Journal
JOURNAL OF MEDICAL GENETICS
Volume 59, Issue 5, Pages 438-444Publisher
BMJ PUBLISHING GROUP
DOI: 10.1136/jmedgenet-2020-107626
Keywords
eye diseases; human genetics; molecular biology; ophthalmology
Categories
Funding
- Foundation Fighting Blindness USA Project Program Award [PPA-0517-0717-RAD]
- 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
- Stichting Blinden-Penning
- Fighting Blindness Ireland [FB18CRE]
- Wellcome Trust [219607/Z/19/Z]
- Royal College of Surgeons (Edinburgh)
- Health Education England Genomics Education Programme (HEE GEP)
- Wellcome Trust [219607/Z/19/Z] Funding Source: Wellcome Trust
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Through whole genome sequencing and functional analysis, a branchpoint variant in BBS1 was identified, resulting in non-syndromic RP in four unrelated individuals. This study highlights the importance of analyzing non-coding regions to provide a conclusive molecular diagnosis.
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.
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