Monogenic hearing loss: genes and variants

Genes linked to Monogenic 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.

  6 disease-causing and 0 uncertain variants in SLC26A4 are linked to Monogenic 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.

  5 disease-causing and 1 uncertain variants in GJB2 are linked to Monogenic 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.

  1 disease-causing and 2 uncertain variants in MYO7A are linked to Monogenic hearing loss.

• 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 Monogenic hearing loss.

• KCNQ1: Potassium voltage-gated channel subfamily KQT member 1

  The protein forms the pore of a voltage-gated potassium channel that helps set electrical activity in heart muscle. Its partnerships with KCNE subunits also support normal function in the inner ear and other tissues, while KCNQ1 variants are linked to long-QT and short-QT syndromes.

  1 disease-causing and 0 uncertain variants in KCNQ1 are linked to Monogenic 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.

  1 disease-causing and 0 uncertain variants in KCNQ4 are linked to Monogenic 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 Monogenic hearing loss.

Weakly linked (only a few uncertain records): CHD7, CLDN14, COL2A1, EDNRB and SIX1.

Where Monogenic hearing loss variants cluster

• GJB2 Transmembrane (positions 21–40): 3 of 5 disease-causing changes, 6.8× more than its size predicts.

Known disease-causing variants in Monogenic hearing loss

Which prediction tools work for Monogenic hearing loss

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

• REVEL: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 95 out of 100
• PolyPhen-2: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 90 out of 100
• SIFT: 81 out of 100
• phyloP: 70 out of 100

Same protein, different disease

• Pendred syndrome is also caused by SLC26A4 variants; they fall mostly in different places as the Monogenic 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 Monogenic hearing loss variants (106 disease-causing).
• Rare genetic deafness is also caused by SLC26A4 variants; they fall mostly in different places as the Monogenic hearing loss variants (14 disease-causing).
• Autosomal recessive nonsyndromic hearing loss 4 is also caused by GJB2 variants; they fall mostly in different places as the Monogenic hearing loss variants (38 disease-causing).
• Nonsyndromic genetic hearing loss is also caused by GJB2 variants; they fall mostly in different places as the Monogenic hearing loss variants (28 disease-causing).
• Rare genetic deafness is also caused by GJB2 variants; they fall mostly in different places as the Monogenic hearing loss variants (25 disease-causing).
• Mutilating keratoderma is also caused by GJB2 variants; they fall mostly in different places as the Monogenic 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 Monogenic hearing loss variants (13 disease-causing).
• Usher syndrome is also caused by MYO7A variants; they fall mostly in different places as the Monogenic 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 Monogenic hearing loss variants (26 disease-causing).
• Rare genetic deafness is also caused by MYO7A variants; they fall mostly in different places as the Monogenic 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 Monogenic hearing loss variants (13 disease-causing).
• Hearing loss is also caused by MYO7A variants; they fall mostly in different places as the Monogenic hearing loss variants (4 disease-causing).
• X-linked Alport syndrome is also caused by COL4A5 variants; they fall mostly in different places as the Monogenic hearing loss variants (341 disease-causing).
• Alport syndrome is also caused by COL4A5 variants; they fall mostly in different places as the Monogenic hearing loss variants (14 disease-causing).
• Long QT syndrome is also caused by KCNQ1 variants; they fall mostly in different places as the Monogenic hearing loss variants (175 disease-causing).
• Cardiac arrhythmia is also caused by KCNQ1 variants; they fall mostly in different places as the Monogenic hearing loss variants (49 disease-causing).
• Atrial fibrillation, familial, 10 is also caused by KCNQ1 variants; they fall mostly in different places as the Monogenic hearing loss variants (8 disease-causing).
• Jervell and Lange-Nielsen syndrome is also caused by KCNQ1 variants; they fall mostly in different places as the Monogenic hearing loss variants (4 disease-causing).
• Short QT syndrome type 3 is also caused by KCNQ1 variants; they fall mostly in different places as the Monogenic hearing loss variants (4 disease-causing).
• Autosomal dominant nonsyndromic hearing loss is also caused by KCNQ4 variants; they fall mostly in different places as the Monogenic hearing loss variants (19 disease-causing).

Diseases related to Monogenic hearing loss

• Rare genetic deafness, also linked to COL4A5, GJB2, KCNQ4, MYO7A and 2 more
• Autosomal recessive nonsyndromic hearing loss 4, also linked to GJB2, MYO7A, SLC26A4 and TECTA
• Autosomal dominant nonsyndromic hearing loss, 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, MYO7A, SLC26A4 and TECTA
• Deafness, also linked to GJB2, MYO7A, SLC26A4 and TECTA
• Epilepsy, also linked to KCNQ1 and KCNQ4
• Retinitis pigmentosa, also linked to MYO7A
• Long QT syndrome, also linked to KCNQ1
• X-linked Alport syndrome, also linked to COL4A5
• RASopathy, also linked to SLC26A4
• Alport syndrome, also linked to COL4A5

Frequently asked questions

Which genes are linked to Monogenic hearing loss?

In CATVariant, Monogenic hearing loss is linked to 7 analyzed proteins: SLC26A4 (Pendrin), GJB2 (Gap junction beta-2 protein), MYO7A (Unconventional myosin-VIIa), COL4A5 (Collagen alpha-5(IV) chain), KCNQ1 (Potassium voltage-gated channel subfamily KQT member 1), KCNQ4 (Potassium voltage-gated channel subfamily KQT member 4) and 1 more.

How many genetic variants are linked to Monogenic hearing loss?

24 variants: 16 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 8 are of uncertain significance or have conflicting reports.

Which uncertain variants in Monogenic 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 Monogenic hearing loss?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.95, based on 8 disease-causing and 97 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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