Neuronopathy, distal hereditary motor, autosomal dominant

Summary

Neuronopathy, distal hereditary motor, autosomal dominant (MONDO:0015362) is a disease (an umbrella term covering 11 Mondo subtypes) with 11 cohort genes.

At a glance

• Umbrella term: 11 Mondo subtypes
• Cohort genes: 11
• ClinVar variants: 64

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	neuronopathy, distal hereditary motor, autosomal dominant
Mondo ID	MONDO:0015362
OMIM	182960
Orphanet	140465
DOID	DOID:0111198
UMLS	C5548212
MedGen	1787720
GARD	0019926
Is cancer (heuristic)	no

Also known as: autosomal dominant dHMN · autosomal dominant distal hereditary motor neuropathy · autosomal dominant distal spinal muscular atrophy · distal hereditary motor neuropathy, autosomal dominant

Data availability: 64 ClinVar variants · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 11 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › neuronopathy, distal hereditary motor, autosomal dominant

Related subtypes (191): autosomal dominant polycystic liver disease, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, tuberous sclerosis, Treacher-Collins syndrome, hereditary breast ovarian cancer syndrome, autosomal dominant polycystic kidney disease, Lynch syndrome, branchio-oto-renal syndrome, autosomal dominant Aarskog syndrome, acroosteolysis dominant type, ADULT syndrome, autosomal dominant Alport syndrome, amelogenesis imperfecta type 1B, Townes-Brocks syndrome, nevoid basal cell carcinoma syndrome, blepharophimosis, ptosis, and epicanthus inversus syndrome, autosomal dominant brachyolmia, branchiooculofacial syndrome, pheochromocytoma/paraganglioma syndrome 4, cataract-aberrant oral frenula-growth delay syndrome, cherubism, autosomal dominant chondrodysplasia punctata, autosomal dominant popliteal pterygium syndrome, blepharocheilodontic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Beare-Stevenson cutis gyrata syndrome, autosomal dominant vibratory urticaria, neurohypophyseal diabetes insipidus, autosomal dominant Kenny-Caffey syndrome, Rapp-Hodgkin syndrome, Ehlers-Danlos syndrome, classic type, autosomal dominant Ehlers-Danlos syndrome, vascular type, multiple endocrine neoplasia type 1, Coffin-Siris syndrome 1, isolated congenital adermatoglyphia, Flynn-Aird syndrome, Frasier syndrome, hand-foot-genital syndrome, Holt-Oram syndrome, hyperkeratosis-hyperpigmentation syndrome, autosomal dominant ichthyosis vulgaris, hyper-IgE recurrent infection syndrome 1, autosomal dominant, autosomal dominant keratitis, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, LADD syndrome, trichorhinophalangeal syndrome type II, Noonan syndrome with multiple lentigines, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, Marfan syndrome, melanoma, cutaneous malignant, susceptibility to, 2, autosomal dominant primary microcephaly, autosomal dominant progressive external ophthalmoplegia, monilethrix, Muir-Torre syndrome, autosomal dominant myoglobinuria, autosomal dominant centronuclear myopathy, nail-patella syndrome, multiple endocrine neoplasia type 2B, autosomal dominant omodysplasia, pheochromocytoma/paraganglioma syndrome 1, Pelger-Huet anomaly, multiple endocrine neoplasia type 2A, piebaldism, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, generalized juvenile polyposis/juvenile polyposis coli, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Peutz-Jeghers syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, autosomal dominant distal renal tubular acidosis, retinoschisis, autosomal dominant, autosomal dominant Robinow syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, autosomal dominant sideroblastic anemia, spondyloepiphyseal dysplasia tarda, autosomal dominant, proximal symphalangism, calcaneonavicular coalition, thanatophoric dysplasia type 1, trichorhinophalangeal syndrome type I, Muckle-Wells syndrome, autosomal dominant hypophosphatemic rickets, von Hippel-Lindau disease, Denys-Drash syndrome, autosomal dominant severe congenital neutropenia, Costello syndrome, EEC syndrome, multiple cutaneous and