Bardet-Biedl syndrome: genes and variants

Genes linked to Bardet-Biedl syndrome

• BBS2: BBSome complex member BBS2

  It contributes to BBSome assembly and ciliary cargo trafficking, which are required for signaling in photoreceptors, kidney, hypothalamus, and other tissues. Biallelic loss-of-function variants cause Bardet-Biedl syndrome.

  19 disease-causing and 268 uncertain variants in BBS2 are linked to Bardet-Biedl syndrome.

• BBS1: BBSome complex member BBS1

  Within the BBSome, it helps control trafficking of membrane proteins into and out of primary cilia. Biallelic pathogenic variants cause Bardet-Biedl syndrome, with retinal degeneration, obesity, renal abnormalities, polydactyly, and variable neurodevelopmental features.

  16 disease-causing and 253 uncertain variants in BBS1 are linked to Bardet-Biedl syndrome.

• BBS4: BBSome complex member BBS4

  It helps assemble and localize the BBSome and links ciliary trafficking machinery to the cytoskeleton. Biallelic pathogenic variants cause Bardet-Biedl syndrome, with characteristic retinal, metabolic, renal, and developmental manifestations.

  9 disease-causing and 192 uncertain variants in BBS4 are linked to Bardet-Biedl syndrome.

• IFT172: Intraflagellar transport protein 172 homolog

  It supports intraflagellar transport required for assembly and maintenance of primary and sensory cilia. Biallelic pathogenic variants cause ciliopathies that can involve retinal degeneration, skeletal abnormalities, kidney disease, or Joubert-spectrum neurologic findings.

  3 disease-causing and 225 uncertain variants in IFT172 are linked to Bardet-Biedl syndrome.

• ALMS1: Centrosome-associated protein ALMS1

  It contributes to primary-cilium function, intracellular trafficking, and metabolic homeostasis in multiple tissues. Biallelic pathogenic variants cause Alstrom syndrome, which typically combines retinal degeneration, hearing loss, obesity, insulin resistance, and cardiomyopathy.

  1 disease-causing and 1 uncertain variants in ALMS1 are linked to Bardet-Biedl syndrome.

• CEP290: Centrosomal protein of 290 kDa

  It organizes the transition zone of primary and sensory cilia and is essential for ciliary protein trafficking, especially in photoreceptors. Biallelic pathogenic variants cause a broad ciliopathy spectrum including Leber congenital amaurosis, Joubert syndrome, and nephronophthisis-related disease.

  0 disease-causing and 123 uncertain variants in CEP290 are linked to Bardet-Biedl syndrome.

Weakly linked (only a few uncertain records): F8 and WDR19.

Known disease-causing variants in Bardet-Biedl syndrome

Which prediction tools work for Bardet-Biedl syndrome

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

• CADD: 96 out of 100
• REVEL: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MutPred2: 91 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 86 out of 100
• PolyPhen-2: 84 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 81 out of 100
• AlphaMissense: 67 out of 100
• MetaLR: 61 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• Retinitis pigmentosa is also caused by IFT172 variants; they fall mostly in different places as the Bardet-Biedl syndrome variants (7 disease-causing).
• Short-rib thoracic dysplasia 10 with or without polydactyly is also caused by IFT172 variants; they fall mostly in different places as the Bardet-Biedl syndrome variants (6 disease-causing).
• Alstrom syndrome is also caused by ALMS1 variants; they fall mostly in different places as the Bardet-Biedl syndrome variants (4 disease-causing).

Diseases related to Bardet-Biedl syndrome

• Retinitis pigmentosa, also linked to ALMS1, BBS1, BBS2, CEP290 and 1 more
• Leber congenital amaurosis, also linked to ALMS1 and CEP290
• Monogenic diabetes, also linked to ALMS1
• Senior-Loken syndrome, also linked to CEP290
• Nephronophthisis, also linked to CEP290
• Joubert syndrome, also linked to CEP290
• CEP290-related ciliopathy, also linked to CEP290
• Short-rib thoracic dysplasia 10 with or without polydactyly, also linked to IFT172
• Alstrom syndrome, also linked to ALMS1
• BBS2-related ciliopathy, also linked to BBS2
• Meckel syndrome, also linked to CEP290
• Meckel-Gruber syndrome, also linked to CEP290

Frequently asked questions

Which genes are linked to Bardet-Biedl syndrome?

In CATVariant, Bardet-Biedl syndrome is linked to 6 analyzed proteins: BBS2 (BBSome complex member BBS2), BBS1 (BBSome complex member BBS1), BBS4 (BBSome complex member BBS4), IFT172 (Intraflagellar transport protein 172 homolog), ALMS1 (Centrosome-associated protein ALMS1) and CEP290 (Centrosomal protein of 290 kDa).

How many genetic variants are linked to Bardet-Biedl syndrome?

1,275 variants: 48 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 1,064 are of uncertain significance or have conflicting reports.

Which uncertain variants in Bardet-Biedl 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 Bardet-Biedl syndrome?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.96, based on 30 disease-causing and 167 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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