Auditory neuropathy
diseaseOn this page
Also known as ANSDauditory dys-synchronyauditory neuropathy spectrum disorderfamilial auditory neuropathyprogressive auditory neuropathy
Summary
Auditory neuropathy (MONDO:0021944) is a disease (an umbrella term covering 5 Mondo subtypes) with 20 cohort genes and 4 clinical trials.
At a glance
- Umbrella term: 5 Mondo subtypes
- Cohort genes: 20
- ClinVar variants: 56
- Clinical trials: 4
Clinical features
No curated clinical features (Orphanet) for this disease.
Identifiers
Disease identifiers
| Field | Value |
|---|---|
| Canonical name | auditory neuropathy |
| Mondo ID | MONDO:0021944 |
| MeSH | C538268 |
| OMIM | 609129 |
| NCIT | C116364 |
| SNOMED CT | 443805006 |
| UMLS | C1852271 |
| MedGen | 338895 |
| GARD | 0009274 |
| Is cancer (heuristic) | no |
Also known as: ANSD · auditory dys-synchrony · auditory neuropathy · auditory neuropathy spectrum disorder · familial auditory neuropathy · progressive auditory neuropathy
Data availability: 56 ClinVar variants · 1 GenCC gene-disease record · 1 cell line.
Disease family
An umbrella term covering 5 Mondo subtypes.
Classification path: disease › human disease › disease by body system or component › auditory system disorder › hearing disorder › hearing loss disorder › auditory neuropathy
Related subtypes (10): Johanson-Blizzard syndrome, noise induced hearing loss, nonsyndromic genetic hearing loss, sudden hearing loss disorder, sensorineural hearing loss disorder, conductive hearing loss disorder, central hearing loss, X-linked deafness, hearing loss, mixed conductive-sensorineural, drug-induced hearing loss
Subtypes (5): X-linked hereditary sensory and autonomic neuropathy with hearing loss, autosomal recessive nonsyndromic hearing loss 9, autosomal dominant auditory neuropathy 1, auditory neuropathy, autosomal dominant 3, auditory neuropathy, autosomal dominant 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
56 retrieved; paginated sample, class counts are floors:
33 likely pathogenic, 11 pathogenic, 7 conflicting classifications of pathogenicity, 3 uncertain significance, 1 pathogenic/likely pathogenic, 1 drug response
| ClinVar | Variant (HGVS) | Gene | Classification | Review |
|---|---|---|---|---|
| 2683863 | NM_001127222.2(CACNA1A):c.-5_10del (p.Met1_Phe4del) | CACNA1A | Pathogenic | criteria provided, single submitter |
| 2683871 | NM_000260.4(MYO7A):c.2070dup (p.Gly691fs) | MYO7A | Pathogenic | criteria provided, single submitter |
| 2683878 | NM_006158.5(NEFL):c.760del (p.Leu254fs) | NEFL | Pathogenic | criteria provided, single submitter |
| 2683890 | NM_130837.3(OPA1):c.1366G>C (p.Gly456Arg) | OPA1 | Pathogenic | criteria provided, single submitter |
| 2683861 | NM_194248.3(OTOF):c.4225A>T (p.Lys1409Ter) | OTOF | Pathogenic | criteria provided, single submitter |
| 2683865 | NM_194323.3(OTOF):c.3532del (p.Val1178fs) | OTOF | Pathogenic | criteria provided, single submitter |
| 2683866 | NM_194248.3(OTOF):c.3399C>A (p.Tyr1133Ter) | OTOF | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 2683870 | NM_194248.3(OTOF):c.4033C>T (p.Gln1345Ter) | OTOF | Pathogenic | criteria provided, single submitter |
| 2683872 | NM_194248.3(OTOF):c.2377G>T (p.Glu793Ter) | OTOF | Pathogenic | criteria provided, single submitter |
| 2683873 | NM_194248.3(OTOF):c.765+1G>C | OTOF | Pathogenic | criteria provided, single submitter |
| 2683880 | NM_194248.3(OTOF):c.5450G>A (p.Trp1817Ter) | OTOF | Pathogenic | criteria provided, single submitter |
| 2683891 | NM_194248.3(OTOF):c.3321dup (p.Ile1108fs) | OTOF | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 2683856 | NM_004208.4(AIFM1):c.1415C>T (p.Ala472Val) | AIFM1 | Likely pathogenic | criteria provided, single submitter |
| 2683874 | NM_004208.4(AIFM1):c.1408A>T (p.Thr470Ser) | AIFM1 | Likely pathogenic | criteria provided, single submitter |
| 2683879 | NM_004208.4(AIFM1):c.902A>T (p.Lys301Ile) | AIFM1 | Likely pathogenic | criteria provided, single submitter |
| 2683882 | NM_004208.4(AIFM1):c.1394C>T (p.Ala465Val) | AIFM1 | Likely pathogenic | criteria provided, single submitter |
| 2683877 | NM_001792.5(CDH2):c.1805C>G (p.Ala602Gly) | CDH2 | Likely pathogenic | criteria provided, single submitter |
| 2683883 | NM_004984.4(KIF5A):c.2396A>G (p.Lys799Arg) | KIF5A | Likely pathogenic | criteria provided, single submitter |
| 2683864 | NM_014874.4(MFN2):c.754A>G (p.Asn252Asp) | MFN2 | Likely pathogenic | criteria provided, single submitter |
