Auditory neuropathy: genes and variants

Genes linked to Auditory neuropathy

• OTOF: Otoferlin

  It couples calcium entry to synaptic-vesicle fusion at inner hair-cell ribbon synapses, enabling rapid transmission of acoustic signals to the auditory nerve. Biallelic loss-of-function variants cause DFNB9 auditory neuropathy or nonsyndromic sensorineural hearing loss.

  6 disease-causing and 1 uncertain variants in OTOF are linked to Auditory neuropathy.

• OPA1: Dynamin-like GTPase OPA1, mitochondrial

  A mitochondrial dynamin-related GTPase that fuses inner mitochondrial membranes and shapes cristae. By maintaining mitochondrial architecture and respiratory-chain function, it supports cell energy production, and OPA1 variants cause inherited optic-atrophy syndromes.

  2 disease-causing and 0 uncertain variants in OPA1 are linked to Auditory neuropathy.

• NOTCH3: Neurogenic locus notch homolog protein 3

  Its signaling helps maintain vascular smooth-muscle and mural-cell identity in small arteries. Pathogenic cysteine-altering variants cause CADASIL, with migraine, recurrent ischemic strokes, white-matter disease, and progressive cognitive impairment.

  2 disease-causing and 0 uncertain variants in NOTCH3 are linked to Auditory neuropathy.

• CDH2: Cadherin-2

  It mediates calcium-dependent cell-cell adhesion in neural, cardiac, and mesenchymal tissues and helps organize adherens junctions during development. Heterozygous pathogenic variants can cause a syndromic neurodevelopmental disorder with variable cardiac and craniofacial abnormalities.

  1 disease-causing and 1 uncertain variants in CDH2 are linked to Auditory neuropathy.

• MYO7A: Unconventional myosin-VIIa

  Its actin-based motor supports stereocilia organization in inner-ear hair cells and transport processes in retinal cells. Biallelic pathogenic variants cause Usher syndrome type 1B, while other alleles can cause nonsyndromic hearing loss.

  1 disease-causing and 1 uncertain variants in MYO7A are linked to Auditory neuropathy.

• KIF5A: Kinesin heavy chain isoform 5A

  It drives anterograde transport of organelles and proteins along axonal microtubules and is especially important in long motor neurons. Pathogenic variants can cause hereditary spastic paraplegia, axonal Charcot-Marie-Tooth disease, or amyotrophic lateral sclerosis depending on the affected region and mechanism.

  1 disease-causing and 0 uncertain variants in KIF5A are linked to Auditory neuropathy.

• MFN2: Mitofusin-2

  It promotes outer-mitochondrial-membrane fusion and coordinates mitochondrial transport, distribution, and contacts with other organelles. Pathogenic variants are a major cause of Charcot-Marie-Tooth disease type 2A and related axonal neuropathies.

  1 disease-causing and 0 uncertain variants in MFN2 are linked to Auditory neuropathy.

• TMEM43: Transmembrane protein 43

  A multi-pass membrane protein that helps organize protein complexes at the inner nuclear membrane and retain emerin. It also participates in innate-immune signaling and contributes to electrical coupling in the inner ear, with variants linked to cardiomyopathy and auditory neuropathy.

  0 disease-causing and 28 uncertain variants in TMEM43 are linked to Auditory neuropathy.

Weakly linked (only a few uncertain records): PLP1.

Known disease-causing variants in Auditory neuropathy

Which prediction tools work for Auditory neuropathy

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• CATVariant: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 85 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 82 out of 100

