BBS1 branchpoint variant is associated with non-syndromic retinitis pigmentosa
BBS1 branchpoint variant is associated with non-syndromic retinitis pigmentosa
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DOI：
10.1136/jmedgenet-2020-107626
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发表时间：
2021-04-28
影响因子：
4
通讯作者：
Roosing, Susanne
中科院分区：
文献类型：
--
作者：
Fadaie, Zeinab;Whelan, Laura;Roosing, Susanne
遗传性视网膜疾病（IRD）可由超过270个基因的变异引起。Bardet-Biedl综合征1（BBS 1）基因是这些基因之一，可能与综合征型和非综合征型常染色体隐性视网膜色素变性（RP）相关。在这里，我们确定了一个分支点变异体在BBS 1和评估其致病性的体外功能分析。方法对3例无亲缘关系的单等位基因BBS 1型非综合征型RP患者进行全基因组测序。第四例接受MGCM 105基因面板分析。使用中基因剪接测定法对BBS 1中推定的致病性分支点变体进行功能分析。在确认其致病性后，对患者进行临床重新评估，包括评估Bardet-Biedl综合征的非眼部特征。结果先证者的临床评估显示所有个体均表现为非综合征型RP伴黄斑受累。通过详细的变异分析和优先排序，BBS 1中的两种致病性变异，最常见的错义变异，c.1169T>G（p.（Met 390 Arg））和分支点变体c.592- 21 A>T。分离分析证实，在所有家系中，先证者为c.1169T>G和c.592- 21 A>T的复合杂合子。分支点变体的功能分析揭示了复杂的剪接缺陷，包括外显子8和外显子7/8跳跃，以及外显子8的部分框内缺失。结论一个假定的严重分支点变异的BBS 1，连同一个轻度的错义变异，在4个无关个体的非综合征RP的基础。据我们所知，这是第一次报告的致病性分支点变异的IRD，导致复杂的剪接缺陷。此外，本研究强调了非编码区分析的重要性，以提供结论性的分子诊断。
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.