Hearing loss: genes and variants

Genes linked to Hearing loss

• 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 0 uncertain variants in OTOF are linked to Hearing loss.

• GJB2: Gap junction beta-2 protein

  Its connexin 26 channels support potassium and metabolite recycling within the cochlea and communication across epithelial gap junctions. Biallelic pathogenic variants are among the most common causes of congenital nonsyndromic hearing loss, while dominant variants can cause syndromic deafness with skin disease.

  4 disease-causing and 1 uncertain variants in GJB2 are linked to Hearing loss.

• 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.

  4 disease-causing and 1 uncertain variants in MYO7A are linked to Hearing loss.

• SLC12A2: Solute carrier family 12 member 2

  It brings sodium, potassium, and chloride into cells and supports cell-volume control, epithelial secretion, and neuronal chloride homeostasis. Pathogenic variants can cause developmental disorders with hearing loss, growth abnormalities, or neurologic impairment.

  2 disease-causing and 14 uncertain variants in SLC12A2 are linked to Hearing loss.

• TECTA: Alpha-tectorin

  Its extracellular matrix organizes the tectorial membrane that mechanically couples sound-induced motion to cochlear hair cells. Dominant or recessive pathogenic variants cause nonsyndromic hearing loss, with characteristic frequency patterns depending on the affected region.

  1 disease-causing and 0 uncertain variants in TECTA are linked to Hearing loss.

• ATP7B: Copper-transporting ATPase 2

  A copper-transporting ATPase that moves excess copper out of cells and helps deliver it from liver cells into bile. Its trafficking between intracellular membranes is central to copper homeostasis, and ATP7B dysfunction causes Wilson disease.

  1 disease-causing and 0 uncertain variants in ATP7B are linked to Hearing loss.

• PCDH15: Protocadherin-15

  It forms part of the tip-link complex that converts mechanical deflection of inner-ear hair bundles into electrical signals and also supports photoreceptor structure. Biallelic pathogenic variants cause Usher syndrome type 1F or nonsyndromic hearing loss.

  1 disease-causing and 0 uncertain variants in PCDH15 are linked to Hearing loss.

• SLC26A4: Pendrin

  SLC26A4, known as pendrin, is an anion exchanger that transports chloride, iodide, and bicarbonate without directly using sodium. It supports ion balance in the inner ear and thyroid, and SLC26A4 variants cause Pendred syndrome and inherited deafness.

  1 disease-causing and 0 uncertain variants in SLC26A4 are linked to Hearing loss.

• CLDN14: Claudin-14

  0 disease-causing and 0 uncertain variants in CLDN14 are linked to Hearing loss.

• GJB6: Gap junction beta-6 protein

  It forms connexin 30 gap junctions in the cochlea, skin, and other epithelia and contributes to intercellular ion and metabolite exchange. Deletions or pathogenic variants can cause nonsyndromic hearing loss or ectodermal dysplasia syndromes.

  0 disease-causing and 0 uncertain variants in GJB6 are linked to Hearing loss.

• USH1C: Harmonin

  It organizes protein complexes in inner-ear hair-cell stereocilia and photoreceptor structures. Biallelic pathogenic variants cause Usher syndrome type 1C with congenital severe hearing loss and progressive retinitis pigmentosa, or in some alleles isolated deafness.

  0 disease-causing and 0 uncertain variants in USH1C are linked to Hearing loss.

• ABCC1: Multidrug resistance-associated protein 1

  1 disease-causing and 1 uncertain variants in ABCC1 are linked to Hearing loss.

Weakly linked (only a few uncertain records): KCNJ10.