| 2683857 | NM_000260.4(MYO7A):c.580C>T (p.Pro194Ser) | MYO7A | Likely pathogenic | criteria provided, single submitter |
| 2637069 | NM_000435.3(NOTCH3):c.2129A>G (p.Tyr710Cys) | NOTCH3 | Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 2683875 | NM_000435.3(NOTCH3):c.709G>T (p.Val237Leu) | NOTCH3 | Likely pathogenic | criteria provided, single submitter |
| 2683867 | NM_130837.3(OPA1):c.1498C>G (p.Arg500Gly) | OPA1 | Likely pathogenic | criteria provided, single submitter |
| 2683885 | NM_130837.3(OPA1):c.2803_2807del (p.Phe935fs) | OPA1 | Likely pathogenic | criteria provided, single submitter |
| 1185100 | NM_194248.3(OTOF):c.2406+2dup | OTOF | Likely pathogenic | criteria provided, single submitter |
| 1185101 | NM_194248.3(OTOF):c.2610_2615dup (p.Leu870_Leu871dup) | OTOF | Likely pathogenic | criteria provided, single submitter |
| 1185622 | NM_194248.3(OTOF):c.5209ATC[1] (p.Ile1738del) | OTOF | Likely pathogenic | criteria provided, single submitter |
| 2683859 | NM_194248.3(OTOF):c.1539_1554del (p.His513fs) | OTOF | Likely pathogenic | criteria provided, single submitter |
| 2683860 | NM_194248.3(OTOF):c.5330A>G (p.Asp1777Gly) | OTOF | Likely pathogenic | criteria provided, single submitter |
| 2683868 | NM_194248.3(OTOF):c.2688del (p.Lys896fs) | OTOF | Likely pathogenic | criteria provided, single submitter |
Genes & proteins
Mendelian disease overlap and somatic drivers
GenCC: 5 · Orphanet: 73 · 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 |
|---|---|---|---|---|
| DIAPH3 | Limited | Autosomal dominant | autosomal dominant auditory neuropathy 1 | 5 |
Orphanet rare-disease linkage (cohort genes)
| Gene | Orphanet ID | Rare disease |
|---|---|---|
| DIAPH3 | Orphanet:90635 | Rare autosomal dominant non-syndromic sensorineural deafness type DFNA |
| TWNK | Orphanet:1186 | Infantile-onset spinocerebellar ataxia |
| TWNK | Orphanet:254892 | Autosomal dominant progressive external ophthalmoplegia |
| TWNK | Orphanet:363534 | Mitochondrial DNA depletion syndrome, hepatocerebrorenal form |
| TWNK | Orphanet:642945 | Perrault syndrome type 1 |
| TWNK | Orphanet:642976 | Perrault syndrome type 2 |
| TWNK | Orphanet:70595 | Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome |
| TIMM8A | Orphanet:52368 | Mohr-Tranebjaerg syndrome |
| MED12 | Orphanet:1415 | Hardikar syndrome |
| MED12 | Orphanet:293707 | Blepharophimosis-intellectual disability syndrome, MKB type |
| MED12 | Orphanet:776 | Lujan-Fryns syndrome |
| MED12 | Orphanet:777 | X-linked non-syndromic intellectual disability |
| MED12 | Orphanet:93932 | FG syndrome type 1 |
| WFS1 | Orphanet:3463 | Wolfram syndrome |
| WFS1 | Orphanet:411590 | Wolfram-like syndrome |
| WFS1 | Orphanet:90635 | Rare autosomal dominant non-syndromic sensorineural deafness type DFNA |
| WFS1 | Orphanet:98991 | Early-onset nuclear cataract |
| CACNA1A | Orphanet:2131 | Alternating hemiplegia of childhood |
| CACNA1A | Orphanet:2382 | Lennox-Gastaut syndrome |
| CACNA1A | Orphanet:442835 | Non-specific early-onset epileptic encephalopathy |
| CACNA1A | Orphanet:569 | Familial or sporadic hemiplegic migraine |
| CACNA1A | Orphanet:71518 | Benign paroxysmal torticollis of infancy |
| CACNA1A | Orphanet:97 | Familial paroxysmal ataxia |
| CACNA1A | Orphanet:98758 | Spinocerebellar ataxia type 6 |
| TP63 | Orphanet:1072 | Ankyloblepharon filiforme adnatum-cleft palate syndrome |
| TP63 | Orphanet:141291 | Cleft lip and alveolus |
| TP63 | Orphanet:1896 | EEC syndrome |
| TP63 | Orphanet:199302 | Isolated cleft lip |
| TP63 | Orphanet:199306 | Cleft lip/palate |
| TP63 | Orphanet:2440 | Isolated split hand-split foot malformation |
| TP63 | Orphanet:69085 | Limb-mammary syndrome |
| TP63 | Orphanet:93930 | Classic bladder exstrophy |
| TP63 | Orphanet:978 | ADULT syndrome |
| SLC52A3 | Orphanet:572550 | RFVT3-related riboflavin transporter deficiency |
| MFN2 | Orphanet:2398 | Multiple symmetric lipomatosis |
| MFN2 | Orphanet:64751 | Hereditary motor and sensory neuropathy type 5 |
| MFN2 | Orphanet:90118 | Severe early-onset axonal neuropathy due to MFN2 deficiency |
| MFN2 | Orphanet:90120 | Hereditary motor and sensory neuropathy type 6 |
| MFN2 | Orphanet:99947 | Autosomal dominant Charcot-Marie-Tooth disease type 2A2 |
| CDH2 | Orphanet:293910 | Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant |
| 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 |
| FDXR | Orphanet:542585 | Auditory neuropathy-optic atrophy syndrome |
Cohort genes → proteins
20 cohort genes, 20 distinct canonical proteins.
