Autosomal recessive nonsyndromic hearing loss 4: genes and variants

Genes linked to Autosomal recessive nonsyndromic hearing loss 4

• 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.

  106 disease-causing and 70 uncertain variants in SLC26A4 are linked to Autosomal recessive nonsyndromic hearing loss 4.

• 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.

  38 disease-causing and 31 uncertain variants in GJB2 are linked to Autosomal recessive nonsyndromic hearing loss 4.

• 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.

  26 disease-causing and 121 uncertain variants in MYO7A are linked to Autosomal recessive nonsyndromic hearing loss 4.

• 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.

  21 disease-causing and 112 uncertain variants in OTOF are linked to Autosomal recessive nonsyndromic hearing loss 4.

• 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.

  6 disease-causing and 58 uncertain variants in PCDH15 are linked to Autosomal recessive nonsyndromic hearing loss 4.

• KCNJ10: ATP-sensitive inward rectifier potassium channel 10

  3 disease-causing and 44 uncertain variants in KCNJ10 are linked to Autosomal recessive nonsyndromic hearing loss 4.

• 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.

  3 disease-causing and 15 uncertain variants in USH1C are linked to Autosomal recessive nonsyndromic hearing loss 4.

• CLDN14: Claudin-14

  3 disease-causing and 11 uncertain variants in CLDN14 are linked to Autosomal recessive nonsyndromic hearing loss 4.

• 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.

  2 disease-causing and 75 uncertain variants in TECTA are linked to Autosomal recessive nonsyndromic hearing loss 4.

• 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.

  2 disease-causing and 40 uncertain variants in GJB6 are linked to Autosomal recessive nonsyndromic hearing loss 4.

• FOXI1: Forkhead box protein I1

  It regulates genes needed for acid-base transport in kidney intercalated cells and ion homeostasis in the inner ear. Biallelic pathogenic variants can cause enlarged vestibular aqueduct with hearing loss, and disruption can also affect renal acidification.

  1 disease-causing and 58 uncertain variants in FOXI1 are linked to Autosomal recessive nonsyndromic hearing loss 4.

• MET: Hepatocyte growth factor receptor

  Hepatocyte-growth-factor signaling through this pathway promotes cell survival, proliferation, motility, and invasive growth during development and tissue repair. Exon 14 skipping, amplification, activating mutations, or fusions can drive cancer and create actionable therapeutic dependencies.

  0 disease-causing and 209 uncertain variants in MET are linked to Autosomal recessive nonsyndromic hearing loss 4.

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

Where Autosomal recessive nonsyndromic hearing loss 4 variants cluster

• SLC26A4 Extracellular (positions 406–421): 8 of 106 disease-causing changes, 3.7× more than its size predicts.
• GJB2 Transmembrane (positions 74–94): 9 of 38 disease-causing changes, 2.5× more than its size predicts.
• SLC26A4 Transmembrane (positions 88–108): 8 of 106 disease-causing changes, 2.8× more than its size predicts.
• SLC26A4 Cytoplasmic (positions 443–448): 4 of 106 disease-causing changes, 4.9× more than its size predicts.
• GJB2 Extracellular (positions 41–73): 11 of 38 disease-causing changes, 2.0× more than its size predicts.

Known disease-causing variants in Autosomal recessive nonsyndromic hearing loss 4

Showing 60 of 211.

Uncertain variants in Autosomal recessive nonsyndromic hearing loss 4 that look disease-causing

