Pendred syndrome: genes and variants

Genes linked to Pendred syndrome

• 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 94 uncertain variants in SLC26A4 are linked to Pendred syndrome.

• KCNJ10: ATP-sensitive inward rectifier potassium channel 10

  1 disease-causing and 14 uncertain variants in KCNJ10 are linked to Pendred syndrome.

• 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.

  0 disease-causing and 5 uncertain variants in FOXI1 are linked to Pendred syndrome.

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

Where Pendred syndrome variants cluster

• SLC26A4 Transmembrane (positions 136–156): 10 of 106 disease-causing changes, 3.5× more than its size predicts.
• SLC26A4 Extracellular (positions 406–421): 7 of 106 disease-causing changes, 3.2× more than its size predicts.
• SLC26A4 Cytoplasmic (positions 443–448): 4 of 106 disease-causing changes, 4.9× more than its size predicts.
• SLC26A4 Cytoplasmic (positions 131–135): 3 of 106 disease-causing changes, 4.4× more than its size predicts.
• SLC26A4 Transmembrane (positions 88–108): 5 of 106 disease-causing changes, 1.8× more than its size predicts.

Known disease-causing variants in Pendred syndrome

Showing 60 of 107.

Uncertain variants in Pendred syndrome that look disease-causing

Which prediction tools work for Pendred syndrome

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)
• REVEL: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 93 out of 100
• ESM1b (LLR): 88 out of 100
• AlphaGenome (regulatory): 86 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 83 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 82 out of 100
• SIFT: 81 out of 100
• AlphaGenome (splicing): 74 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 71 out of 100

Same protein, different disease

• Autosomal recessive nonsyndromic hearing loss 4 is also caused by SLC26A4 variants; they fall in the same places as the Pendred syndrome variants (106 disease-causing).
• Rare genetic deafness is also caused by SLC26A4 variants; they fall in the same places as the Pendred syndrome variants (14 disease-causing).
• Monogenic hearing loss is also caused by SLC26A4 variants; they fall in the same places as the Pendred syndrome variants (6 disease-causing).
• EAST syndrome is also caused by KCNJ10 variants; they fall mostly in different places as the Pendred syndrome variants (12 disease-causing).

Diseases related to Pendred syndrome

• Autosomal recessive nonsyndromic hearing loss 4, also linked to FOXI1, KCNJ10 and SLC26A4
• Sensorineural hearing loss disorder, also linked to FOXI1 and SLC26A4
• RASopathy, also linked to SLC26A4
• Rare genetic deafness, also linked to SLC26A4
• Hearing loss, also linked to SLC26A4
• Monogenic hearing loss, also linked to SLC26A4
• EAST syndrome, also linked to KCNJ10
• Bilateral sensorineural hearing impairment, also linked to KCNJ10
• Deafness, also linked to SLC26A4
• Microcephaly, also linked to KCNJ10

Frequently asked questions

Which genes are linked to Pendred syndrome?

In CATVariant, Pendred syndrome is linked to 3 analyzed proteins: SLC26A4 (Pendrin), KCNJ10 (ATP-sensitive inward rectifier potassium channel 10) and FOXI1 (Forkhead box protein I1).

How many genetic variants are linked to Pendred syndrome?

254 variants: 107 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 114 are of uncertain significance or have conflicting reports.

Which uncertain variants in Pendred syndrome look disease-causing?

5 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example SLC26A4 Y78H, SLC26A4 M147I, SLC26A4 F667S, SLC26A4 G389W and SLC26A4 Q421R. These are leads for expert review, not diagnoses.

Which variant effect predictor works best for Pendred syndrome?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.93, based on 106 disease-causing and 24 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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