Evidence partition
| Subset | Genes |
|---|---|
| multi_evidence | 20 |
Cohort genes (full)
| Symbol | HGNC | Ensembl | UniProt | Name | Evidence |
|---|---|---|---|---|---|
| DIAPH3 | HGNC:15480 | ENSG00000139734 | Q9NSV4 | Protein diaphanous homolog 3 | gencc,clinvar |
| TWNK | HGNC:1160 | ENSG00000107815 | Q96RR1 | Twinkle mtDNA helicase | clinvar |
| TIMM8A | HGNC:11817 | ENSG00000126953 | O60220 | Mitochondrial import inner membrane translocase subunit Tim8 A | clinvar |
| MED12 | HGNC:11957 | ENSG00000184634 | Q93074 | Mediator of RNA polymerase II transcription subunit 12 | clinvar |
| WFS1 | HGNC:12762 | ENSG00000109501 | O76024 | Wolframin | clinvar |
| CACNA1A | HGNC:1388 | ENSG00000141837 | O00555 | Voltage-dependent P/Q-type calcium channel subunit alpha-1A | clinvar |
| TP63 | HGNC:15979 | ENSG00000073282 | Q9H3D4 | Tumor protein 63 | clinvar |
| SLC52A3 | HGNC:16187 | ENSG00000101276 | Q9NQ40 | Solute carrier family 52, riboflavin transporter, member 3 | clinvar |
| MFN2 | HGNC:16877 | ENSG00000116688 | O95140 | Mitofusin-2 | clinvar |
| CDH2 | HGNC:1759 | ENSG00000170558 | P19022 | Cadherin-2 | clinvar |
| TRPV4 | HGNC:18083 | ENSG00000111199 | Q9HBA0 | Transient receptor potential cation channel subfamily V member 4 | clinvar |
| FDXR | HGNC:3642 | ENSG00000161513 | P22570 | NADPH:adrenodoxin oxidoreductase, mitochondrial | clinvar |
| KIF5A | HGNC:6323 | ENSG00000155980 | Q12840 | Kinesin heavy chain isoform 5A | clinvar |
| MT-RNR1 | HGNC:7470 | ENSG00000211459 | A0A0C5B5G6 | Mitochondrial-derived peptide MOTS-c | clinvar |
| MYO7A | HGNC:7606 | ENSG00000137474 | Q13402 | Unconventional myosin-VIIa | clinvar |
| NEFL | HGNC:7739 | ENSG00000277586 | P07196 | Neurofilament light polypeptide | clinvar |
| NOTCH3 | HGNC:7883 | ENSG00000074181 | Q9UM47 | Neurogenic locus notch homolog protein 3 | clinvar |
| OPA1 | HGNC:8140 | ENSG00000198836 | O60313 | Dynamin-like GTPase OPA1, mitochondrial | clinvar |
| OTOF | HGNC:8515 | ENSG00000115155 | Q9HC10 | Otoferlin | clinvar |
| AIFM1 | HGNC:8768 | ENSG00000156709 | O95831 | Apoptosis-inducing factor 1, mitochondrial | clinvar |
Cohort function summary
Lead sentence per gene, UniProt-curated.
