Institute of Human Genetics, Heidelberg University and University Hospital Heidelberg, Heidelberg, Germany.
Centre for Child and Adolescent Medicine, Division of Child Neurology and Metabolic Medicine, Heidelberg University and University Hospital Heidelberg, Heidelberg, Germany.
J Inherit Metab Dis. 2024 Sep;47(5):945-970. doi: 10.1002/jimd.12750. Epub 2024 May 16.
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.
鉴于测序成本的降低以及对遗传变异对健康和疾病影响的深入了解，基因组新生儿筛查 (gNBS) 即将成为现实。正在进行的 gNBS 试点研究的关键是选择要包含的目标疾病和相关基因。在这项研究中，我们对来自 gNBS 研究的七个已发表的基因-疾病清单进行了全面分析，评估了基因-疾病的数量、组成、组比例以及个体疾病的 ClinGen 分类。尽管有共同的选择标准，但我们观察到总基因数量（中位数 480，范围 237-889）和疾病组组成存在很大差异。确定了 53 个基因的交集，主要是遗传性代谢疾病（83%，44/53）。每个研究都调查了一组独特的基因-疾病对，并且每个研究中包含的独特基因-疾病对的总数与包括的基因总数呈正相关。虽然大多数对都获得了“明确”或“强烈”的 ClinGen 分类，但有些被标记为“反驳”（n=5）或“有争议”（n=28），特别是在遗传性心脏病中。重要的是，17%-48%的基因缺乏 ClinGen 分类。这项研究强调了目前缺乏 gNBS 目标疾病选择标准的共识建议，导致提出的基因-疾病对及其与基因变异的耦合以及 ClinGen 分类的使用存在多样性。我们的研究结果为未来 gNBS 计划中目标疾病和伴随基因变异的选择提供了重要的见解，强调了为确保筛查的客观性、完整性和广泛接受性，需要不断合作和讨论标准协调以进行面板选择的必要性。
