMP22	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
416789	NM_000304.4(PMP22):c.178+7C>A	PMP22	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
8431	NM_000304.4(PMP22):c.353C>T (p.Thr118Met)	PMP22	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
8435	NM_000304.4(PMP22):c.19_20del (p.Ser7fs)	PMP22	Conflicting classifications of pathogenicity	no assertion criteria provided
8443	NM_000304.4(PMP22):c.199G>A (p.Ala67Thr)	PMP22	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 21 · Orphanet: 34 · 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
PMP22	Definitive	Autosomal dominant	hereditary neuropathy with liability to pressure palsies	21

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PMP22	Orphanet:101081	Charcot-Marie-Tooth disease type 1A
PMP22	Orphanet:3115	Roussy-Lévy syndrome
PMP22	Orphanet:640	Hereditary neuropathy with liability to pressure palsies
PMP22	Orphanet:64748	Dejerine-Sottas syndrome
PMP22	Orphanet:90658	Charcot-Marie-Tooth disease type 1E
PMP22	Orphanet:98916	Acute inflammatory demyelinating polyradiculoneuropathy
CACNA1S	Orphanet:397755	Periodic paralysis with transient compartment-like syndrome
CACNA1S	Orphanet:423	Malignant hyperthermia of anesthesia
CACNA1S	Orphanet:681	Hypokalemic periodic paralysis
CACNA1S	Orphanet:79102	Thyrotoxic periodic paralysis
SYNE1	Orphanet:319332	Autosomal recessive myogenic arthrogryposis multiplex congenita
SYNE1	Orphanet:88644	Autosomal recessive ataxia, Beauce type
SYNE1	Orphanet:98853	Autosomal dominant Emery-Dreifuss muscular dystrophy
LMNA	Orphanet:154	Familial isolated dilated cardiomyopathy
LMNA	Orphanet:157973	Congenital muscular dystrophy due to LMNA mutation
LMNA	Orphanet:1662	Restrictive dermopathy
LMNA	Orphanet:168796	Heart-hand syndrome, Slovenian type
LMNA	Orphanet:2229	Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome
LMNA	Orphanet:2348	Familial partial lipodystrophy, Dunnigan type
LMNA	Orphanet:280365	Autosomal semi-dominant severe lipodystrophic laminopathy
LMNA	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
LMNA	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
LMNA	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
LMNA	Orphanet:300751	Familial dilated cardiomyopathy with conduction defect due to LMNA mutation
LMNA	Orphanet:363618	LMNA-related cardiocutaneous progeria syndrome
LMNA	Orphanet:54260	Left ventricular noncompaction
LMNA	Orphanet:675396	Epithelioid hemangioma
LMNA	Orphanet:740	Hutchinson-Gilford progeria syndrome
LMNA	Orphanet:79084	Familial partial lipodystrophy, Köbberling type
LMNA	Orphanet:79474	Atypical Werner syndrome
LMNA	Orphanet:90153	Mandibuloacral dysplasia with type A lipodystrophy
LMNA	Orphanet:98853	Autosomal dominant Emery-Dreifuss muscular dystrophy
LMNA	Orphanet:98855	Autosomal recessive Emery-Dreifuss muscular dystrophy
LMNA	Orphanet:98856	Charcot-Marie-Tooth disease type 2B1