| Symbol | Protein name | Function (lead sentence) |
|---|---|---|
| DIAPH3 | Protein diaphanous homolog 3 | Actin nucleation and elongation factor required for the assembly of F-actin structures, such as actin cables and stress fibers. |
| TWNK | Twinkle mtDNA helicase | Mitochondrial helicase involved in mtDNA replication and repair. |
| TIMM8A | Mitochondrial import inner membrane translocase subunit Tim8 A | Mitochondrial intermembrane chaperone that participates in the import and insertion of some multi-pass transmembrane proteins into the mitochondrial inner membrane. |
| MED12 | Mediator of RNA polymerase II transcription subunit 12 | Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. |
| WFS1 | Wolframin | Participates in the regulation of cellular Ca(2+) homeostasis, at least partly, by modulating the filling state of the endoplasmic reticulum Ca(2+) store. |
| CACNA1A | Voltage-dependent P/Q-type calcium channel subunit alpha-1A | Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene exp… |
| TP63 | Tumor protein 63 | Acts as a sequence specific DNA binding transcriptional activator or repressor. |
| SLC52A3 | Solute carrier family 52, riboflavin transporter, member 3 | Plasma membrane transporter mediating the uptake by cells of the water soluble vitamin B2/riboflavin that plays a key role in biochemical oxidation-reduction reactions of the carbohydrate, lipid, and amino acid metabolism. |
| MFN2 | Mitofusin-2 | Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion. |
| CDH2 | Cadherin-2 | Calcium-dependent cell adhesion protein; preferentially mediates homotypic cell-cell adhesion by dimerization with a CDH2 chain from another cell. |
| TRPV4 | Transient receptor potential cation channel subfamily V member 4 | Non-selective calcium permeant cation channel involved in osmotic sensitivity and mechanosensitivity. |
| FDXR | NADPH:adrenodoxin oxidoreductase, mitochondrial | Serves as the first electron transfer protein in all the mitochondrial P450 systems including cholesterol side chain cleavage in all steroidogenic tissues, steroid 11-beta hydroxylation in the adrenal cortex, 25-OH-vitamin D3-24 hydroxylat… |
| KIF5A | Kinesin heavy chain isoform 5A | Microtubule-dependent motor required for slow axonal transport of neurofilament proteins (NFH, NFM and NFL). |
| MT-RNR1 | Mitochondrial-derived peptide MOTS-c | Regulates insulin sensitivity and metabolic homeostasis. |
| MYO7A | Unconventional myosin-VIIa | Myosins are actin-based motor molecules with ATPase activity. |
| NEFL | Neurofilament light polypeptide | Neurofilaments usually contain three intermediate filament proteins: NEFL, NEFM, and NEFH which are involved in the maintenance of neuronal caliber. |
| NOTCH3 | Neurogenic locus notch homolog protein 3 | Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 to regulate cell-fate determination. |
| OPA1 | Dynamin-like GTPase OPA1, mitochondrial | Dynamin-related GTPase that is essential for normal mitochondrial morphology by mediating fusion of the mitochondrial inner membranes, regulating cristae morphology and maintaining respiratory chain function. |
| OTOF | Otoferlin | Key calcium ion sensor involved in the Ca(2+)-triggered synaptic vesicle-plasma membrane fusion and in the control of neurotransmitter release at these output synapses. |
| AIFM1 | Apoptosis-inducing factor 1, mitochondrial | Functions both as NADH oxidoreductase and as regulator of apoptosis. |
Protein-family classification
Druggable: 5 · Difficult: 3 · Unknown: 12 · Druggable fraction: 0.25
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 | 2 | 11.2× | 0.068 |
| Enzyme (other) | 3 | 1.8× | 0.539 |
| Scaffold/PPI | 2 | 1.7× | 0.539 |
| Other/Unknown | 12 | 1.1× | 0.554 |
| Transcription factor | 1 | 0.4× | 0.924 |
Per-gene assignment
| Symbol | Family | Druggable? | EC | InterPro (top 3) |
|---|---|---|---|---|
| DIAPH3 | Other/Unknown | no | FH3_dom, GTPase-bd, ARM-like | |
| TWNK | Enzyme (other) | yes | 3.6.4.12 | DNA_helicase_DnaB-like_C, Twinkle-like, P-loop_NTPase |
| TIMM8A | Other/Unknown | no | Tim10-like, Tim10-like_dom_sf | |
| MED12 | Other/Unknown | no | Mediator_Med12, Mediator_Med12_catenin-bd, Mediator_Med12_LCEWAV | |
