BBS1 branchpoint variant is associated with non-syndromic retinitis pigmentosa

Zeinab Fadaie, Laura Whelan, Adrian Dockery, Catherina H Z Li, L Ingeborgh van der Born, Carel B Hoyng, Christian Gilissen, Jordi Corominas, Charlie Rowlands, Roly Megaw, Anne K Lampe, Frans P M Cremers, Gwyneth Jane Farrar, Jamie M Ellingford, Paul F Kenna, Susanne Roosing

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelOnderzoekpeer review

Samenvatting

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.

Originele taal-2Engels
TijdschriftJournal of Medical Genetics
DOI's
StatusE-publicatie vóór gedrukte publicatie - 28 apr 2021

Trefwoorden

  • eye diseases
  • human genetics
  • molecular biology
  • ophthalmology

Vingerafdruk

Duik in de onderzoeksthema's van 'BBS1 branchpoint variant is associated with non-syndromic retinitis pigmentosa'. Samen vormen ze een unieke vingerafdruk.

Citeer dit