Autosomal dominant nonsyndromic hearing loss: genes and variants

Genes linked to Autosomal dominant nonsyndromic 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.

  19 disease-causing and 27 uncertain variants in KCNQ4 are linked to Autosomal dominant nonsyndromic 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.

  15 disease-causing and 91 uncertain variants in TECTA are linked to Autosomal dominant nonsyndromic 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.

  13 disease-causing and 128 uncertain variants in MYO7A are linked to Autosomal dominant nonsyndromic hearing loss.

• SIX1: Homeobox protein SIX1

  It regulates developmental programs in the ear, kidney, craniofacial structures, and skeletal muscle together with EYA-family cofactors. Heterozygous pathogenic variants cause branchio-otic or branchio-oto-renal syndrome with hearing loss and variable branchial or renal abnormalities.

  8 disease-causing and 61 uncertain variants in SIX1 are linked to Autosomal dominant nonsyndromic 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.

  8 disease-causing and 13 uncertain variants in GJB2 are linked to Autosomal dominant nonsyndromic 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.

  3 disease-causing and 41 uncertain variants in GJB6 are linked to Autosomal dominant nonsyndromic hearing loss.

• POLE: DNA polymerase epsilon catalytic subunit A

  It performs leading-strand DNA synthesis and proofreads newly incorporated bases during replication. Germline exonuclease-domain variants cause polymerase-proofreading-associated polyposis, while somatic proofreading defects create ultramutated tumors with distinctive mutation signatures.

  1 disease-causing and 0 uncertain variants in POLE are linked to Autosomal dominant nonsyndromic hearing loss.

• NLRP3: NACHT, LRR and PYD domains-containing protein 3

  It assembles a widely used inflammasome in response to diverse danger signals, driving caspase-1 activation and release of IL-1beta and IL-18. Gain-of-function variants cause cryopyrin-associated periodic syndromes, while excessive activation contributes to common inflammatory diseases.

  0 disease-causing and 0 uncertain variants in NLRP3 are linked to Autosomal dominant nonsyndromic hearing loss.

• MCM2: DNA replication licensing factor MCM2

  It is part of the MCM2-7 helicase that unwinds DNA at replication forks and licenses origins before S phase. Excess or dysregulated expression is common in proliferative cancers and is widely used as a marker of active DNA replication.

  0 disease-causing and 9 uncertain variants in MCM2 are linked to Autosomal dominant nonsyndromic hearing loss.

Weakly linked (only a few uncertain records): ABCC1 and USH2A.

Where Autosomal dominant nonsyndromic hearing loss variants cluster

• KCNQ4 Segment H5 (positions 271–292): 9 of 19 disease-causing changes, 15.0× more than its size predicts.
• TECTA ZP (positions 1805–2059): 10 of 15 disease-causing changes, 5.6× more than its size predicts.
• KCNQ4 Cytoplasmic (positions 224–235): 3 of 19 disease-causing changes, 9.1× more than its size predicts.
• MYO7A Myosin motor (positions 65–741): 7 of 13 disease-causing changes, 1.8× more than its size predicts.
• GJB2 Extracellular (positions 157–189): 3 of 8 disease-causing changes, 2.6× more than its size predicts.

Known disease-causing variants in Autosomal dominant nonsyndromic hearing loss

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Which prediction tools work for Autosomal dominant nonsyndromic hearing loss

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

• AlphaMissense: 100 out of 100
• REVEL: 97 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)
• MutPred2: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 90 out of 100
• CADD: 89 out of 100
• phyloP: 78 out of 100

Same protein, different disease

• Rare genetic deafness is also caused by TECTA variants; they fall mostly in different places as the Autosomal dominant nonsyndromic hearing loss variants (3 disease-causing).
• Usher syndrome is also caused by MYO7A variants; they fall mostly in different places as the Autosomal dominant nonsyndromic 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 Autosomal dominant nonsyndromic hearing loss variants (26 disease-causing).
• Rare genetic deafness is also caused by MYO7A variants; they fall mostly in different places as the Autosomal dominant nonsyndromic hearing loss variants (23 disease-causing).
• Hearing loss is also caused by MYO7A variants; they fall mostly in different places as the Autosomal dominant nonsyndromic hearing loss variants (4 disease-causing).
• Nonsyndromic genetic hearing loss is also caused by MYO7A variants; they fall partly in the same places as the Autosomal dominant nonsyndromic 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 Autosomal dominant nonsyndromic hearing loss variants (38 disease-causing).
• Nonsyndromic genetic hearing loss is also caused by GJB2 variants; they fall mostly in different places as the Autosomal dominant nonsyndromic hearing loss variants (28 disease-causing).
• Rare genetic deafness is also caused by GJB2 variants; they fall mostly in different places as the Autosomal dominant nonsyndromic hearing loss variants (25 disease-causing).
• Mutilating keratoderma is also caused by GJB2 variants; they fall mostly in different places as the Autosomal dominant nonsyndromic 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 Autosomal dominant nonsyndromic hearing loss variants (13 disease-causing).
• Branchiootic syndrome is also caused by SIX1 variants; they fall partly in the same places as the Autosomal dominant nonsyndromic hearing loss variants (11 disease-causing).

Diseases related to Autosomal dominant nonsyndromic hearing loss

• Autosomal recessive nonsyndromic hearing loss 4, also linked to GJB2, GJB6, MYO7A and TECTA
• Rare genetic deafness, also linked to GJB2, KCNQ4, MYO7A and TECTA
• Nonsyndromic genetic hearing loss, also linked to GJB2, KCNQ4, MYO7A and TECTA
• Hearing loss, also linked to GJB2, GJB6, MYO7A and TECTA
• Monogenic hearing loss, also linked to GJB2, KCNQ4, MYO7A and TECTA
• Deafness, also linked to GJB2, MCM2, MYO7A and TECTA
• X-linked mixed hearing loss with perilymphatic gusher, also linked to GJB2 and GJB6
• Retinitis pigmentosa, also linked to MYO7A
• Noonan syndrome, also linked to GJB2
• Usher syndrome, also linked to MYO7A
• Ovarian cancer, also linked to POLE
• Acute myeloid leukemia, also linked to POLE

Frequently asked questions

Which genes are linked to Autosomal dominant nonsyndromic hearing loss?

In CATVariant, Autosomal dominant nonsyndromic hearing loss is linked to 9 analyzed proteins: KCNQ4 (Potassium voltage-gated channel subfamily KQT member 4), TECTA (Alpha-tectorin), MYO7A (Unconventional myosin-VIIa), SIX1 (Homeobox protein SIX1), GJB2 (Gap junction beta-2 protein), GJB6 (Gap junction beta-6 protein) and 3 more.

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

545 variants: 67 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 373 are of uncertain significance or have conflicting reports.

Which uncertain variants in Autosomal dominant nonsyndromic 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 Autosomal dominant nonsyndromic hearing loss?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 1.00, based on 17 disease-causing and 9 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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