Branchiootic syndrome: genes and variants

Genes linked to Branchiootic syndrome

• 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.

  11 disease-causing and 61 uncertain variants in SIX1 are linked to Branchiootic syndrome.

• EYA1: Protein phosphatase EYA1

  It functions as a transcriptional coactivator and phosphatase in developmental programs that form the ear, kidney, and craniofacial structures. Haploinsufficiency causes branchio-oto-renal spectrum disorders with hearing loss, branchial anomalies, and variable renal malformations.

  2 disease-causing and 48 uncertain variants in EYA1 are linked to Branchiootic syndrome.

Where Branchiootic syndrome variants cluster

• SIX1 Homeobox (positions 124–183): 4 of 11 disease-causing changes, 1.7× more than its size predicts.

Known disease-causing variants in Branchiootic syndrome

Which prediction tools work for Branchiootic syndrome

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

• CATVariant: 100 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)
• PolyPhen-2: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 58 out of 100

Same protein, different disease

• Autosomal dominant nonsyndromic hearing loss is also caused by SIX1 variants; they fall partly in the same places as the Branchiootic syndrome variants (8 disease-causing).
• Branchiootorenal syndrome 1 is also caused by EYA1 variants; they fall mostly in different places as the Branchiootic syndrome variants (5 disease-causing).
• Melnick-Fraser syndrome is also caused by EYA1 variants; they fall mostly in different places as the Branchiootic syndrome variants (4 disease-causing).
• Anterior segment anomalies and cataract is also caused by EYA1 variants; they fall mostly in different places as the Branchiootic syndrome variants (3 disease-causing).

Diseases related to Branchiootic syndrome

• Melnick-Fraser syndrome, also linked to EYA1 and SIX1
• Rare genetic deafness, also linked to EYA1
• Autosomal dominant nonsyndromic hearing loss, also linked to SIX1
• Branchiootorenal syndrome 1, also linked to EYA1
• Otofaciocervical syndrome, also linked to EYA1

Frequently asked questions

Which genes are linked to Branchiootic syndrome?

In CATVariant, Branchiootic syndrome is linked to 2 analyzed proteins: SIX1 (Homeobox protein SIX1) and EYA1 (Protein phosphatase EYA1).

How many genetic variants are linked to Branchiootic syndrome?

141 variants: 13 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 109 are of uncertain significance or have conflicting reports.

Which uncertain variants in Branchiootic syndrome 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 Branchiootic syndrome?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.58, based on 10 disease-causing and 19 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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