Cohort genes → proteins

10 cohort genes, 8 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	10

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PMP22	HGNC:9118	ENSG00000109099	Q01453	Peripheral myelin protein 22	gencc,clinvar
CACNA1S	HGNC:1397	ENSG00000081248	Q13698	Voltage-dependent L-type calcium channel subunit alpha-1S	clinvar
CDRT15	HGNC:14395	ENSG00000223510	Q96T59	CMT1A duplicated region transcript 15 protein	clinvar
SYNE1	HGNC:17089	ENSG00000131018	Q8NF91	Nesprin-1	clinvar
ADORA2B	HGNC:264	ENSG00000170425	P29275	Adenosine receptor A2b	clinvar
MIR4731	HGNC:41597	ENSG00000265110		microRNA 4731	clinvar
TVP23C-CDRT4	HGNC:42961	ENSG00000259024		TVP23C-CDRT4 readthrough	clinvar
HS3ST3B1	HGNC:5198	ENSG00000125430	Q9Y662	Heparan sulfate glucosamine 3-O-sulfotransferase 3B1	clinvar
LMNA	HGNC:6636	ENSG00000160789	P02545	Prelamin-A/C	clinvar
MALL	HGNC:6818	ENSG00000144063	Q13021	MAL-like protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PMP22	Peripheral myelin protein 22	Might be involved in growth regulation, and in myelinization in the peripheral nervous system.
CACNA1S	Voltage-dependent L-type calcium channel subunit alpha-1S	Pore-forming, alpha-1S subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents in skeletal muscle.
SYNE1	Nesprin-1	Multi-isomeric modular protein which forms a linking network between organelles and the actin cytoskeleton to maintain the subcellular spatial organization.
ADORA2B	Adenosine receptor A2b	Receptor for adenosine.
HS3ST3B1	Heparan sulfate glucosamine 3-O-sulfotransferase 3B1	Sulfotransferase that utilizes 3’-phospho-5’-adenylyl sulfate (PAPS) to catalyze the transfer of a sulfo group to an N-unsubstituted glucosamine linked to a 2-O-sulfo iduronic acid unit on heparan sulfate.
LMNA	Prelamin-A/C	Lamins are intermediate filament proteins that assemble into a filamentous meshwork, and which constitute the major components of the nuclear lamina, a fibrous layer on the nucleoplasmic side of the inner nuclear membrane.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 7 · Druggable fraction: 0.3

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	11.2×	0.345
GPCR	1	2.4×	0.463
Other/Unknown	7	1.2×	0.463
Enzyme (other)	1	1.2×	0.581

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PMP22	Other/Unknown	no		PMP22, PMP22/EMP/MP20/Claudin, PMP22_EMP_MP20
CACNA1S	Ion channel	yes		VDCCAlpha1, VDCC_L_a1su, VDCC_L_a1ssu
CDRT15	Other/Unknown	no
SYNE1	Other/Unknown	no		Actinin_actin-bd_CS, CH_dom, Spectrin_repeat
ADORA2B	GPCR	yes		GPCR_Rhodpsn, Adeno_A2B_rcpt, Adenosn_rcpt
MIR4731	Other/Unknown	no
TVP23C-CDRT4	Other/Unknown	no
HS3ST3B1	Enzyme (other)	yes	2.8.2.30	Sulfotransferase_dom, P-loop_NTPase, NST/OST
LMNA	Other/Unknown	no		Lamin_tail_dom, IF_conserved, Lamin_tail_dom_sf
MALL	Other/Unknown	no		Marvel, MAL, MARVEL-CKLF_proteins

Expression context

Cohort genes with no expression data: 0.

7 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)	10
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	2
dorsal root ganglion	1
olfactory bulb	1
trigeminal ganglion	1
gluteal muscle	1
hindlimb stylopod muscle	1
triceps brachii	1
left testis	1
right testis	1
calcaneal tendon	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
bronchial epithelial cell	1
mucosa of transverse colon	1
pigmented layer of retina	1
blood	1
skeletal muscle tissue	1
sural nerve	1
islet of Langerhans	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PMP22	294	ubiquitous	marker	olfactory bulb, trigeminal ganglion, dorsal root ganglion
CACNA1S	105	tissue_specific	marker	gluteal muscle, hindlimb stylopod muscle, triceps brachii
CDRT15	127		yes	right testis, male germ line stem cell (sensu Vertebrata) in testis, left testis
SYNE1	275	ubiquitous	marker	cerebellar hemisphere, right hemisphere of cerebellum, calcaneal tendon
ADORA2B	207	ubiquitous	marker	mucosa of transverse colon, bronchial epithelial cell, pigmented layer of retina
MIR4731	80		yes	sural nerve, skeletal muscle tissue, blood
TVP23C-CDRT4	133	broad	yes	male germ line stem cell (sensu Vertebrata) in testis, ventricular zone, islet of Langerhans
HS3ST3B1	206	ubiquitous	marker	tibia, parotid gland, epithelium of nasopharynx
LMNA	295	ubiquitous	marker	nipple, mucosa of stomach, skin of abdomen
MALL	141	ubiquitous	marker	lower esophagus mucosa, duodenum, esophagus mucosa