mucosal venous malformations, diffuse nonepidermolytic palmoplantar keratoderma, Timothy syndrome, pheochromocytoma/paraganglioma syndrome 2, spondyloepimetaphyseal dysplasia with multiple dislocations, Brooke-Spiegler syndrome, macrocephaly-autism syndrome, pheochromocytoma/paraganglioma syndrome 3, Duane-radial ray syndrome, PCWH syndrome, heart-hand syndrome, Slovenian type, congenital stationary night blindness autosomal dominant 3, mandibulofacial dysostosis-microcephaly syndrome, multiple endocrine neoplasia type 4, juvenile cataract-microcornea-renal glucosuria syndrome, Crouzon syndrome-acanthosis nigricans syndrome, Birk-Barel syndrome, thrombophilia due to protein S deficiency, autosomal dominant, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, colorectal cancer, hereditary nonpolyposis, type 6, colorectal cancer, hereditary nonpolyposis, type 7, brain small vessel disease 2A, autosomal dominant, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, hypopigmentation-punctate palmoplantar keratoderma syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, Houge-Janssens syndrome 2, severe achondroplasia-developmental delay-acanthosis nigricans syndrome, dyskeratosis congenita, autosomal dominant 6, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, autosomal dominant complex spastic paraplegia, early-onset autosomal dominant Alzheimer disease, muscular dystrophy, limb-girdle, autosomal dominant, Feingold syndrome, Carney complex, autosomal dominant coarctation of aorta, autosomal dominant spondylocostal dysostosis, autosomal dominant hypohidrotic ectodermal dysplasia, Cowden disease, autosomal dominant distal myopathy, autosomal dominant rhegmatogenous retinal detachment, palmoplantar keratoderma-spastic paralysis syndrome, Alagille syndrome due to a JAG1 point mutation, PTEN hamartoma tumor syndrome, gastric adenocarcinoma and proximal polyposis of the stomach, autosomal dominant proximal renal tubular acidosis, autosomal dominant spastic ataxia, Waardenburg syndrome, hereditary retinoblastoma, autosomal dominant hypocalcemia, Li-Fraumeni syndrome, Loeys-Dietz syndrome, hereditary hemorrhagic telangiectasia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, microcephalic osteodysplastic dysplasia, Saul-Wilson type, autosomal dominant intermediate Charcot-Marie-Tooth disease, autosomal dominant cutis laxa, autosomal dominant nonsyndromic hearing loss, autosomal dominant optic atrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, autosomal dominant cerebellar ataxia, autosomal dominant osteopetrosis, autosomal dominant epidermolytic ichthyosis, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, distal arthrogryposis type 2B1, neurofibromatosis, autosomal dominant cataract, arthrogryposis, distal, type 2B2, arthrogryposis, distal, type 2B3, Charcot-Marie-Tooth disease, demyelinating, type 1G, Delpire-McNeill syndrome, LAMA5-related multisystemic syndrome, autosomal dominant oculocutaneous albinism, Charcot-Marie-tooth disease, axonal, type 2DD, Pilarowski-Bjornsson syndrome, intellectual disability, autosomal dominant, fatty acyl-CoA reductase 1 upregulation, GUCY2D-related dominant retinopathy, RPE65-related dominant retinopathy, autosomal dominant titinopathy, NOG-related symphalangism spectrum disorder, ALPL-related autosomal dominant hypophosphatasia, MYH10-related neurodevelopmental disorder with congenital anomalies, spastic paraplegia 30A, autosomal dominant, TMEM127-related tumor predisposition, MAX-related tumor predisposition, BMPR1A-related juvenile polyposis syndrome, RP1-related dominant retinopathy, Birt-Hogg-Dube syndrome, inclusion body myopathy and brain white matter abnormalities, KINSSHIP syndrome, autosomal dominant nebulin-related myopathy, IMPG1-related dominant retinopathy, PROM1-related dominant retinopathy, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome, ALG8-related autosomal dominant polycystic kidney and/or liver disease, NOTCH1-related AOS spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder, familial antiphospholipid syndrome