Which prediction tools work for Autosomal recessive nonsyndromic hearing loss 4

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

• MetaLR: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MutPred2: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• REVEL: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 94 out of 100
• ESM1b (LLR): 90 out of 100
• SIFT: 88 out of 100
• PolyPhen-2: 87 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• EVE: 86 out of 100
• CADD: 85 out of 100
• AlphaGenome (regulatory): 81 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 75 out of 100
• AlphaGenome (splicing): 57 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• Pendred syndrome is also caused by SLC26A4 variants; they fall in the same places as the Autosomal recessive nonsyndromic hearing loss 4 variants (106 disease-causing).
• Rare genetic deafness is also caused by SLC26A4 variants; they fall in the same places as the Autosomal recessive nonsyndromic hearing loss 4 variants (14 disease-causing).
• Monogenic hearing loss is also caused by SLC26A4 variants; they fall in the same places as the Autosomal recessive nonsyndromic hearing loss 4 variants (6 disease-causing).
• Nonsyndromic genetic hearing loss is also caused by GJB2 variants; they fall in the same places as the Autosomal recessive nonsyndromic hearing loss 4 variants (28 disease-causing).
• Rare genetic deafness is also caused by GJB2 variants; they fall in the same places as the Autosomal recessive nonsyndromic hearing loss 4 variants (25 disease-causing).
• Mutilating keratoderma is also caused by GJB2 variants; they fall in the same places as the Autosomal recessive nonsyndromic hearing loss 4 variants (15 disease-causing).
• Ichthyosis, hystrix-like, with hearing loss is also caused by GJB2 variants; they fall in the same places as the Autosomal recessive nonsyndromic hearing loss 4 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 Autosomal recessive nonsyndromic hearing loss 4 variants (13 disease-causing).
• Usher syndrome is also caused by MYO7A variants; they fall mostly in different places as the Autosomal recessive nonsyndromic hearing loss 4 variants (80 disease-causing).
• Rare genetic deafness is also caused by MYO7A variants; they fall mostly in different places as the Autosomal recessive nonsyndromic hearing loss 4 variants (23 disease-causing).
• Autosomal dominant nonsyndromic hearing loss is also caused by MYO7A variants; they fall mostly in different places as the Autosomal recessive nonsyndromic hearing loss 4 variants (13 disease-causing).
• Hearing loss is also caused by MYO7A variants; they fall mostly in different places as the Autosomal recessive nonsyndromic hearing loss 4 variants (4 disease-causing).
• Nonsyndromic genetic hearing loss is also caused by MYO7A variants; they fall mostly in different places as the Autosomal recessive nonsyndromic hearing loss 4 variants (4 disease-causing).
• Nonsyndromic genetic hearing loss is also caused by OTOF variants; they fall partly in the same places as the Autosomal recessive nonsyndromic hearing loss 4 variants (8 disease-causing).
• Bilateral sensorineural hearing impairment is also caused by OTOF variants; they fall mostly in different places as the Autosomal recessive nonsyndromic hearing loss 4 variants (6 disease-causing).
• Hearing loss is also caused by OTOF variants; they fall mostly in different places as the Autosomal recessive nonsyndromic hearing loss 4 variants (6 disease-causing).
• Auditory neuropathy is also caused by OTOF variants; they fall mostly in different places as the Autosomal recessive nonsyndromic hearing loss 4 variants (6 disease-causing).
• Auditory neuropathy spectrum disorder is also caused by OTOF variants; they fall mostly in different places as the Autosomal recessive nonsyndromic hearing loss 4 variants (4 disease-causing).
• Usher syndrome is also caused by PCDH15 variants; they fall mostly in different places as the Autosomal recessive nonsyndromic hearing loss 4 variants (4 disease-causing).
• EAST syndrome is also caused by KCNJ10 variants; they fall mostly in different places as the Autosomal recessive nonsyndromic hearing loss 4 variants (12 disease-causing).

Diseases related to Autosomal recessive nonsyndromic hearing loss 4

• Hearing loss, 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
• Pendred syndrome, also linked to FOXI1, KCNJ10 and SLC26A4
• Auditory neuropathy, also linked to MYO7A and OTOF
• Bilateral sensorineural hearing impairment, also linked to KCNJ10 and OTOF
• Sensorineural hearing loss disorder, also linked to FOXI1 and SLC26A4
• X-linked mixed hearing loss with perilymphatic gusher, also linked to GJB2 and GJB6

Frequently asked questions

Which genes are linked to Autosomal recessive nonsyndromic hearing loss 4?

In CATVariant, Autosomal recessive nonsyndromic hearing loss 4 is linked to 12 analyzed proteins: SLC26A4 (Pendrin), GJB2 (Gap junction beta-2 protein), MYO7A (Unconventional myosin-VIIa), OTOF (Otoferlin), PCDH15 (Protocadherin-15), KCNJ10 (ATP-sensitive inward rectifier potassium channel 10) and 6 more.

How many genetic variants are linked to Autosomal recessive nonsyndromic hearing loss 4?

1,317 variants: 211 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 844 are of uncertain significance or have conflicting reports.

Which uncertain variants in Autosomal recessive nonsyndromic hearing loss 4 look disease-causing?

8 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example GJB2 G45R, GJB2 T86M, GJB2 G59S, GJB2 G12D and SLC26A4 E29G. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Autosomal recessive nonsyndromic hearing loss 4?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.94, based on 132 disease-causing and 63 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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