RT Journal Article SR Electronic T1 BBS1 branchpoint variant is associated with non-syndromic retinitis pigmentosa JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 438 OP 444 DO 10.1136/jmedgenet-2020-107626 VO 59 IS 5 A1 Zeinab Fadaie A1 Laura Whelan A1 Adrian Dockery A1 Catherina H Z Li A1 L Ingeborgh van den Born A1 Carel B Hoyng A1 Christian Gilissen A1 Jordi Corominas A1 Charlie Rowlands A1 Roly Megaw A1 Anne K Lampe A1 Frans P M Cremers A1 Gwyneth Jane Farrar A1 Jamie M Ellingford A1 Paul F. Kenna A1 Susanne Roosing YR 2022 UL http://jmg.bmj.com/content/59/5/438.abstract AB 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.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).