Subtypes (11): neuronopathy, distal hereditary motor, autosomal dominant 1, hereditary spastic paraplegia 17, neuronopathy, distal hereditary motor, autosomal dominant 8, distal hereditary motor neuropathy type 2, distal hereditary motor neuropathy type 7, neuronopathy, distal hereditary motor, type 9, neuronopathy, distal hereditary motor, type 5, neuronopathy, distal hereditary motor, autosomal dominant 10, neuronopathy, distal hereditary motor, autosomal dominant 11, myopathy, myofibrillar, 13, with rimmed vacuoles, neuronopathy, distal hereditary motor, autosomal dominant 15

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

64 retrieved; paginated sample, class counts are floors:

23 uncertain significance, 14 pathogenic, 12 conflicting classifications of pathogenicity, 8 pathogenic/likely pathogenic, 5 likely pathogenic, 1 benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
55857	NM_001003800.2(BICD2):c.320C>T (p.Ser107Leu)	BICD2	Pathogenic	criteria provided, multiple submitters, no conflicts
637066	NM_001003800.2(BICD2):c.1604C>T (p.Ala535Val)	BICD2	Pathogenic	no assertion criteria provided
246081	NM_001376.5(DYNC1H1):c.1793G>T (p.Arg598Leu)	DYNC1H1	Pathogenic	criteria provided, multiple submitters, no conflicts
637518	NM_001376.5(DYNC1H1):c.1834G>A (p.Val612Met)	DYNC1H1	Pathogenic	criteria provided, multiple submitters, no conflicts
204303	NM_002180.3(IGHMBP2):c.449+1G>T	IGHMBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217449	NM_002180.3(IGHMBP2):c.983_987del (p.Lys328fs)	IGHMBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217450	NM_002180.3(IGHMBP2):c.1478C>T (p.Thr493Ile)	IGHMBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
521206	NM_002180.3(IGHMBP2):c.439C>T (p.Arg147Ter)	IGHMBP2	Pathogenic	criteria provided, multiple submitters, no conflicts
620136	NM_002180.3(IGHMBP2):c.1336C>T (p.Gln446Ter)	IGHMBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
637262	NM_002180.3(IGHMBP2):c.2362C>T (p.Arg788Ter)	IGHMBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
637263	NM_002180.3(IGHMBP2):c.388C>T (p.Arg130Ter)	IGHMBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
637264	NM_002180.3(IGHMBP2):c.1218del (p.Thr407fs)	IGHMBP2	Pathogenic	criteria provided, single submitter
637269	NM_002180.3(IGHMBP2):c.711+1G>C	IGHMBP2	Pathogenic	criteria provided, single submitter
637270	NM_002180.3(IGHMBP2):c.780del (p.Gln260fs)	IGHMBP2	Pathogenic	criteria provided, single submitter
637277	NM_002180.3(IGHMBP2):c.2598_2601del (p.Lys868fs)	IGHMBP2	Pathogenic	criteria provided, multiple submitters, no conflicts
637947	NM_002180.3(IGHMBP2):c.1615_1623del (p.Ser539_Tyr541del)	IGHMBP2	Pathogenic	criteria provided, single submitter
9118	NM_002180.3(IGHMBP2):c.2611+1G>T	IGHMBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
200939	NM_170707.4(LMNA):c.1057C>T (p.Gln353Ter)	LMNA	Pathogenic	criteria provided, multiple submitters, no conflicts
234619	NM_021625.5(TRPV4):c.290C>G (p.Pro97Arg)	TRPV4	Pathogenic	criteria provided, single submitter
30472	NM_021625.5(TRPV4):c.694C>T (p.Arg232Cys)	TRPV4	Pathogenic	criteria provided, multiple submitters, no conflicts
