Bilateral sensorineural hearing impairment: genes and variants

Genes linked to Bilateral sensorineural hearing impairment

• 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.

  6 disease-causing and 2 uncertain variants in OTOF are linked to Bilateral sensorineural hearing impairment.

• FGFR2: Fibroblast growth factor receptor 2

  Its fibroblast-growth-factor signaling regulates proliferation, differentiation, and developmental patterning across multiple tissues. Germline activating variants cause several craniosynostosis syndromes, while somatic mutations, amplification, or fusions can drive cancer.

  1 disease-causing and 0 uncertain variants in FGFR2 are linked to Bilateral sensorineural hearing impairment.

• 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 Bilateral sensorineural hearing impairment.

• KCNJ10: ATP-sensitive inward rectifier potassium channel 10

  1 disease-causing and 0 uncertain variants in KCNJ10 are linked to Bilateral sensorineural hearing impairment.

Known disease-causing variants in Bilateral sensorineural hearing impairment

Which prediction tools work for Bilateral sensorineural hearing impairment

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

• PolyPhen-2: 87 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 84 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 74 out of 100

Same protein, different disease

• Autosomal recessive nonsyndromic hearing loss 4 is also caused by OTOF variants; they fall mostly in different places as the Bilateral sensorineural hearing impairment variants (21 disease-causing).
• Nonsyndromic genetic hearing loss is also caused by OTOF variants; they fall mostly in different places as the Bilateral sensorineural hearing impairment variants (8 disease-causing).
• Hearing loss is also caused by OTOF variants; they fall mostly in different places as the Bilateral sensorineural hearing impairment variants (6 disease-causing).
• Auditory neuropathy is also caused by OTOF variants; they fall mostly in different places as the Bilateral sensorineural hearing impairment variants (6 disease-causing).
• Auditory neuropathy spectrum disorder is also caused by OTOF variants; they fall mostly in different places as the Bilateral sensorineural hearing impairment variants (4 disease-causing).
• FGFR2-related craniosynostosis is also caused by FGFR2 variants; they fall mostly in different places as the Bilateral sensorineural hearing impairment variants (54 disease-causing).
• Crouzon syndrome is also caused by FGFR2 variants; they fall mostly in different places as the Bilateral sensorineural hearing impairment variants (22 disease-causing).
• Pfeiffer syndrome is also caused by FGFR2 variants; they fall mostly in different places as the Bilateral sensorineural hearing impairment variants (13 disease-causing).
• Acrocephalosyndactyly type I is also caused by FGFR2 variants; they fall mostly in different places as the Bilateral sensorineural hearing impairment variants (6 disease-causing).
• Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis is also caused by FGFR2 variants; they fall mostly in different places as the Bilateral sensorineural hearing impairment variants (5 disease-causing).
• Autosomal dominant nonsyndromic hearing loss is also caused by KCNQ4 variants; they fall mostly in different places as the Bilateral sensorineural hearing impairment variants (19 disease-causing).
• EAST syndrome is also caused by KCNJ10 variants; they fall mostly in different places as the Bilateral sensorineural hearing impairment variants (12 disease-causing).
• Autosomal recessive nonsyndromic hearing loss 4 is also caused by KCNJ10 variants; they fall mostly in different places as the Bilateral sensorineural hearing impairment variants (3 disease-causing).

Diseases related to Bilateral sensorineural hearing impairment

• Autosomal recessive nonsyndromic hearing loss 4, also linked to KCNJ10 and OTOF
• Rare genetic deafness, also linked to KCNQ4 and OTOF
• Nonsyndromic genetic hearing loss, also linked to KCNQ4 and OTOF
• Pendred syndrome, also linked to KCNJ10
• Autosomal dominant nonsyndromic hearing loss, also linked to KCNQ4
• FGFR2-related craniosynostosis, also linked to FGFR2
• Pfeiffer syndrome, also linked to FGFR2
• Crouzon syndrome, also linked to FGFR2
• Hearing loss, also linked to OTOF
• Colorectal cancer, also linked to FGFR2
• Gastric cancer, also linked to FGFR2
• Epilepsy, also linked to KCNQ4

Frequently asked questions

Which genes are linked to Bilateral sensorineural hearing impairment?

In CATVariant, Bilateral sensorineural hearing impairment is linked to 4 analyzed proteins: OTOF (Otoferlin), FGFR2 (Fibroblast growth factor receptor 2), KCNQ4 (Potassium voltage-gated channel subfamily KQT member 4) and KCNJ10 (ATP-sensitive inward rectifier potassium channel 10).

How many genetic variants are linked to Bilateral sensorineural hearing impairment?

11 variants: 9 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 2 are of uncertain significance or have conflicting reports.

Which uncertain variants in Bilateral sensorineural hearing impairment 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 Bilateral sensorineural hearing impairment?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.73, based on 8 disease-causing and 106 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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