Rare genetic deafness: genes and variants

Genes linked to Rare genetic deafness

• 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.

  25 disease-causing and 1 uncertain variants in GJB2 are linked to Rare genetic deafness.

• 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.

  23 disease-causing and 4 uncertain variants in MYO7A are linked to Rare genetic deafness.

• 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.

  14 disease-causing and 1 uncertain variants in SLC26A4 are linked to Rare genetic deafness.

• 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.

  3 disease-causing and 1 uncertain variants in TECTA are linked to Rare genetic deafness.

• EYA1: Protein phosphatase EYA1

  It functions as a transcriptional coactivator and phosphatase in developmental programs that form the ear, kidney, and craniofacial structures. Haploinsufficiency causes branchio-oto-renal spectrum disorders with hearing loss, branchial anomalies, and variable renal malformations.

  3 disease-causing and 0 uncertain variants in EYA1 are linked to Rare genetic deafness.

• 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.

  2 disease-causing and 0 uncertain variants in OTOF are linked to Rare genetic deafness.

• KCNQ4: Potassium voltage-gated channel subfamily KQT member 4

  Its potassium conductance is crucial for electrical homeostasis in cochlear outer hair cells and auditory pathways. Dominant pathogenic variants are a well-established cause of progressive nonsyndromic sensorineural hearing loss, classically DFNA2.

  2 disease-causing and 0 uncertain variants in KCNQ4 are linked to Rare genetic deafness.

• SOX10: Transcription factor SOX-10

  2 disease-causing and 0 uncertain variants in SOX10 are linked to Rare genetic deafness.

• 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 Rare genetic deafness.

• COL4A5: Collagen alpha-5(IV) chain

  It is essential for the alpha3-alpha4-alpha5 type IV collagen network that gives glomerular and cochlear basement membranes their mature mechanical properties. Pathogenic variants cause X-linked Alport syndrome, with progressive kidney disease, hearing loss, and characteristic ocular findings.

  1 disease-causing and 0 uncertain variants in COL4A5 are linked to Rare genetic deafness.

• USH2A: Usherin

  It helps organize extracellular and membrane structures required for cochlear hair-cell and photoreceptor function. Biallelic pathogenic variants cause Usher syndrome type 2A or nonsyndromic retinitis pigmentosa and can also produce isolated hearing loss.

  0 disease-causing and 0 uncertain variants in USH2A are linked to Rare genetic deafness.

Weakly linked (only a few uncertain records): MITF, EDNRB and HSD17B4.

Where Rare genetic deafness variants cluster

• SLC26A4 Extracellular (positions 406–421): 3 of 14 disease-causing changes, 10.4× more than its size predicts.
• GJB2 Transmembrane (positions 74–94): 7 of 25 disease-causing changes, 3.0× more than its size predicts.
• MYO7A MyTH4 2 (positions 1747–1896): 5 of 23 disease-causing changes, 3.2× more than its size predicts.
• MYO7A Myosin motor (positions 65–741): 11 of 23 disease-causing changes, 1.6× more than its size predicts.
• GJB2 Transmembrane (positions 21–40): 5 of 25 disease-causing changes, 2.3× more than its size predicts.

Known disease-causing variants in Rare genetic deafness

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Which prediction tools work for Rare genetic deafness

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

• MutPred2: 100 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• REVEL: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 96 out of 100
• CADD: 92 out of 100
• ESM1b (LLR): 91 out of 100
• PolyPhen-2: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 89 out of 100
• MetaLR: 88 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• EVE: 88 out of 100
• phyloP: 82 out of 100