4999	NM_021625.5(TRPV4):c.943C>T (p.Arg315Trp)	TRPV4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5001	NM_021625.5(TRPV4):c.946C>T (p.Arg316Cys)	TRPV4	Pathogenic	criteria provided, multiple submitters, no conflicts
637065	NM_001003800.2(BICD2):c.565A>T (p.Ile189Phe)	BICD2	Likely pathogenic	criteria provided, single submitter
637515	NM_001376.5(DYNC1H1):c.1195A>G (p.Arg399Gly)	DYNC1H1	Likely pathogenic	criteria provided, single submitter
637517	NM_001376.5(DYNC1H1):c.1808A>T (p.Glu603Val)	DYNC1H1	Likely pathogenic	criteria provided, single submitter
637268	NM_002180.3(IGHMBP2):c.1794C>A (p.Asn598Lys)	IGHMBP2	Likely pathogenic	criteria provided, single submitter
637480	NM_002180.3(IGHMBP2):c.1817G>A (p.Arg606His)	IGHMBP2	Likely pathogenic	criteria provided, single submitter
235235	NM_001003800.2(BICD2):c.269A>G (p.Lys90Arg)	BICD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
637067	NM_001003800.2(BICD2):c.2239C>T (p.Arg747Cys)	BICD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
210883	NM_001376.5(DYNC1H1):c.791G>A (p.Arg264Gln)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 50 · 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
BAG3	Moderate	Autosomal dominant	neuronopathy, distal hereditary motor, autosomal dominant	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BAG3	Orphanet:154	Familial isolated dilated cardiomyopathy
BAG3	Orphanet:199340	BAG3-related myofibrillar myopathy
FIG4	Orphanet:139515	Charcot-Marie-Tooth disease type 4J
FIG4	Orphanet:208441	Bilateral parasagittal parieto-occipital polymicrogyria
FIG4	Orphanet:3472	Yunis-Varon syndrome
FIG4	Orphanet:803	Amyotrophic lateral sclerosis
BICD2	Orphanet:363454	BICD2-related autosomal dominant childhood-onset proximal spinal muscular atrophy
TRPV4	Orphanet:1216	Autosomal dominant congenital benign spinal muscular atrophy
TRPV4	Orphanet:263482	Spondyloepimetaphyseal dysplasia, Maroteaux type
TRPV4	Orphanet:2635	Metatropic dysplasia
TRPV4	Orphanet:431255	Scapuloperoneal spinal muscular atrophy
TRPV4	Orphanet:85169	Familial digital arthropathy-brachydactyly
TRPV4	Orphanet:86820	Familial avascular necrosis of femoral head
TRPV4	Orphanet:93304	Autosomal dominant brachyolmia
TRPV4	Orphanet:93314	Spondylometaphyseal dysplasia, Kozlowski type
TRPV4	Orphanet:99937	Autosomal dominant Charcot-Marie-Tooth disease type 2C
MORC2	Orphanet:466768	Autosomal dominant Charcot-Marie-Tooth disease type 2Z
DYNC1H1	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
DYNC1H1	Orphanet:209341	DYNC1H1-related autosomal dominant childhood-onset proximal spinal muscular atrophy
DYNC1H1	Orphanet:284232	Autosomal dominant Charcot-Marie-Tooth disease type 2O
GARS1	Orphanet:139536	Distal hereditary motor neuropathy type 5
GARS1	Orphanet:99938	Autosomal dominant Charcot-Marie-Tooth disease type 2D
SETX	Orphanet:357043	Amyotrophic lateral sclerosis type 4
SETX	Orphanet:64753	Spinocerebellar ataxia with axonal neuropathy type 2
IGHMBP2	Orphanet:443073	Charcot-Marie-Tooth disease type 2S
IGHMBP2	Orphanet:98920	Spinal muscular atrophy with respiratory distress type 1
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
NEFL	Orphanet:101085	Charcot-Marie-Tooth disease type 1F
NEFL	Orphanet:228374	Charcot-Marie-Tooth disease type 2B5
NEFL	Orphanet:99939	Autosomal dominant Charcot-Marie-Tooth disease type 2E

