| Autor: |
Fadaie, Zeinab, Whelan, Laura, Dockery, Adrian, Li, Catherina H Z, van den Born, L Ingeborgh, Hoyng, Carel B, Gilissen, Christian, Corominas, Jordi, Rowlands, Charlie, Megaw, Roly, Lampe, Anne K, Cremers, Frans P M, Farrar, Gwyneth Jane, Ellingford, Jamie M, Kenna, Paul F., Roosing, Susanne |
| Zdroj: |
Journal of Medical Genetics (JMG); 2022, Vol. 59 Issue: 5 p438-444, 7p |
| Abstrakt: |
BackgroundInherited 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 BBS1and assessed its pathogenicity by in vitro functional analysis.MethodsWhole genome sequencing was performed for three unrelated monoallelic BBS1cases 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.ResultsClinical 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.ConclusionA 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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