| WFS1 | Other/Unknown | no | TPR-like_helical_dom_sf, Wolframin, Wolframin_fam | |
| CACNA1A | Ion channel | yes | VDCCAlpha1, CACNA1A, Ion_trans_dom | |
| TP63 | Transcription factor | no | SAM, p53_tumour_suppressor, p53-like_TF_DNA-bd_sf | |
| SLC52A3 | Other/Unknown | no | Riboflavin_transptr | |
| MFN2 | Other/Unknown | no | Fzo/mitofusin_HR2, Mitofusin_fam, P-loop_NTPase | |
| CDH2 | Other/Unknown | no | Cadherin_Y-type_LIR, Cadherin-like_dom, Cadherin_pro_dom | |
| TRPV4 | Ion channel | yes | Ankyrin_rpt, Ion_trans_dom, TrpV1-4 | |
| FDXR | Other/Unknown | no | Ferredox_Rdtase_adrenod, FAD/NAD-bd_sf, Ferredox_Rdtase | |
| KIF5A | Other/Unknown | no | Kinesin_motor_dom, Kinesin_motor_CS, P-loop_NTPase | |
| MT-RNR1 | Other/Unknown | no | MT-RNR1 | |
| MYO7A | Scaffold/PPI | no | IQ_motif_EF-hand-BS, FERM_domain, MyTH4_dom | |
| NEFL | Other/Unknown | no | Intermed_filament_DNA-bd, IF_conserved, IF_rod_dom | |
| NOTCH3 | Scaffold/PPI | no | EGF-type_Asp/Asn_hydroxyl_site, EGF, Notch_dom | |
| OPA1 | Enzyme (other) | yes | 3.6.5.5 | Dynamin_GTPase, Dynamin, P-loop_NTPase |
| OTOF | Other/Unknown | no | C2_dom, Ferlin_B-domain, FerIin_dom | |
| AIFM1 | Enzyme (other) | yes | 7.1.1.2 | FAD/NAD-linked_Rdtase_dimer_sf, FAD/NAD-binding_dom, AIF_C |
Expression context
Cohort genes with no expression data: 0.
19 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) | 20 |
| unknown | 0 |
Top tissues across cohort
| Tissue | Cohort genes |
|---|---|
| right adrenal gland | 3 |
| right adrenal gland cortex | 3 |
| ventricular zone | 2 |
| endothelial cell | 2 |
| mucosa of transverse colon | 2 |
| left ovary | 2 |
| cerebellar hemisphere | 2 |
| right hemisphere of cerebellum | 2 |
| apex of heart | 2 |
| heart left ventricle | 2 |
| male germ cell | 1 |
| sperm | 1 |
| gastrocnemius | 1 |
| male germ line stem cell (sensu Vertebrata) in testis | 1 |
| tendon of biceps brachii | 1 |
| primordial germ cell in gonad | 1 |
| body of uterus | 1 |
| right ovary | 1 |
| cerebellar cortex | 1 |
| skin of hip | 1 |
Per-gene tissue summary (top 30)
| Symbol | Bgee breadth | FANTOM5 breadth | SCXA | Top tissues |
|---|---|---|---|---|
| DIAPH3 | 204 | ubiquitous | marker | sperm, ventricular zone, male germ cell |
| TWNK | 211 | ubiquitous | yes | male germ line stem cell (sensu Vertebrata) in testis, tendon of biceps brachii, gastrocnemius |
| TIMM8A | 204 | ubiquitous | marker | endothelial cell, primordial germ cell in gonad, mucosa of transverse colon |
| MED12 | 281 | ubiquitous | marker | right adrenal gland cortex, right adrenal gland, left ovary |
| WFS1 | 280 | ubiquitous | marker | right ovary, left ovary, body of uterus |
| CACNA1A | 237 | broad | marker | cerebellar hemisphere, right hemisphere of cerebellum, cerebellar cortex |
| TP63 | 207 | broad | marker | upper leg skin, skin of hip, upper arm skin |
| SLC52A3 | 169 | broad | marker | right testis, mucosa of transverse colon, left testis |
| MFN2 | 297 | ubiquitous | marker | apex of heart, heart left ventricle, cardiac ventricle |
| CDH2 | 233 | ubiquitous | marker | heart right ventricle, ventricular zone, stromal cell of endometrium |
| TRPV4 | 171 | ubiquitous | marker | cartilage tissue, lower esophagus mucosa, olfactory segment of nasal mucosa |
| FDXR | 208 | ubiquitous | marker | right adrenal gland cortex, right adrenal gland, left adrenal gland cortex |
| KIF5A | 198 | broad | marker | right frontal lobe, right hemisphere of cerebellum, cerebellar hemisphere |
| MT-RNR1 | 134 | ubiquitous | marker | granulocyte, monocyte, prefrontal cortex |
| MYO7A | 186 | broad | marker | right adrenal gland cortex, right adrenal gland, left adrenal gland |
| NEFL | 214 | broad | marker | dorsal root ganglion, pons, lateral nuclear group of thalamus |
| NOTCH3 | 273 | ubiquitous | marker | popliteal artery, tibial artery, right coronary artery |
| OPA1 | 288 | ubiquitous | marker | adrenal tissue, calcaneal tendon, endothelial cell |
| OTOF | 109 | tissue_specific | marker | nucleus accumbens, putamen, caudate nucleus |
| AIFM1 | 273 | ubiquitous | marker | apex of heart, adult mammalian kidney, heart left ventricle |
Protein interactions among cohort
Intra-cohort edges: 4.
