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BBS1 branchpoint variant is associated with non-syndromic retinitis pigmentosa.
- Source :
- Journal of Medical Genetics; May2022, Vol. 59 Issue 5, p438-444, 7p
- Publication Year :
- 2022
-
Abstract
- 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 nonsyndromic 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 BardetBiedl 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>Gand 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 inframe 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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00222593
- Volume :
- 59
- Issue :
- 5
- Database :
- Complementary Index
- Journal :
- Journal of Medical Genetics
- Publication Type :
- Academic Journal
- Accession number :
- 157157870
- Full Text :
- https://doi.org/10.1136/jmedgenet-2020-107626