Cohort genes → proteins

11 cohort genes, 11 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	11

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BAG3	HGNC:939	ENSG00000151929	O95817	BAG family molecular chaperone regulator 3	gencc
FIG4	HGNC:16873	ENSG00000112367	Q92562	Polyphosphoinositide phosphatase	clinvar
BICD2	HGNC:17208	ENSG00000185963	Q8TD16	Protein bicaudal D homolog 2	clinvar
TRPV4	HGNC:18083	ENSG00000111199	Q9HBA0	Transient receptor potential cation channel subfamily V member 4	clinvar
MORC2	HGNC:23573	ENSG00000133422	Q9Y6X9	ATPase MORC2	clinvar
DYNC1H1	HGNC:2961	ENSG00000197102	Q14204	Cytoplasmic dynein 1 heavy chain 1	clinvar
GARS1	HGNC:4162	ENSG00000106105	P41250	Glycine–tRNA ligase	clinvar
SETX	HGNC:445	ENSG00000107290	Q7Z333	Helicase senataxin	clinvar
IGHMBP2	HGNC:5542	ENSG00000132740	P38935	DNA-binding protein SMUBP-2	clinvar
LMNA	HGNC:6636	ENSG00000160789	P02545	Prelamin-A/C	clinvar
NEFL	HGNC:7739	ENSG00000277586	P07196	Neurofilament light polypeptide	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BAG3	BAG family molecular chaperone regulator 3	Co-chaperone and adapter protein that connects different classes of molecular chaperones including heat shock proteins 70 (HSP70s), e.g.
FIG4	Polyphosphoinositide phosphatase	Dual specificity phosphatase component of the PI(3,5)P2 regulatory complex which regulates both the synthesis and turnover of phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2).
BICD2	Protein bicaudal D homolog 2	Acts as an adapter protein linking the dynein motor complex to various cargos and converts dynein from a non-processive to a highly processive motor in the presence of dynactin.
TRPV4	Transient receptor potential cation channel subfamily V member 4	Non-selective calcium permeant cation channel involved in osmotic sensitivity and mechanosensitivity.
MORC2	ATPase MORC2	ATP-dependent chromatin remodeler essential for epigenetic silencing by the HUSH (human silencing hub) complex.
DYNC1H1	Cytoplasmic dynein 1 heavy chain 1	Cytoplasmic dynein 1 acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules.
GARS1	Glycine–tRNA ligase	Catalyzes the ATP-dependent ligation of glycine to the 3’-end of its cognate tRNA, via the formation of an aminoacyl-adenylate intermediate (Gly-AMP).
SETX	Helicase senataxin	ATP-dependent 5’->3’ DNA/RNA helicase that preferentially unwinds RNA substrates over DNA, playing a crucial role in resolving R-loops and promoting transcription termination.
IGHMBP2	DNA-binding protein SMUBP-2	5’ to 3’ helicase that unwinds RNA and DNA duplexes in an ATP-dependent reaction.
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.
NEFL	Neurofilament light polypeptide	Neurofilaments usually contain three intermediate filament proteins: NEFL, NEFM, and NEFH which are involved in the maintenance of neuronal caliber.

Protein-family classification

Druggable: 2 · Difficult: 3 · Unknown: 6 · Druggable fraction: 0.18

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	10.1×	0.472
Scaffold/PPI	1	1.6×	0.654
Transcription factor	2	1.5×	0.654
Enzyme (other)	1	1.1×	0.654
Other/Unknown	6	1.0×	0.654

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BAG3	Scaffold/PPI	no		WW_dom, BAG_domain, WW_dom_sf
FIG4	Other/Unknown	no		SAC_dom, Fig4-like
BICD2	Other/Unknown	no		BICD
TRPV4	Ion channel	yes		Ankyrin_rpt, Ion_trans_dom, TrpV1-4
MORC2	Transcription factor	no		Znf_CW, HATPase_C_sf, Morc_S5
DYNC1H1	Other/Unknown	no		AAA+_ATPase, Dhc_D6_P-loop, Dynein_heavy_tail
GARS1	Enzyme (other)	yes	6.1.1.14	WHEP-TRS_dom, aa-tRNA-synt_IIb, tRNA-synt_gly
SETX	Other/Unknown	no		P-loop_NTPase, DNA2/NAM7_AAA_11, DNA2/NAM7-like_C
IGHMBP2	Transcription factor	no	3.6.4.12	Znf_AN1, R3H_dom, AAA+_ATPase
LMNA	Other/Unknown	no		Lamin_tail_dom, IF_conserved, Lamin_tail_dom_sf
NEFL	Other/Unknown	no		Intermed_filament_DNA-bd, IF_conserved, IF_rod_dom

Expression context

Cohort genes with no expression data: 0.