Same protein, different disease

• Autosomal recessive nonsyndromic hearing loss 4 is also caused by GJB2 variants; they fall partly in the same places as the Rare genetic deafness variants (38 disease-causing).
• Nonsyndromic genetic hearing loss is also caused by GJB2 variants; they fall partly in the same places as the Rare genetic deafness variants (28 disease-causing).
• Mutilating keratoderma is also caused by GJB2 variants; they fall in the same places as the Rare genetic deafness variants (15 disease-causing).
• Ichthyosis, hystrix-like, with hearing loss is also caused by GJB2 variants; they fall partly in the same places as the Rare genetic deafness variants (13 disease-causing).
• Autosomal dominant keratitis-ichthyosis-hearing loss syndrome is also caused by GJB2 variants; they fall partly in the same places as the Rare genetic deafness variants (13 disease-causing).
• Usher syndrome is also caused by MYO7A variants; they fall mostly in different places as the Rare genetic deafness variants (80 disease-causing).
• Autosomal recessive nonsyndromic hearing loss 4 is also caused by MYO7A variants; they fall mostly in different places as the Rare genetic deafness variants (26 disease-causing).
• Autosomal dominant nonsyndromic hearing loss is also caused by MYO7A variants; they fall mostly in different places as the Rare genetic deafness variants (13 disease-causing).
• Hearing loss is also caused by MYO7A variants; they fall mostly in different places as the Rare genetic deafness variants (4 disease-causing).
• Nonsyndromic genetic hearing loss is also caused by MYO7A variants; they fall mostly in different places as the Rare genetic deafness variants (4 disease-causing).
• Pendred syndrome is also caused by SLC26A4 variants; they fall mostly in different places as the Rare genetic deafness variants (106 disease-causing).
• Autosomal recessive nonsyndromic hearing loss 4 is also caused by SLC26A4 variants; they fall mostly in different places as the Rare genetic deafness variants (106 disease-causing).
• Autosomal dominant nonsyndromic hearing loss is also caused by TECTA variants; they fall mostly in different places as the Rare genetic deafness variants (15 disease-causing).
• Branchiootorenal syndrome 1 is also caused by EYA1 variants; they fall mostly in different places as the Rare genetic deafness variants (5 disease-causing).
• Melnick-Fraser syndrome is also caused by EYA1 variants; they fall mostly in different places as the Rare genetic deafness variants (4 disease-causing).
• Anterior segment anomalies and cataract is also caused by EYA1 variants; they fall mostly in different places as the Rare genetic deafness variants (3 disease-causing).
• Autosomal recessive nonsyndromic hearing loss 4 is also caused by OTOF variants; they fall mostly in different places as the Rare genetic deafness variants (21 disease-causing).
• Nonsyndromic genetic hearing loss is also caused by OTOF variants; they fall mostly in different places as the Rare genetic deafness variants (8 disease-causing).
• Bilateral sensorineural hearing impairment is also caused by OTOF variants; they fall mostly in different places as the Rare genetic deafness variants (6 disease-causing).
• Hearing loss is also caused by OTOF variants; they fall mostly in different places as the Rare genetic deafness variants (6 disease-causing).
• Auditory neuropathy is also caused by OTOF variants; they fall mostly in different places as the Rare genetic deafness variants (6 disease-causing).

Diseases related to Rare genetic deafness

• Autosomal recessive nonsyndromic hearing loss 4, also linked to GJB2, MYO7A, OTOF, PCDH15 and 2 more
• Hearing loss, also linked to GJB2, MYO7A, OTOF, PCDH15 and 2 more
• Monogenic hearing loss, also linked to COL4A5, GJB2, KCNQ4, MYO7A and 2 more
• Deafness, also linked to GJB2, MYO7A, OTOF, PCDH15 and 2 more
• Nonsyndromic genetic hearing loss, also linked to GJB2, KCNQ4, MYO7A, OTOF and 1 more
• Autosomal dominant nonsyndromic hearing loss, also linked to GJB2, KCNQ4, MYO7A and TECTA
• Usher syndrome, also linked to MYO7A, PCDH15 and USH2A
• Retinitis pigmentosa, also linked to MYO7A and USH2A
• Auditory neuropathy, also linked to MYO7A and OTOF
• Bilateral sensorineural hearing impairment, also linked to KCNQ4 and OTOF
• Sensorineural hearing loss disorder, also linked to SLC26A4 and USH2A
• X-linked Alport syndrome, also linked to COL4A5

Frequently asked questions

Which genes are linked to Rare genetic deafness?

In CATVariant, Rare genetic deafness is linked to 11 analyzed proteins: GJB2 (Gap junction beta-2 protein), MYO7A (Unconventional myosin-VIIa), SLC26A4 (Pendrin), TECTA (Alpha-tectorin), EYA1 (Protein phosphatase EYA1), OTOF (Otoferlin) and 5 more.

How many genetic variants are linked to Rare genetic deafness?

128 variants: 76 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 7 are of uncertain significance or have conflicting reports.

Which uncertain variants in Rare genetic deafness 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 Rare genetic deafness?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.96, based on 35 disease-causing and 80 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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