Nonsyndromic genetic hearing loss: genes and variants

Genes linked to Nonsyndromic genetic 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.

  28 disease-causing and 20 uncertain variants in GJB2 are linked to Nonsyndromic genetic 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.

  8 disease-causing and 3 uncertain variants in OTOF are linked to Nonsyndromic genetic 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 3 uncertain variants in MYO7A are linked to Nonsyndromic genetic 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.

  2 disease-causing and 1 uncertain variants in TECTA are linked to Nonsyndromic genetic hearing loss.

• 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 Nonsyndromic genetic hearing loss.

Weakly linked (only a few uncertain records): COL4A5, CLDN14 and SLC26A4.

Where Nonsyndromic genetic hearing loss variants cluster

• OTOF C2 7 (positions 1714–1865): 3 of 8 disease-causing changes, 4.9× more than its size predicts.
• GJB2 Transmembrane (positions 21–40): 6 of 28 disease-causing changes, 2.4× more than its size predicts.
• GJB2 Transmembrane (positions 74–94): 5 of 28 disease-causing changes, 1.9× more than its size predicts.

Known disease-causing variants in Nonsyndromic genetic hearing loss

Uncertain variants in Nonsyndromic genetic hearing loss that look disease-causing

Which prediction tools work for Nonsyndromic genetic hearing loss

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

• CATVariant: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• REVEL: 97 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 96 out of 100
• MutPred2: 95 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 89 out of 100
• SIFT: 88 out of 100
• PolyPhen-2: 88 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 76 out of 100
• EVE: 72 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 Nonsyndromic genetic hearing loss variants (38 disease-causing).
• Rare genetic deafness is also caused by GJB2 variants; they fall partly in the same places as the Nonsyndromic genetic hearing loss variants (25 disease-causing).
• Mutilating keratoderma is also caused by GJB2 variants; they fall partly in the same places as the Nonsyndromic genetic hearing loss 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 Nonsyndromic genetic hearing loss 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 Nonsyndromic genetic hearing loss variants (13 disease-causing).
• Autosomal recessive nonsyndromic hearing loss 4 is also caused by OTOF variants; they fall mostly in different places as the Nonsyndromic genetic hearing loss variants (21 disease-causing).
• Bilateral sensorineural hearing impairment is also caused by OTOF variants; they fall mostly in different places as the Nonsyndromic genetic hearing loss variants (6 disease-causing).
• Hearing loss is also caused by OTOF variants; they fall mostly in different places as the Nonsyndromic genetic hearing loss variants (6 disease-causing).
• Auditory neuropathy is also caused by OTOF variants; they fall mostly in different places as the Nonsyndromic genetic hearing loss variants (6 disease-causing).
• Auditory neuropathy spectrum disorder is also caused by OTOF variants; they fall mostly in different places as the Nonsyndromic genetic hearing loss variants (4 disease-causing).
• Usher syndrome is also caused by MYO7A variants; they fall mostly in different places as the Nonsyndromic genetic 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 Nonsyndromic genetic hearing loss variants (26 disease-causing).
• Rare genetic deafness is also caused by MYO7A variants; they fall mostly in different places as the Nonsyndromic genetic 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 Nonsyndromic genetic hearing loss variants (13 disease-causing).
• Hearing loss is also caused by MYO7A variants; they fall mostly in different places as the Nonsyndromic genetic hearing loss variants (4 disease-causing).
• Autosomal dominant nonsyndromic hearing loss is also caused by TECTA variants; they fall mostly in different places as the Nonsyndromic genetic hearing loss variants (15 disease-causing).
• Rare genetic deafness is also caused by TECTA variants; they fall mostly in different places as the Nonsyndromic genetic hearing loss variants (3 disease-causing).
• Autosomal dominant nonsyndromic hearing loss is also caused by KCNQ4 variants; they fall mostly in different places as the Nonsyndromic genetic hearing loss variants (19 disease-causing).

Diseases related to Nonsyndromic genetic hearing loss

• Rare genetic deafness, also linked to GJB2, KCNQ4, MYO7A, OTOF and 1 more
• Autosomal recessive nonsyndromic hearing loss 4, also linked to GJB2, MYO7A, OTOF and TECTA
• Autosomal dominant nonsyndromic hearing loss, also linked to GJB2, KCNQ4, MYO7A and TECTA
• Hearing loss, also linked to GJB2, MYO7A, OTOF and TECTA
• Monogenic hearing loss, also linked to GJB2, KCNQ4, MYO7A and TECTA
• Deafness, also linked to GJB2, MYO7A, OTOF and TECTA
• Auditory neuropathy, also linked to MYO7A and OTOF
• Bilateral sensorineural hearing impairment, also linked to KCNQ4 and OTOF
• Retinitis pigmentosa, also linked to MYO7A
• Noonan syndrome, also linked to GJB2
• Usher syndrome, also linked to MYO7A
• Epilepsy, also linked to KCNQ4

Frequently asked questions

Which genes are linked to Nonsyndromic genetic hearing loss?

In CATVariant, Nonsyndromic genetic hearing loss is linked to 5 analyzed proteins: GJB2 (Gap junction beta-2 protein), OTOF (Otoferlin), MYO7A (Unconventional myosin-VIIa), TECTA (Alpha-tectorin) and KCNQ4 (Potassium voltage-gated channel subfamily KQT member 4).

How many genetic variants are linked to Nonsyndromic genetic hearing loss?

105 variants: 44 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 30 are of uncertain significance or have conflicting reports.

Which uncertain variants in Nonsyndromic genetic hearing loss look disease-causing?

1 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example GJB2 M195I. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Nonsyndromic genetic hearing loss?

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 12 disease-causing and 59 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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