Hub genes (top 10 by interactor count)
| Symbol | Interactor count |
|---|---|
| CDH2 | 5,623 |
| AIFM1 | 4,780 |
| NEFL | 4,644 |
| NOTCH3 | 4,403 |
| MFN2 | 3,853 |
| WFS1 | 3,409 |
| MED12 | 3,322 |
| KIF5A | 3,241 |
| TP63 | 2,893 |
| OPA1 | 2,630 |
Intra-cohort edges
| A | B | Sources |
|---|---|---|
| MFN2 | OPA1 | string_interaction |
| OTOF | SLC52A3 | string_interaction |
| OTOF | WFS1 | string_interaction |
| TIMM8A | WFS1 | intact |
Structural data
PDB: 13 · AlphaFold-only: 7 · No structure: 0
Cohort genes with PDB structures (top 30)
| Symbol | UniProt | PDB entries |
|---|---|---|
| TP63 | Q9H3D4 | 26 |
| AIFM1 | O95831 | 26 |
| TRPV4 | Q9HBA0 | 19 |
| OPA1 | O60313 | 11 |
| NOTCH3 | Q9UM47 | 6 |
| CACNA1A | O00555 | 4 |
| KIF5A | Q12840 | 4 |
| MED12 | Q93074 | 3 |
| MFN2 | O95140 | 3 |
| DIAPH3 | Q9NSV4 | 2 |
| TWNK | Q96RR1 | 2 |
| SLC52A3 | Q9NQ40 | 1 |
| MYO7A | Q13402 | 1 |
AlphaFold-only cohort genes (top 30 by pLDDT)
| Symbol | UniProt | pLDDT |
|---|---|---|
| FDXR | P22570 | 91.66 |
| TIMM8A | O60220 | 87.07 |
| CDH2 | P19022 | 79.68 |
| OTOF | Q9HC10 | 76.98 |
| WFS1 | O76024 | 73.85 |
| NEFL | P07196 | 73.66 |
| MT-RNR1 | A0A0C5B5G6 | 72.00 |
Function
Pathway analysis
Distinct Reactome pathways touched by cohort: 140. Enrichment computed across 20 evidence-associated genes (19 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 19 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| Pathway | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| Electron transport from NADPH to Ferredoxin | 1 | 150.3× | 0.108 | FDXR |
| FASTK family proteins regulate processing and stability of mitochondrial RNAs | 1 | 150.3× | 0.108 | MT-RNR1 |
| Defective LFNG causes SCDO3 | 1 | 120.2× | 0.108 | NOTCH3 |
| Defective CYP11A1 causes AICSR | 1 | 120.2× | 0.108 | FDXR |
| tRNA processing in the mitochondrion | 1 | 120.2× | 0.108 | MT-RNR1 |
| Miro GTPase Cycle | 1 | 120.2× | 0.108 | MFN2 |
| Regulation of Apoptosis | 1 | 100.2× | 0.108 | OPA1 |
| Pre-NOTCH Processing in the Endoplasmic Reticulum | 1 | 100.2× | 0.108 | NOTCH3 |
| Vitamin B2 (riboflavin) metabolism | 1 | 85.9× | 0.108 | SLC52A3 |
| RHOT2 GTPase cycle | 1 | 85.9× | 0.108 | MFN2 |
| Mitochondrial RNA degradation | 1 | 85.9× | 0.108 | MT-RNR1 |
| Noncanonical activation of NOTCH3 | 1 | 75.1× | 0.108 | NOTCH3 |
| rRNA processing in the mitochondrion | 1 | 66.8× | 0.108 | MT-RNR1 |
| Activation of PUMA and translocation to mitochondria | 1 | 60.1× | 0.108 | TP63 |
| Strand-asynchronous mitochondrial DNA replication | 1 | 60.1× | 0.108 | TWNK |
| Mitophagy | 1 | 54.6× | 0.108 | MFN2 |
| RHO GTPases activate KTN1 | 1 | 54.6× | 0.108 | KIF5A |
| Presynaptic depolarization and calcium channel opening | 1 | 50.1× | 0.108 | CACNA1A |
| TP53 Regulates Transcription of Caspase Activators and Caspases | 1 | 50.1× | 0.108 | TP63 |
| TP53 Regulates Transcription of Death Receptors and Ligands | 1 | 50.1× | 0.108 | TP63 |
| Metabolic disorders of biological oxidation enzymes | 1 | 46.2× | 0.108 | FDXR |
| rRNA modification in the mitochondrion | 1 | 46.2× | 0.108 | MT-RNR1 |
| Regulation of MITF-M-dependent genes involved in extracellular matrix, focal adhesion and epithelial-to-mesenchymal transition | 1 | 46.2× | 0.108 | CDH2 |
| Mitochondrial iron-sulfur cluster biogenesis | 1 | 42.9× | 0.108 | FDXR |
| Pregnenolone biosynthesis | 1 | 42.9× | 0.108 | FDXR |
| Regulation of TP53 Activity through Association with Co-factors | 1 | 42.9× | 0.108 | TP63 |
| Sensory processing of sound by inner hair cells of the cochlea | 2 | 17.2× | 0.108 | MYO7A, OTOF |
