开发溶酶体疾病基因整理优先级评分系统

IF 3.7 2区 生物学 Q2 ENDOCRINOLOGY & METABOLISM Molecular genetics and metabolism Pub Date : 2024-09-01 DOI:10.1016/j.ymgme.2024.108572
Matheus Vernet Machado Bressan Wilke , Jennifer Goldstein , Emily Groopman , Shruthi Mohan , Amber Waddell , Raquel Fernandez , Hongjie Chen , Deeksha Bali , Heather Baudet , Lorne Clarke , Christina Hung , Rong Mao , Tatiana Yuzyuk , William J. Craigen , Filippo Pinto e Vairo
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引用次数: 0

摘要

导言溶酶体功能障碍引起的疾病往往涉及多个系统,导致大量的发病率和死亡率。确保溶酶体疾病(LD)患者的准确诊断非常重要,尤其是随着基因检测作为主要诊断方法的地位日益突出。随着外显子组和基因组测序等更全面检测方法的使用,与溶酶体疾病相关的基因列表不断扩大,了解这些基因的临床有效性以及确定适合纳入多基因检测和测序面板的基因势在必行。临床基因组资源(ClinGen)致力于确定基因和变异的临床重要性,以支持精准医疗。作为这项工作的一部分,ClinGen 开发了一个半定量框架,用于评估基因在疾病中作用的证据强度。考虑到不同实验室提供的 LD 面板中基因组成的多样性,以及对影响次级溶酶体功能的基因变异不断发展的理解,我们开发了一套定义 LD 的评分系统(溶酶体疾病评分系统 - LDSS)。该系统旨在帮助确定基因的优先级,以便进行临床有效性整理,并评估基因是否适合用于 LD 靶向测序板。方法通过文献综述(包括与经典指定的 LD 和 LFRD 相关的术语),我们确定了 14 项标准,分为 "整体定义"、"表型 "和 "病理生理学"。这些标准包括 "未消化或部分消化的大分子在溶酶体内积聚 "和 "与影响多个器官和系统的广泛临床表现相关 "等概念。这些标准及其各自的加权值通过专家小组的评估进行了完善,将其区分为 "主要 "和 "次要 "标准。结果最终的 LDSS 包括 4 个主要标准和 10 个次要标准,定义 LD 的临界值为 2 个主要标准或 1 个主要标准和 3 个次要标准。有趣的是,当同时应用 LDN 列表和包含临床面板中的基因并作为 LFRD 基因公布的综合基因列表时,我们发现了 4 个基因(GRN、SLC29A3、CLN7 和 VPS33A)不在 LDN 列表中,但被认为与 LD 相关。相反,LDN 列表中的一些非经典基因,如 MTOR、OCRL 和 SLC9A6,因其相关疾病实体而获得的 LDSS 分数较低。虽然这些基因可能不适合纳入临床 LD 多基因小组,但可以考虑将它们纳入其他非 LD 基因小组。通过识别在 LDSS 中得分较高的基因,该方法提高了 ClinGen LD GCEP 基因筛选的效率。结论 LDSS 不仅是在临床有效性筛选之前确定基因优先级的工具,还有助于目前关于 LD 定义的讨论。此外,LDSS 还提供了一个灵活的框架,可以适应未来的发现,从而确保其在不断扩展的 LD 研究领域中的相关性。
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Developing a scoring system for gene curation prioritization in lysosomal diseases

Introduction

Diseases caused by lysosomal dysfunction often exhibit multisystemic involvement, resulting in substantial morbidity and mortality. Ensuring accurate diagnoses for individuals with lysosomal diseases (LD) is of great importance, especially with the increasing prominence of genetic testing as a primary diagnostic method. As the list of genes associated with LD continues to expand due to the use of more comprehensive tests such as exome and genome sequencing, it is imperative to understand the clinical validity of the genes, as well as identify appropriate genes for inclusion in multi-gene testing and sequencing panels. The Clinical Genome Resource (ClinGen) works to determine the clinical importance of genes and variants to support precision medicine. As part of this work, ClinGen has developed a semi-quantitative framework to assess the strength of evidence for the role of a gene in a disease. Given the diversity in gene composition across LD panels offered by various laboratories and the evolving comprehension of genetic variants affecting secondary lysosomal functions, we developed a scoring system to define LD (Lysosomal Disease Scoring System - LDSS). This system sought to aid in the prioritization of genes for clinical validity curation and assess their suitability for LD-targeted sequencing panels.

Methods

Through literature review encompassing terms associated with both classically designated LD and LFRD, we identified 14 criteria grouped into “Overall Definition,” “Phenotype,” and “Pathophysiology.” These criteria included concepts such as the “accumulation of undigested or partially digested macromolecules within the lysosome” and being “associated with a wide spectrum of clinical manifestations impacting multiple organs and systems.” The criteria, along with their respective weighted values, underwent refinement through expert panel evaluation differentiating them between “major” and “minor” criteria. Subsequently, the LDSS underwent validation on 12 widely acknowledged LD and was later tested by applying these criteria to the Lysosomal Disease Network's (LDN) official Gene List.

Results

The final LDSS comprised 4 major criteria and 10 minor criteria, with a cutoff of 2 major or 1 major and 3 minor criteria established to define LD. Interestingly, when applied to both the LDN list and a comprehensive gene list encompassing genes included in clinical panels and published as LFRD genes, we identified four genes (GRN, SLC29A3, CLN7 and VPS33A) absent from the LDN list, that were deemed associated with LD. Conversely, a subset of non-classic genes included in the LDN list, such as MTOR, OCRL, and SLC9A6, received lower LDSS scores for their associated disease entities. While these genes may not be suitable for inclusion in clinical LD multi-gene panels, they could be considered for inclusion on other, non-LD gene panels.

Discussion

The LDSS offers a systematic approach to prioritize genes for clinical validity assessment. By identifying genes with high scores on the LDSS, this method enhanced the efficiency of gene curation by the ClinGen LD GCEP.

Conclusion

The LDSS not only serves as a tool for gene prioritization prior to clinical validity curation, but also contributes to the ongoing discussion on the definition of LD. Moreover, the LDSS provides a flexible framework adaptable to future discoveries, ensuring its relevance in the ever-expanding landscape of LD research.

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来源期刊
Molecular genetics and metabolism
Molecular genetics and metabolism 生物-生化与分子生物学
CiteScore
5.90
自引率
7.90%
发文量
621
审稿时长
34 days
期刊介绍: Molecular Genetics and Metabolism contributes to the understanding of the metabolic and molecular basis of disease. This peer reviewed journal publishes articles describing investigations that use the tools of biochemical genetics and molecular genetics for studies of normal and disease states in humans and animal models.
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