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Original research
BBS1 branchpoint variant is associated with non-syndromic retinitis pigmentosa
  1. Zeinab Fadaie1,2,
  2. Laura Whelan3,
  3. Adrian Dockery3,
  4. Catherina H Z Li2,4,
  5. L Ingeborgh van den Born5,
  6. Carel B Hoyng2,4,
  7. Christian Gilissen1,6,
  8. Jordi Corominas1,6,
  9. Charlie Rowlands7,8,
  10. Roly Megaw9,10,
  11. Anne K Lampe11,
  12. Frans P M Cremers1,2,
  13. Gwyneth Jane Farrar3,
  14. Jamie M Ellingford7,8,
  15. Paul F. Kenna3,12,
  16. Susanne Roosing1,2
  1. 1 Department of Human Genetics, Radboudumc, Nijmegen, The Netherlands
  2. 2 Donders Institute for Brain Cognition and Behaviour, RadboudUMC, Nijmegen, The Netherlands
  3. 3 School of Genetics & Microbiology, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland
  4. 4 Department of Ophthalmology, Radboudumc, Nijmegen, The Netherlands
  5. 5 Eye Hospital Rotterdam, Rotterdam Ophthalmic Institute, Rotterdam, The Netherlands
  6. 6 Radboud Institute of Molecular Life Sciences, RadboudUMC, Nijmegen, The Netherlands
  7. 7 North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, St Mary’s Hospital, Manchester, UK
  8. 8 Division of Evolution and Genomic Sciences, Neuroscience and Mental Health Domain, The University of Manchester Faculty of Biology Medicine and Health, Manchester, UK
  9. 9 MRC Human Genetics Unit, University of Edinburgh Western General Hospital, Edinburgh, UK
  10. 10 Princess Alexandra Eye Pavilion, Department of Ophthalmology, University of Edinburgh Western General Hospital, Edinburgh, UK
  11. 11 South East of Scotland Clinical Genetics Service, Western General Hospital, Edinburgh, UK
  12. 12 Research Foundation, Royal Victoria Eye and Ear Hospital, Dublin, Ireland
  1. Correspondence to Susanne Roosing, Department of Human Genetics, Radboudumc, Nijmegen 6525 GA, The Netherlands; Susanne.Roosing{at}


Background Inherited retinal diseases (IRDs) can be caused by variants in >270 genes. The Bardet-Biedl syndrome 1 (BBS1) gene is one of these genes and may be associated with syndromic and non-syndromic autosomal recessive retinitis pigmentosa (RP). Here, we identified a branchpoint variant in BBS1 and assessed its pathogenicity by in vitro functional analysis.

Methods Whole genome sequencing was performed for three unrelated monoallelic BBS1 cases with non-syndromic RP. A fourth case received MGCM 105 gene panel analysis. Functional analysis using a midigene splice assay was performed for the putative pathogenic branchpoint variant in BBS1. After confirmation of its pathogenicity, patients were clinically re-evaluated, including assessment of non-ocular features of Bardet-Biedl syndrome.

Results Clinical assessments of probands showed that all individuals displayed non-syndromic RP with macular involvement. Through detailed variant analysis and prioritisation, two pathogenic variants in BBS1, the most common missense variant, c.1169T>G (p.(Met390Arg)), and a branchpoint variant, c.592-21A>T, were identified. Segregation analysis confirmed that in all families, probands were compound heterozygous for c.1169T>G and c.592-21A>T. Functional analysis of the branchpoint variant revealed a complex splicing defect including exon 8 and exon 7/8 skipping, and partial in-frame deletion of exon 8.

Conclusion A putative severe branchpoint variant in BBS1, together with a mild missense variant, underlies non-syndromic RP in four unrelated individuals. To our knowledge, this is the first report of a pathogenic branchpoint variant in IRDs that results in a complex splice defect. In addition, this research highlights the importance of the analysis of non-coding regions in order to provide a conclusive molecular diagnosis.

  • eye diseases
  • human genetics
  • molecular biology
  • ophthalmology

Data availability statement

Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as online supplemental information. The pathogenic variant data is submitted to Leiden Open Variation Database (LOVD).

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Data availability statement

Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as online supplemental information. The pathogenic variant data is submitted to Leiden Open Variation Database (LOVD).

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  • Correction notice This article has been corrected since it was published Online First. The name of author Dr L Ingeborgh van den Born has been corrected.

  • Contributors ZF performed data analyses, sequencing analyses, RNA expression studies. CHZL, LIvdB, CBH, CR, AKL and PK collected clinical cases and performed clinical examinations of patients. CG and JC provided infrastructure, and bioinformatic expert input. JF, FPMC, AD and JME provided strategic support, expert input and supervision for the project. ZF, LW, FPMC and SR contributed significantly to design of the study. ZF, LW, PK and SR wrote the manuscript. All authors reviewed and approved the manuscript.

  • Funding The work of ZF and CHZL is funded by the Foundation Fighting Blindness USA Project Program Award, grant no. PPA‐0517-0717‐RAD (to FPMC, SR and CBH). The research was supported by the Algemene Nederlandse Vereniging ter Voorkoming van Blindheid, Oogfonds, Landelijke Stichting voor Blinden en Slechtzienden; Rotterdamse Stichting Blindenbelangen, Stichting Blindenhulp, Stichting tot Verbetering van het Lot der Blinden and Stichting Blinden-Penning (to SR and FPMC). The work of LW is supported by Fighting Blindness Ireland, grant FB18CRE (to FPMC, SR and JF). RM is supported by the Wellcome Trust (Fellowship number 219607/Z/19/Z) and the Royal College of Surgeons (Edinburgh). JME is funded by a postdoctoral research fellowship from the Health Education England Genomics Education Programme (HEE GEP).

  • Disclaimer The views expressed in this publication are those of the authors and not necessarily those of the HEE GEP.

  • Competing interests None declared.

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

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.