| Mitochondrial protein degradation | 2 | 12.0× | 0.108 | TWNK, OPA1 |
| Post-translational protein phosphorylation | 2 | 10.5× | 0.108 | WFS1, CDH2 |
| Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) | 2 | 9.1× | 0.108 | WFS1, CDH2 |
GO biological processes by enrichment
Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 20 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 sound | 5 | 25.2× | 4e-04 | DIAPH3, WFS1, SLC52A3, MYO7A, OTOF |
| axonal transport of mitochondrion | 2 | 140.4× | 0.014 | NEFL, OPA1 |
| microtubule polymerization | 2 | 88.7× | 0.016 | DIAPH3, TRPV4 |
| mitochondrial fusion | 2 | 84.3× | 0.016 | MFN2, OPA1 |
| negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway | 2 | 84.3× | 0.016 | WFS1, OPA1 |
| post-anal tail morphogenesis | 2 | 73.3× | 0.017 | MED12, TP63 |
| ectoderm and mesoderm interaction | 1 | 842.6× | 0.022 | TP63 |
| epidermal cell division | 1 | 842.6× | 0.022 | TP63 |
| protein-containing complex remodeling | 1 | 842.6× | 0.022 | DIAPH3 |
| hyperosmotic salinity response | 1 | 842.6× | 0.022 | TRPV4 |
| intermediate filament polymerization or depolymerization | 1 | 842.6× | 0.022 | NEFL |
| pigment granule transport | 1 | 842.6× | 0.022 | MYO7A |
| blood vessel endothelial cell delamination | 1 | 842.6× | 0.022 | TRPV4 |
| mitochondrial inner membrane fusion | 1 | 842.6× | 0.022 | OPA1 |
| calcium ion import across plasma membrane | 2 | 54.4× | 0.022 | CACNA1A, TRPV4 |
| spinal cord development | 2 | 51.1× | 0.022 | MED12, NEFL |
| cell-cell junction assembly | 2 | 44.4× | 0.022 | CDH2, TRPV4 |
| vasopressin secretion | 1 | 421.3× | 0.022 | TRPV4 |
| positive regulation of striated muscle contraction | 1 | 421.3× | 0.022 | TRPV4 |
| regulation of response to osmotic stress | 1 | 421.3× | 0.022 | TRPV4 |
| cloacal septation | 1 | 421.3× | 0.022 | TP63 |
| squamous basal epithelial stem cell differentiation involved in prostate gland acinus development | 1 | 421.3× | 0.022 | TP63 |
| flavin adenine dinucleotide biosynthetic process | 1 | 421.3× | 0.022 | SLC52A3 |
| mesenchymal cell migration | 1 | 421.3× | 0.022 | CDH2 |
| calcium ion import into cytosol | 1 | 421.3× | 0.022 | TRPV4 |
| negative regulation of ATF6-mediated unfolded protein response | 1 | 421.3× | 0.022 | WFS1 |
| response to sodium arsenite | 1 | 421.3× | 0.022 | NEFL |
| response to acrylamide | 1 | 421.3× | 0.022 | NEFL |
| positive regulation of somatic stem cell population maintenance | 1 | 421.3× | 0.022 | TP63 |
| positive regulation of synaptic vesicle clustering | 1 | 421.3× | 0.022 | CDH2 |
Therapeutics
Drug target analysis
Approved (phase 4): 2 · Phase ≥3: 3 · Phased (≥1): 5 · Undrugged: 15
Druggability breadth: 10 of 20 evidence-associated genes (50%) 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 |
|---|---|
| CACNA1A | NIMODIPINE |
| OPA1 | MOMELOTINIB |
Top cohort targets by molecule count
| Symbol | Molecules | Max phase |
|---|---|---|
| TRPV4 | 6 | 3 |
| CACNA1A | 2 | 4 |
| OPA1 | 2 | 4 |
| MED12 | 1 | 2 |
| NOTCH3 | 1 | 2 |
| DIAPH3 | 0 | 0 |
| TWNK | 0 | 0 |
| TIMM8A | 0 | 0 |
| WFS1 | 0 | 0 |
| TP63 | 0 | 0 |
Drugs targeting cohort genes (top 30)
| Molecule | Max phase | Targets in cohort |
|---|---|---|
| NIMODIPINE | 4 | CACNA1A |
| TACRINE | 4 | CACNA1A |
| MOMELOTINIB | 4 | OPA1 |
| CANNABINOL | 3 | TRPV4 |
| TIVANTINIB | 3 | OPA1 |
| MOLIBRESIB | 2 | MED12 |
| TETRAHYDROCANNABIVARIN | 2 | TRPV4 |
| CANNABIDIVARIN | 2 | TRPV4 |
| GSK2798745 | 2 | TRPV4 |
| CANNABIGEROL | 2 | TRPV4 |
| VAREGACESTAT | 2 | NOTCH3 |
| ABT-102 | 1 | TRPV4 |
Bioactivity and enzyme data
Enzyme cohort genes (≥1 EC): 3.