Known disease-causing variants in Hearing loss

Which prediction tools work for Hearing loss

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

• REVEL: 89 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 89 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 88 out of 100
• CATVariant: 86 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 86 out of 100
• MetaLR: 81 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 80 out of 100
• phyloP: 76 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 Hearing loss variants (21 disease-causing).
• Nonsyndromic genetic hearing loss is also caused by OTOF variants; they fall mostly in different places as the Hearing loss variants (8 disease-causing).
• Bilateral sensorineural hearing impairment is also caused by OTOF variants; they fall mostly in different places as the Hearing loss variants (6 disease-causing).
• Auditory neuropathy is also caused by OTOF variants; they fall mostly in different places as the Hearing loss variants (6 disease-causing).
• Auditory neuropathy spectrum disorder is also caused by OTOF variants; they fall mostly in different places as the Hearing loss variants (4 disease-causing).
• Usher syndrome is also caused by MYO7A variants; they fall mostly in different places as the Hearing loss variants (80 disease-causing).
• Autosomal recessive nonsyndromic hearing loss 4 is also caused by MYO7A variants; they fall mostly in different places as the Hearing loss variants (26 disease-causing).
• Rare genetic deafness is also caused by MYO7A variants; they fall mostly in different places as the Hearing loss variants (23 disease-causing).
• Autosomal dominant nonsyndromic hearing loss is also caused by MYO7A variants; they fall mostly in different places as the Hearing loss variants (13 disease-causing).
• Nonsyndromic genetic hearing loss is also caused by MYO7A variants; they fall mostly in different places as the Hearing loss variants (4 disease-causing).
• Autosomal recessive nonsyndromic hearing loss 4 is also caused by GJB2 variants; they fall mostly in different places as the Hearing loss variants (38 disease-causing).
• Nonsyndromic genetic hearing loss is also caused by GJB2 variants; they fall mostly in different places as the Hearing loss variants (28 disease-causing).
• Rare genetic deafness is also caused by GJB2 variants; they fall mostly in different places as the Hearing loss variants (25 disease-causing).
• Mutilating keratoderma is also caused by GJB2 variants; they fall mostly in different places as the Hearing loss variants (15 disease-causing).
• Ichthyosis, hystrix-like, with hearing loss is also caused by GJB2 variants; they fall mostly in different places as the Hearing loss variants (13 disease-causing).
• Autosomal dominant nonsyndromic hearing loss is also caused by TECTA variants; they fall mostly in different places as the Hearing loss variants (15 disease-causing).
• Rare genetic deafness is also caused by TECTA variants; they fall mostly in different places as the Hearing loss variants (3 disease-causing).
• Pendred syndrome is also caused by SLC26A4 variants; they fall mostly in different places as the Hearing loss variants (106 disease-causing).
• Autosomal recessive nonsyndromic hearing loss 4 is also caused by SLC26A4 variants; they fall mostly in different places as the Hearing loss variants (106 disease-causing).
• Rare genetic deafness is also caused by SLC26A4 variants; they fall mostly in different places as the Hearing loss variants (14 disease-causing).
• Monogenic hearing loss is also caused by SLC26A4 variants; they fall mostly in different places as the Hearing loss variants (6 disease-causing).

Diseases related to Hearing loss

• Autosomal recessive nonsyndromic hearing loss 4, also linked to CLDN14, GJB2, GJB6, MYO7A and 5 more
• Deafness, also linked to CLDN14, GJB2, MYO7A, OTOF and 4 more
• Rare genetic deafness, also linked to GJB2, MYO7A, OTOF, PCDH15 and 2 more
• Autosomal dominant nonsyndromic hearing loss, also linked to GJB2, GJB6, MYO7A and TECTA
• Nonsyndromic genetic hearing loss, also linked to GJB2, MYO7A, OTOF and TECTA
• Monogenic hearing loss, also linked to GJB2, MYO7A, SLC26A4 and TECTA
• Usher syndrome, also linked to MYO7A, PCDH15 and USH1C
• Auditory neuropathy, also linked to MYO7A and OTOF
• Sensorineural hearing loss disorder, also linked to SLC12A2 and SLC26A4
• X-linked mixed hearing loss with perilymphatic gusher, also linked to GJB2 and GJB6
• Retinitis pigmentosa, also linked to MYO7A
• Wilson disease, also linked to ATP7B

Frequently asked questions

Which genes are linked to Hearing loss?

In CATVariant, Hearing loss is linked to 12 analyzed proteins: OTOF (Otoferlin), GJB2 (Gap junction beta-2 protein), MYO7A (Unconventional myosin-VIIa), SLC12A2 (Solute carrier family 12 member 2), TECTA (Alpha-tectorin), ATP7B (Copper-transporting ATPase 2) and 6 more.

How many genetic variants are linked to Hearing loss?

100 variants: 21 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 18 are of uncertain significance or have conflicting reports.

Which uncertain variants in Hearing loss 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 Hearing loss?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.88, based on 12 disease-causing and 264 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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