TY - JOUR
T1 - BBS1 branchpoint variant is associated with non-syndromic retinitis pigmentosa
AU - Fadaie, Zeinab
AU - Whelan, Laura
AU - Dockery, Adrian
AU - Li, Catherina H Z
AU - van der Born, L Ingeborgh
AU - Hoyng, Carel B
AU - Gilissen, Christian
AU - Corominas, Jordi
AU - Rowlands, Charlie
AU - Megaw, Roly
AU - Lampe, Anne K
AU - Cremers, Frans P M
AU - Farrar, Gwyneth Jane
AU - Ellingford, Jamie M
AU - Kenna, Paul F
AU - Roosing, Susanne
N1 - © Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.
PY - 2022/5
Y1 - 2022/5
N2 - 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.
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.
KW - Bardet-Biedl Syndrome/diagnosis
KW - DNA Mutational Analysis
KW - Humans
KW - Microtubule-Associated Proteins/genetics
KW - Mutation/genetics
KW - Pedigree
KW - Retina/pathology
KW - Retinitis Pigmentosa/diagnosis
UR - https://www.mendeley.com/catalogue/dbeef141-d93d-378c-a3c5-24631a60cc73/
U2 - 10.1136/jmedgenet-2020-107626
DO - 10.1136/jmedgenet-2020-107626
M3 - Article
C2 - 33910932
SN - 0022-2593
VL - 59
SP - 438
EP - 444
JO - Journal of Medical Genetics
JF - Journal of Medical Genetics
IS - 5
ER -