Comparative analysis of gene and disease selection in genomic newborn screening studies

IF 4.2 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Isabel R. Betzler, Maja Hempel, Ulrike Mütze, Stefan Kölker, Eva Winkler, Nicola Dikow, Sven F. Garbade, Christian P. Schaaf, Heiko Brennenstuhl
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Abstract

Genomic newborn screening (gNBS) is on the horizon given the decreasing costs of sequencing and the advanced understanding of the impact of genetic variants on health and diseases. Key to ongoing gNBS pilot studies is the selection of target diseases and associated genes to be included. In this study, we present a comprehensive analysis of seven published gene–disease lists from gNBS studies, evaluating gene–disease count, composition, group proportions, and ClinGen curations of individual disorders. Despite shared selection criteria, we observe substantial variation in total gene count (median 480, range 237–889) and disease group composition. An intersection was identified for 53 genes, primarily inherited metabolic diseases (83%, 44/53). Each study investigated a subset of exclusive gene–disease pairs, and the total number of exclusive gene–disease pairs was positively correlated with the total number of genes included per study. While most pairs receive “Definitive” or “Strong” ClinGen classifications, some are labeled as “Refuted” (n = 5) or “Disputed” (n = 28), particularly in genetic cardiac diseases. Importantly, 17%–48% of genes lack ClinGen curation. This study underscores the current absence of consensus recommendations for selection criteria for target diseases for gNBS resulting in diversity in proposed gene–disease pairs, their coupling with gene variations and the use of ClinGen curation. Our findings provide crucial insights into the selection of target diseases and accompanying gene variations for future gNBS program, emphasizing the necessity for ongoing collaboration and discussion about criteria harmonization for panel selection to ensure the screening's objectivity, integrity, and broad acceptance.

Abstract Image

基因组新生儿筛查研究中基因和疾病选择的比较分析。
随着测序成本的降低以及对基因变异对健康和疾病影响的深入了解,基因组新生儿筛查(gNBS)即将到来。正在进行的 gNBS 试验研究的关键是选择目标疾病和相关基因。在本研究中,我们对 gNBS 研究中已发表的七份基因-疾病列表进行了全面分析,评估了基因-疾病的数量、组成、组别比例以及 ClinGen 对单个疾病的编辑。尽管选择标准相同,但我们观察到基因总数(中位数为 480 个,范围为 237-889 个)和疾病组构成存在很大差异。我们发现有 53 个基因存在交叉,主要是遗传代谢性疾病(83%,44/53)。每项研究都调查了一部分排他性基因-疾病配对,排他性基因-疾病配对的总数与每项研究包含的基因总数呈正相关。虽然大多数基因对都获得了 "确定 "或 "强 "的 ClinGen 分类,但也有一些基因对被标记为 "驳斥"(5 个)或 "有争议"(28 个),尤其是在遗传性心脏病方面。重要的是,17%-48% 的基因缺乏 ClinGen 分类。这项研究强调,目前对 gNBS 目标疾病的选择标准缺乏共识性建议,导致提出的基因-疾病配对、其与基因变异的耦合以及 ClinGen 资料的使用存在多样性。我们的研究结果为未来 gNBS 计划目标疾病和伴随基因变异的选择提供了重要的启示,强调了持续合作和讨论统一面板选择标准的必要性,以确保筛查的客观性、完整性和广泛接受性。
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来源期刊
Journal of Inherited Metabolic Disease
Journal of Inherited Metabolic Disease 医学-内分泌学与代谢
CiteScore
9.50
自引率
7.10%
发文量
117
审稿时长
4-8 weeks
期刊介绍: The Journal of Inherited Metabolic Disease (JIMD) is the official journal of the Society for the Study of Inborn Errors of Metabolism (SSIEM). By enhancing communication between workers in the field throughout the world, the JIMD aims to improve the management and understanding of inherited metabolic disorders. It publishes results of original research and new or important observations pertaining to any aspect of inherited metabolic disease in humans and higher animals. This includes clinical (medical, dental and veterinary), biochemical, genetic (including cytogenetic, molecular and population genetic), experimental (including cell biological), methodological, theoretical, epidemiological, ethical and counselling aspects. The JIMD also reviews important new developments or controversial issues relating to metabolic disorders and publishes reviews and short reports arising from the Society''s annual symposia. A distinction is made between peer-reviewed scientific material that is selected because of its significance for other professionals in the field and non-peer- reviewed material that aims to be important, controversial, interesting or entertaining (“Extras”).
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