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LMNA	7,173
SYNE1	2,886
CACNA1S	1,818
ADORA2B	1,118
MALL	986
PMP22	647
HS3ST3B1	459
CDRT15	137
MIR4731	0
TVP23C-CDRT4	0

Intra-cohort edges

A	B	Sources
CDRT15	HS3ST3B1	string_interaction
LMNA	SYNE1	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 4 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LMNA	P02545	28
ADORA2B	P29275	4
SYNE1	Q8NF91	3
CACNA1S	Q13698	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MALL	Q13021	90.13
PMP22	Q01453	89.87
HS3ST3B1	Q9Y662	83.45
CDRT15	Q96T59	52.21

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 41. Enrichment computed across 10 evidence-associated genes (6 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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Breakdown of the nuclear lamina	1	634.4×	0.029	LMNA
Adenosine P1 receptors	1	475.8×	0.029	ADORA2B
Meiotic synapsis	2	47.0×	0.029	SYNE1, LMNA
Nucleotide-like (purinergic) receptors	1	317.2×	0.032	ADORA2B
Depolymerization of the Nuclear Lamina	1	126.9×	0.047	LMNA
Initiation of Nuclear Envelope (NE) Reformation	1	100.2×	0.047	LMNA
IRE1alpha activates chaperones	1	86.5×	0.047	LMNA
Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer’s disease models	1	86.5×	0.047	LMNA
Nuclear Envelope Breakdown	1	76.1×	0.047	LMNA
Anti-inflammatory response favouring Leishmania parasite infection	1	65.6×	0.047	ADORA2B
Leishmania parasite growth and survival	1	65.6×	0.047	ADORA2B
Surfactant metabolism	1	61.4×	0.047	ADORA2B
EGR2 and SOX10-mediated initiation of Schwann cell myelination	1	61.4×	0.047	PMP22
Unfolded Protein Response (UPR)	1	59.5×	0.047	LMNA
HS-GAG biosynthesis	1	57.7×	0.047	HS3ST3B1
Meiosis	1	47.6×	0.049	SYNE1
NCAM signaling for neurite out-growth	1	45.3×	0.049	CACNA1S
ADORA2B mediated anti-inflammatory cytokines production	1	42.3×	0.049	ADORA2B
NCAM1 interactions	1	41.4×	0.049	CACNA1S
Oncogenic MAPK signaling	1	41.4×	0.049	LMNA
XBP1(S) activates chaperone genes	1	35.9×	0.054	LMNA
Reproduction	1	31.7×	0.058	SYNE1
Signaling by BRAF and RAF1 fusions	1	28.4×	0.059	LMNA
Leishmania infection	1	27.2×	0.059	ADORA2B
Parasitic Infection Pathways	1	27.2×	0.059	ADORA2B
Disease	2	4.4×	0.112	ADORA2B, LMNA
Class A/1 (Rhodopsin-like receptors)	1	12.4×	0.116	ADORA2B
G alpha (s) signalling events	1	12.2×	0.116	ADORA2B
GPCR ligand binding	1	10.7×	0.127	ADORA2B
Diseases of signal transduction by growth factor receptors and second messengers	1	9.5×	0.138	LMNA