9 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)	11
unknown	0

Top tissues across cohort

Tissue	Cohort genes
lateral nuclear group of thalamus	3
cartilage tissue	2
mucosa of stomach	2
body of tongue	1
gastrocnemius	1
skeletal muscle tissue of rectus abdominis	1
endothelial cell	1
middle temporal gyrus	1
gingiva	1
gingival epithelium	1
hair follicle	1
lower esophagus mucosa	1
olfactory segment of nasal mucosa	1
cervix squamous epithelium	1
male germ cell	1
sperm	1
cortical plate	1
ganglionic eminence	1
ventricular zone	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BAG3	286	ubiquitous	marker	gastrocnemius, skeletal muscle tissue of rectus abdominis, body of tongue
FIG4	295	ubiquitous	marker	middle temporal gyrus, endothelial cell, lateral nuclear group of thalamus
BICD2	290	ubiquitous	marker	gingival epithelium, gingiva, hair follicle
TRPV4	171	ubiquitous	marker	cartilage tissue, lower esophagus mucosa, olfactory segment of nasal mucosa
MORC2	292	ubiquitous	yes	cervix squamous epithelium, sperm, male germ cell
DYNC1H1	290	ubiquitous	marker	cortical plate, ganglionic eminence, ventricular zone
GARS1	293	ubiquitous	marker	secondary oocyte, cartilage tissue, lateral nuclear group of thalamus
SETX	281	ubiquitous	marker	right testis, calcaneal tendon, left testis
IGHMBP2	189	ubiquitous	yes	mucosa of stomach, esophagogastric junction muscularis propria, lower esophagus muscularis layer
LMNA	295	ubiquitous	marker	nipple, mucosa of stomach, skin of abdomen
NEFL	214	broad	marker	dorsal root ganglion, pons, lateral nuclear group of thalamus

Protein interactions among cohort

Intra-cohort edges: 8.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LMNA	7,173
BAG3	4,957
NEFL	4,644
DYNC1H1	4,215
SETX	3,127
GARS1	2,426
BICD2	2,275
TRPV4	1,948
IGHMBP2	1,265
FIG4	1,257

Intra-cohort edges

A	B	Sources
BAG3	DYNC1H1	intact
BICD2	DYNC1H1	string_interaction
BICD2	NEFL	biogrid_interaction, intact
DYNC1H1	IGHMBP2	string_interaction
FIG4	SETX	string_interaction
GARS1	IGHMBP2	string_interaction
IGHMBP2	MORC2	string_interaction
IGHMBP2	SETX	string_interaction

Structural data

PDB: 8 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DYNC1H1	Q14204	97
LMNA	P02545	28
TRPV4	Q9HBA0	19
GARS1	P41250	14
MORC2	Q9Y6X9	9
IGHMBP2	P38935	4
BICD2	Q8TD16	2
FIG4	Q92562	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NEFL	P07196	73.66
BAG3	O95817	57.98
SETX	Q7Z333	52.93