Cohort genes with ChEMBL bioactivity (full, sorted by assay count)
| Symbol | Assays | Type breakdown |
|---|---|---|
| TRPV4 | 99 | Binding:94, Functional:5 |
| CACNA1A | 19 | Binding:18, Functional:1 |
| KIF5A | 8 | Binding:8 |
| MED12 | 6 | Binding:6 |
| CDH2 | 4 | Binding:3, Functional:1 |
| MFN2 | 3 | Binding:3 |
| NOTCH3 | 3 | Binding:3 |
| OPA1 | 2 | Binding:2 |
| AIFM1 | 2 | Binding:2 |
| WFS1 | 1 | Binding:1 |
Cohort enzymes (BRENDA EC)
| Symbol | EC numbers | Names |
|---|---|---|
| TWNK | 3.6.4.12 | DNA helicase |
| OPA1 | 3.6.5.5 | dynamin GTPase |
| AIFM1 | 7.1.1.2 | NADH:ubiquinone reductase (H+-translocating) |
Pharmacogenomics
Cohort genes with a PharmGKB record: 20; with CPIC/DPWG dosing guidelines: 1.
Cohort genes with a CPIC/DPWG dosing guideline
| Symbol | CPIC guidelines |
|---|---|
| MT-RNR1 | 1 |
Chemical tractability of cohort targets
12 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) |
|---|---|---|
| NIMODIPINE | 4 | CACNA1A |
| TACRINE | 4 | CACNA1A |
| MOMELOTINIB | 4 | OPA1 |
| CANNABINOL | 3 | TRPV4 |
| TIVANTINIB | 3 | OPA1 |
| MOLIBRESIB | 2 | MED12 |
| TETRAHYDROCANNABIVARIN | 2 | TRPV4 |
| CANNABIDIVARIN | 2 | TRPV4 |
| GSK2798745 | 2 | TRPV4 |
| CANNABIGEROL | 2 | TRPV4 |
| VAREGACESTAT | 2 | NOTCH3 |
| ABT-102 | 1 | TRPV4 |
Druggability pyramid
Cohort genes binned by druggability tier (high → low):
| Tier | Definition | Genes | Symbols |
|---|---|---|---|
| A | Approved (phase 4 drug) | 2 | CACNA1A, OPA1 |
| B | Phased (≥1) drug, not yet approved | 3 | MED12, TRPV4, NOTCH3 |
| C | Druggable family + PDB, no drug | 2 | TWNK, AIFM1 |
| D | Druggable family + AlphaFold only, no drug | 0 | |
| E | Difficult family or no structure, no drug | 13 | DIAPH3, TIMM8A, WFS1, TP63, SLC52A3, MFN2, CDH2, FDXR, KIF5A, MT-RNR1 (+3 more) |
Undrugged target profiles
15 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).
| Symbol | ChEMBL assays | Drugged partners (top 3) |
|---|---|---|
| DIAPH3 | 0 | — |
| TWNK | 0 | — |
| TIMM8A | 0 | — |
| WFS1 | 1 | — |
| TP63 | 0 | — |
| SLC52A3 | 0 | — |
| MFN2 | 3 | — |
| CDH2 | 4 | — |
| FDXR | 0 | — |
| KIF5A | 8 | — |
| MT-RNR1 | 0 | — |
| MYO7A | 0 | — |
| NEFL | 0 | — |
| OTOF | 0 | — |
| AIFM1 | 2 | — |
Clinical trials & evidence
Clinical trials
Clinical trials: 4.
Phase distribution (across all retrieved trials)
| Phase | Trials |
|---|---|
| Not specified | 3 |
| PHASE1/PHASE2 | 1 |
Top trials by phase / activity
| NCT | Phase | Status | Title |
|---|---|---|---|
| NCT07032038 | PHASE1/PHASE2 | NOT_YET_RECRUITING | First In Human Randomised Trial of Rincell-1 in Adults With a Cochlear Implant |
| NCT01023932 | Not specified | COMPLETED | Auditory Neuropathy and Cochlear Implants |
| NCT05666466 | Not specified | UNKNOWN | Noninvasive Diagnostic Techniques in Determination of Site of Lesion of Auditory Neuropathy Spectrum Disorder |
| NCT06125015 | Not specified | COMPLETED | Unexpected ABR Results in Patients Suspected With Auditory Neuropathy Spectrum Disorder |