Same protein, different disease

• Autosomal recessive nonsyndromic hearing loss 4 is also caused by OTOF variants; they fall mostly in different places as the Auditory neuropathy variants (21 disease-causing).
• Nonsyndromic genetic hearing loss is also caused by OTOF variants; they fall mostly in different places as the Auditory neuropathy variants (8 disease-causing).
• Bilateral sensorineural hearing impairment is also caused by OTOF variants; they fall mostly in different places as the Auditory neuropathy variants (6 disease-causing).
• Hearing loss is also caused by OTOF variants; they fall mostly in different places as the Auditory neuropathy variants (6 disease-causing).
• Auditory neuropathy spectrum disorder is also caused by OTOF variants; they fall mostly in different places as the Auditory neuropathy variants (4 disease-causing).
• Autosomal dominant optic atrophy classic form is also caused by OPA1 variants; they fall mostly in different places as the Auditory neuropathy variants (13 disease-causing).
• Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy is also caused by OPA1 variants; they fall mostly in different places as the Auditory neuropathy variants (10 disease-causing).
• Optic atrophy is also caused by OPA1 variants; they fall mostly in different places as the Auditory neuropathy variants (7 disease-causing).
• Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 is also caused by NOTCH3 variants; they fall mostly in different places as the Auditory neuropathy variants (89 disease-causing).
• Lateral meningocele syndrome is also caused by NOTCH3 variants; they fall mostly in different places as the Auditory neuropathy variants (12 disease-causing).
• Myofibromatosis, infantile, 2 is also caused by NOTCH3 variants; they fall mostly in different places as the Auditory neuropathy variants (12 disease-causing).
• Usher syndrome is also caused by MYO7A variants; they fall mostly in different places as the Auditory neuropathy variants (80 disease-causing).
• Autosomal recessive nonsyndromic hearing loss 4 is also caused by MYO7A variants; they fall mostly in different places as the Auditory neuropathy variants (26 disease-causing).
• Rare genetic deafness is also caused by MYO7A variants; they fall mostly in different places as the Auditory neuropathy variants (23 disease-causing).
• Autosomal dominant nonsyndromic hearing loss is also caused by MYO7A variants; they fall mostly in different places as the Auditory neuropathy variants (13 disease-causing).
• Hearing loss is also caused by MYO7A variants; they fall mostly in different places as the Auditory neuropathy variants (4 disease-causing).
• Axon pathfinding, cardiac, ocular and genital defects is also caused by CDH2 variants; they fall mostly in different places as the Auditory neuropathy variants (4 disease-causing).
• Corpus callosum, agenesis of is also caused by CDH2 variants; they fall mostly in different places as the Auditory neuropathy variants (4 disease-causing).
• Hereditary spastic paraplegia is also caused by KIF5A variants; they fall mostly in different places as the Auditory neuropathy variants (24 disease-causing).

Diseases related to Auditory neuropathy

• Charcot-Marie-Tooth disease, also linked to KIF5A and MFN2
• Autosomal recessive nonsyndromic hearing loss 4, also linked to MYO7A and OTOF
• Rare genetic deafness, also linked to MYO7A and OTOF
• Nonsyndromic genetic hearing loss, also linked to MYO7A and OTOF
• Hearing loss, also linked to MYO7A and OTOF
• Deafness, also linked to MYO7A and OTOF
• Peripheral neuropathy, also linked to KIF5A and MFN2
• Retinitis pigmentosa, also linked to MYO7A
• Hereditary spastic paraplegia, also linked to KIF5A
• Amyotrophic lateral sclerosis, also linked to KIF5A
• Usher syndrome, also linked to MYO7A
• Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, also linked to NOTCH3

Frequently asked questions

Which genes are linked to Auditory neuropathy?

In CATVariant, Auditory neuropathy is linked to 8 analyzed proteins: OTOF (Otoferlin), OPA1 (Dynamin-like GTPase OPA1, mitochondrial), NOTCH3 (Neurogenic locus notch homolog protein 3), CDH2 (Cadherin-2), MYO7A (Unconventional myosin-VIIa), KIF5A (Kinesin heavy chain isoform 5A) and 2 more.

How many genetic variants are linked to Auditory neuropathy?

67 variants: 14 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 31 are of uncertain significance or have conflicting reports.

Which uncertain variants in Auditory neuropathy look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Auditory neuropathy?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.82, based on 8 disease-causing and 339 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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