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 62. Enrichment computed across 11 evidence-associated genes (9 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 9 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
COPI-independent Golgi-to-ER retrograde traffic	2	46.1×	0.050	BICD2, DYNC1H1
Breakdown of the nuclear lamina	1	423.0×	0.070	LMNA
Synthesis of PIPs at the late endosome membrane	1	105.7×	0.070	FIG4
Depolymerization of the Nuclear Lamina	1	84.6×	0.070	LMNA
Synthesis of PIPs at the early endosome membrane	1	79.3×	0.070	FIG4
Synthesis of PIPs at the Golgi membrane	1	70.5×	0.070	FIG4
Initiation of Nuclear Envelope (NE) Reformation	1	66.8×	0.070	LMNA
Ras activation upon Ca2+ influx through NMDA receptor	1	63.4×	0.070	NEFL
Unblocking of NMDA receptors, glutamate binding and activation	1	60.4×	0.070	NEFL
Negative regulation of NMDA receptor-mediated neuronal transmission	1	60.4×	0.070	NEFL
Mitochondrial tRNA aminoacylation	1	57.7×	0.070	GARS1
IRE1alpha activates chaperones	1	57.7×	0.070	LMNA
Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer’s disease models	1	57.7×	0.070	LMNA
Long-term potentiation	1	52.9×	0.070	NEFL
Nuclear Envelope Breakdown	1	50.8×	0.070	LMNA
Cytosolic tRNA aminoacylation	1	48.8×	0.070	GARS1
Fatty acyl-CoA biosynthesis	1	48.8×	0.070	MORC2
TRP channels	1	45.3×	0.070	TRPV4
Cellular response to heat stress	1	43.8×	0.070	BAG3
Regulation of endogenous retroelements	1	40.9×	0.070	MORC2
Unfolded Protein Response (UPR)	1	39.6×	0.070	LMNA
Cellular responses to stress	2	8.2×	0.070	LMNA, BAG3
Cellular responses to stimuli	2	7.0×	0.084	LMNA, BAG3
Assembly and cell surface presentation of NMDA receptors	1	28.2×	0.085	NEFL
Oncogenic MAPK signaling	1	27.6×	0.085	LMNA
Aggrephagy	1	27.6×	0.085	DYNC1H1
XBP1(S) activates chaperone genes	1	23.9×	0.094	LMNA
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	1	21.5×	0.101	DYNC1H1
Signaling by BRAF and RAF1 fusions	1	18.9×	0.104	LMNA
Regulation of endogenous retroelements by the Human Silencing Hub (HUSH) complex	1	18.1×	0.104	MORC2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 10 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
retrograde axonal transport	2	306.4×	0.003	DYNC1H1, NEFL
nuclear migration	2	146.5×	0.007	DYNC1H1, LMNA
spinal cord development	2	102.1×	0.009	NEFL, BAG3
striated muscle cell apoptotic process	1	1685.2×	0.011	BAG3
hyperosmotic salinity response	1	1685.2×	0.011	TRPV4
intermediate filament polymerization or depolymerization	1	1685.2×	0.011	NEFL
positive regulation of termination of DNA-templated transcription	1	1685.2×	0.011	SETX
blood vessel endothelial cell delamination	1	1685.2×	0.011	TRPV4
cellular response to heat	2	68.8×	0.011	TRPV4, BAG3
vasopressin secretion	1	842.6×	0.012	TRPV4
positive regulation of striated muscle contraction	1	842.6×	0.012	TRPV4
regulation of response to osmotic stress	1	842.6×	0.012	TRPV4
mitochondrial glycyl-tRNA aminoacylation	1	842.6×	0.012	GARS1
microtubule anchoring at microtubule organizing center	1	842.6×	0.012	BICD2
calcium ion import into cytosol	1	842.6×	0.012	TRPV4
response to sodium arsenite	1	842.6×	0.012	NEFL
response to acrylamide	1	842.6×	0.012	NEFL
negative regulation of striated muscle cell apoptotic process	1	561.7×	0.012	BAG3
diadenosine tetraphosphate biosynthetic process	1	561.7×	0.012	GARS1
neurofilament bundle assembly	1	561.7×	0.012	NEFL
cellular hypotonic salinity response	1	561.7×	0.012	TRPV4
positive regulation of macrophage inflammatory protein 1 alpha production	1	561.7×	0.012	TRPV4
protein transport along microtubule	1	561.7×	0.012	BAG3
DNA double-strand break attachment to nuclear envelope	1	561.7×	0.012	LMNA
positive regulation of termination of RNA polymerase II transcription, poly(A)-coupled	1	561.7×	0.012	SETX
establishment or maintenance of microtubule cytoskeleton polarity	1	421.3×	0.014	LMNA
minus-end-directed organelle transport along microtubule	1	421.3×	0.014	BICD2
positive regulation of neuron projection development	2	27.4×	0.014	FIG4, SETX
positive regulation of microtubule depolymerization	1	337.0×	0.015	TRPV4
regulation of axon diameter	1	337.0×	0.015	NEFL

