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Mutations in chaperonin-like BBS genes are a major contributor to disease development in a multiethnic Bardet–Biedl syndrome patient population
  1. Gail Billingsley1,
  2. Jenea Bin1,
  3. Karen J Fieggen2,
  4. Jacque L Duncan3,
  5. Christina Gerth4,
  6. Koji Ogata5,
  7. Shoshana S Wodak6,7,8,
  8. Elias I Traboulsi9,
  9. Gerald A Fishman10,
  10. Andrew Paterson1,
  11. David Chitayat11,12,
  12. Tanja Knueppel13,
  13. José M Millán14,
  14. Grant A Mitchell15,
  15. Catherine Deveault1,
  16. Elise Héon1,4
  1. 1Department of Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
  2. 2Division of Human Genetics, University of Cape Town, Cape Town, South Africa
  3. 3Department of Ophthalmology, UCSF, San Francisco, California, USA
  4. 4Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, Toronto, Ontario, Canada
  5. 5Centre for Computational Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
  6. 6Molecular Structure and Function Program, The Hospital for Sick Children, Toronto, Ontario, Canada
  7. 7Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada
  8. 8Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
  9. 9Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
  10. 10Department of Ophthalmology & Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, USA
  11. 11Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, Toronto, Ontario, Canada
  12. 12Department of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada
  13. 13Department of Pediatric Nephrology, University Children's Hospital Heidelberg, Heidelberg, Germany
  14. 14Unidad de Genetica, Hospital Universitario La Fe, Valencia, Spain
  15. 15The Program in Genetics and Genome Biology, Division of Medical Genetics, CHU Sainte-Justine, Montréal, Quebec, Canada
  1. Correspondence to Dr Elise Héon, Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, 555 University Avenue, Room M165, Toronto, Ontario M5G 1X8, Canada; eheon{at}


Background Bardet–Biedl syndrome is a pleiotropic disorder with 14 BBS genes identified. BBS1, BBS2, BBS4, BBS5, BBS7, BBS8, and BBS9 form a complex called the BBSome, which is believed to recruit Rab8GTP to the primary cilium and promote ciliogenesis. The second group, the chaperonin-like proteins BBS6, BBS10, and BBS12, have been defined as a vertebrate-specific branch of the type II chaperonin superfamily. These may play a role in the regulation of BBSome assembly.

Methods and results Using sequence analysis, the role of BBS6, 10 and 12 was assessed in the patient population comprising 93 cases from 74 families. Systemic and ocular phenotypes were defined. In the study, chaperonin-like BBS gene mutations accounted for the disease in approximately 36.5% of BBS families. A total of 38 different non-polymorphic exonic sequence variants were identified in 40.5% of BBS families (41.9% cases), of which 26 were novel (68%). Six cases had mutations present in more than one chaperonin-like BBS gene. One case with four mutations in BBS10 had a phenotype of overall greater severity. The phenotypes observed were beyond the classic BBS phenotype as they overlapped with characteristics of MKKS (congenital heart defect, vaginal atresia, hydrometrocolpos, cryptorchidism), as well as Alström syndrome (diabetes, hearing loss, liver abnormalities, endocrine anomalies, cardiomyopathy).

Conclusions While overlap between the MKKS and BBS phenotypes has previously been reported for cases with BBS6 mutations, we also observed MKKS phenotypes involving BBS10 and BBS12 and Alström-like phenotypes associated with mutations in BBS1, BBS2, BBS6, BBS7, BBS9, BBS10 and BBS12 for the first time.

  • Bardet-Biedl syndrome
  • BBS6
  • BBS10
  • BBS12
  • mutation
  • sequencing
  • blindness

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  • Funding Foundation Fighting Blindness-Canada.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of The Hospital for Sick Children.

  • Provenance and peer review Not commissioned; externally peer reviewed.