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of chronic inflammatory response to non-antigenic stimulus	1	2407.4×	0.015	ADORA2B
skeletal muscle adaptation	1	2407.4×	0.015	CACNA1S
nuclear matrix anchoring at nuclear membrane	1	802.5×	0.017	SYNE1
DNA double-strand break attachment to nuclear envelope	1	802.5×	0.017	LMNA
establishment or maintenance of microtubule cytoskeleton polarity	1	601.9×	0.017	LMNA
nuclear pore localization	1	481.5×	0.017	LMNA
extraocular skeletal muscle development	1	401.2×	0.017	CACNA1S
relaxation of vascular associated smooth muscle	1	401.2×	0.017	ADORA2B
negative regulation of mesenchymal cell proliferation	1	401.2×	0.017	LMNA
obsolete positive regulation of cGMP-mediated signaling	1	343.9×	0.017	ADORA2B
positive regulation of muscle contraction	1	343.9×	0.017	CACNA1S
protein localization to nuclear envelope	1	300.9×	0.017	LMNA
regulation of protein localization to nucleus	1	300.9×	0.017	LMNA
myelin assembly	1	267.5×	0.017	PMP22
negative regulation of cardiac muscle hypertrophy in response to stress	1	267.5×	0.017	LMNA
bleb assembly	1	218.9×	0.017	PMP22
positive regulation of mast cell degranulation	1	218.9×	0.017	ADORA2B
ventricular cardiac muscle cell development	1	218.9×	0.017	LMNA
cellular response to caffeine	1	218.9×	0.017	CACNA1S
activation of adenylate cyclase activity	1	160.5×	0.022	ADORA2B
nuclear envelope organization	1	141.6×	0.023	LMNA
glycosaminoglycan biosynthetic process	1	120.4×	0.023	HS3ST3B1
striated muscle contraction	1	120.4×	0.023	CACNA1S
regulation of telomere maintenance	1	120.4×	0.023	LMNA
muscle cell differentiation	1	120.4×	0.023	SYNE1
obsolete cGMP-mediated signaling	1	114.6×	0.023	ADORA2B
negative regulation of release of cytochrome c from mitochondria	1	114.6×	0.023	LMNA
nuclear migration	1	104.7×	0.024	LMNA
mast cell degranulation	1	89.2×	0.025	ADORA2B
myoblast fusion	1	86.0×	0.025	CACNA1S

Therapeutics

Drug target analysis

Approved (phase 4): 4 · Phase ≥3: 4 · Phased (≥1): 4 · Undrugged: 6

Druggability breadth: 4 of 10 evidence-associated genes (40%) 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
PMP22	PROGESTERONE
CACNA1S	BEPRIDIL
ADORA2B	CAFFEINE
LMNA	BEPRIDIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LMNA	823	4
PMP22	213	4
CACNA1S	48	4
ADORA2B	30	4
CDRT15	0	0
SYNE1	0	0
MIR4731	0	0
TVP23C-CDRT4	0	0
HS3ST3B1	0	0
MALL	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PROGESTERONE	4	LMNA, PMP22
CLOTRIMAZOLE	4	LMNA, PMP22
OXAPROZIN	4	LMNA, PMP22
SALMETEROL XINAFOATE	4	LMNA, PMP22
AMIODARONE HYDROCHLORIDE	4	LMNA, PMP22
TRIHEXYPHENIDYL HYDROCHLORIDE	4	PMP22
AMOXAPINE	4	LMNA, PMP22
RALOXIFENE HYDROCHLORIDE	4	LMNA, PMP22
IDARUBICIN	4	LMNA, PMP22
OXYBUTYNIN CHLORIDE	4	PMP22
PINACIDIL ANHYDROUS	4	LMNA, PMP22
NICARDIPINE HYDROCHLORIDE	4	LMNA, PMP22
PILOCARPINE HYDROCHLORIDE	4	LMNA, PMP22
PROTRIPTYLINE HYDROCHLORIDE	4	PMP22
BENZTROPINE MESYLATE	4	PMP22
BUSPIRONE HYDROCHLORIDE	4	PMP22
DOBUTAMINE HYDROCHLORIDE	4	LMNA, PMP22
PROMAZINE HYDROCHLORIDE	4	LMNA, PMP22
DICYCLOMINE HYDROCHLORIDE	4	PMP22
GUANFACINE HYDROCHLORIDE	4	PMP22
HYDROCORTISONE SODIUM SUCCINATE	4	PMP22
BROMOCRIPTINE MESYLATE	4	LMNA, PMP22
DIHYDROERGOTAMINE MESYLATE	4	LMNA, PMP22
DOXAZOSIN MESYLATE	4	LMNA, PMP22
CYCLOBENZAPRINE HYDROCHLORIDE	4	LMNA, PMP22
DEXBROMPHENIRAMINE MALEATE	4	PMP22
CLOMIPRAMINE HYDROCHLORIDE	4	LMNA, PMP22
CHLORMEZANONE	4	LMNA, PMP22
PROMETHAZINE HYDROCHLORIDE	4	LMNA, PMP22
CITALOPRAM HYDROBROMIDE	4	PMP22