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 3 · Phased (≥1): 4 · Undrugged: 7

Druggability breadth: 5 of 11 evidence-associated genes (45%) 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
LMNA	BEPRIDIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LMNA	823	4
TRPV4	6	3
DYNC1H1	1	2
GARS1	1	3
BAG3	0	0
FIG4	0	0
BICD2	0	0
MORC2	0	0
SETX	0	0
IGHMBP2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	LMNA
PHENYLBUTAZONE	4	LMNA
CEFOTAXIME SODIUM	4	LMNA
DIENESTROL	4	LMNA
IFOSFAMIDE	4	LMNA
PROGESTERONE	4	LMNA
CLOTRIMAZOLE	4	LMNA
DAPSONE	4	LMNA
AMINOCAPROIC ACID	4	LMNA
FLUCONAZOLE	4	LMNA
COLCHICINE	4	LMNA
NABUMETONE	4	LMNA
OXAPROZIN	4	LMNA
BUMETANIDE	4	LMNA
GLIPIZIDE	4	LMNA
BROMFENAC	4	LMNA
ROPIVACAINE	4	LMNA
TIZANIDINE	4	LMNA
METAXALONE	4	LMNA
CARBAMAZEPINE	4	LMNA
SALMETEROL XINAFOATE	4	LMNA
AMIODARONE HYDROCHLORIDE	4	LMNA
METHYL SALICYLATE	4	LMNA
DIBUCAINE	4	LMNA
PHENELZINE	4	LMNA
HYDROCORTISONE ACETATE	4	LMNA
BRETYLIUM TOSYLATE	4	LMNA
IMIPRAMINE	4	LMNA
FURAZOLIDONE	4	LMNA
DROPERIDOL	4	LMNA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
TRPV4	99	Binding:94, Functional:5
LMNA	12	Binding:9, Functional:3
BAG3	8	Binding:8
GARS1	8	Binding:8
DYNC1H1	7	Binding:7

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GARS1	6.1.1.14	glycine-tRNA ligase
IGHMBP2	3.6.4.12	DNA helicase

Pharmacogenomics

Cohort genes with a PharmGKB record: 11; 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)
BEPRIDIL	4	LMNA
PHENYLBUTAZONE	4	LMNA
CEFOTAXIME SODIUM	4	LMNA
DIENESTROL	4	LMNA
IFOSFAMIDE	4	LMNA
PROGESTERONE	4	LMNA
CLOTRIMAZOLE	4	LMNA
DAPSONE	4	LMNA
AMINOCAPROIC ACID	4	LMNA
FLUCONAZOLE	4	LMNA
COLCHICINE	4	LMNA
NABUMETONE	4	LMNA
OXAPROZIN	4	LMNA
BUMETANIDE	4	LMNA
GLIPIZIDE	4	LMNA
BROMFENAC	4	LMNA
ROPIVACAINE	4	LMNA
TIZANIDINE	4	LMNA
METAXALONE	4	LMNA
CARBAMAZEPINE	4	LMNA
SALMETEROL XINAFOATE	4	LMNA
AMIODARONE HYDROCHLORIDE	4	LMNA
METHYL SALICYLATE	4	LMNA
DIBUCAINE	4	LMNA
PHENELZINE	4	LMNA
HYDROCORTISONE ACETATE	4	LMNA
BRETYLIUM TOSYLATE	4	LMNA
IMIPRAMINE	4	LMNA
FURAZOLIDONE	4	LMNA
DROPERIDOL	4	LMNA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	LMNA
B	Phased (≥1) drug, not yet approved	3	TRPV4, DYNC1H1, GARS1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	7	BAG3, FIG4, BICD2, MORC2, SETX, IGHMBP2, NEFL

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
BAG3	8	—
FIG4	0	—
BICD2	0	—
MORC2	0	—
SETX	0	—
IGHMBP2	0	—
NEFL	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.