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ADORA2B	907	Binding:632, Functional:273, ADMET:2
CACNA1S	228	Binding:142, Functional:79, Toxicity:5, ADMET:2
LMNA	12	Binding:9, Functional:3
PMP22	1	Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HS3ST3B1	2.8.2.30	[heparan sulfate]-glucosamine 3-sulfotransferase 3

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CACNA1S	228
ADORA2B	907

Pharmacogenomics

Cohort genes with a PharmGKB record: 8; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
CACNA1S	1

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)
PROGESTERONE	4	LMNA, PMP22
CLOTRIMAZOLE	4	LMNA, PMP22
OXAPROZIN	4	LMNA, PMP22
SALMETEROL XINAFOATE	4	LMNA, PMP22
AMIODARONE HYDROCHLORIDE	4	LMNA, PMP22
TRIHEXYPHENIDYL HYDROCHLORIDE	4	PMP22
AMOXAPINE	4	LMNA, PMP22
RALOXIFENE HYDROCHLORIDE	4	LMNA, PMP22
IDARUBICIN	4	LMNA, PMP22
OXYBUTYNIN CHLORIDE	4	PMP22
PINACIDIL ANHYDROUS	4	LMNA, PMP22
NICARDIPINE HYDROCHLORIDE	4	LMNA, PMP22
PILOCARPINE HYDROCHLORIDE	4	LMNA, PMP22
PROTRIPTYLINE HYDROCHLORIDE	4	PMP22
BENZTROPINE MESYLATE	4	PMP22
BUSPIRONE HYDROCHLORIDE	4	PMP22
DOBUTAMINE HYDROCHLORIDE	4	LMNA, PMP22
PROMAZINE HYDROCHLORIDE	4	LMNA, PMP22
DICYCLOMINE HYDROCHLORIDE	4	PMP22
GUANFACINE HYDROCHLORIDE	4	PMP22
HYDROCORTISONE SODIUM SUCCINATE	4	PMP22
BROMOCRIPTINE MESYLATE	4	LMNA, PMP22
DIHYDROERGOTAMINE MESYLATE	4	LMNA, PMP22
DOXAZOSIN MESYLATE	4	LMNA, PMP22
CYCLOBENZAPRINE HYDROCHLORIDE	4	LMNA, PMP22
DEXBROMPHENIRAMINE MALEATE	4	PMP22
CLOMIPRAMINE HYDROCHLORIDE	4	LMNA, PMP22
CHLORMEZANONE	4	LMNA, PMP22
PROMETHAZINE HYDROCHLORIDE	4	LMNA, PMP22
CITALOPRAM HYDROBROMIDE	4	PMP22

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	4	PMP22, CACNA1S, ADORA2B, LMNA
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	HS3ST3B1
E	Difficult family or no structure, no drug	5	CDRT15, SYNE1, MIR4731, TVP23C-CDRT4, MALL

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SYNE1	0	LMNA
CDRT15	0	—
MIR4731	0	—
TVP23C-CDRT4	0	—
HS3ST3B1	0	—
MALL	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01401257	PHASE2	COMPLETED	Phase II, Randomized, Placebo-controlled Trial in Patients With Charcot-marie-tooth Disease Type 1A
NCT05902351	Not specified	RECRUITING	Natural History Study for Charcot Marie Tooth Disease