PDF(Pubmed)
Abstract：
Despite the inevitable shift in medical practice towards a deeper understanding of disease etiology and progression through multigenic analysis, the profound historical impact of Mendelian diseases cannot be overlooked. These diseases, such as cystic fibrosis and thalassemia, are characterized by a single variant in a single gene leading to clinical conditions, and have significantly shaped our medical knowledge and treatments. In this respect, the monogenic approach inevitably results in the underutilization of Next-Generation Sequencing (NGS) data. Herein, a retrospective study was performed to assess the diagnostic value of the clinical exome in 32 probands with specific phenotypic characteristics (patients with autoinflammation and immunological dysregulation, N = 20; patients diagnosed with Hemolytic uremic syndrome N = 9; and patients with Waldenström macroglobulinemia, N = 3). A gene enrichment analysis was performed using the *. VCF file generated by SOPHiA-DDM-v4. This analysis selected a subset of genes containing pathogenic or likely pathogenic variants with autosomal dominant (AD) inheritance. In addition, all variants of uncertain significance (VUS) were included, filtered by AD inheritance mode, the presence of compound heterozygotes, and a minor allele frequency (MAF) cutoff of 0.05 %. The aim of the pipeline described here is based on a perspective shift that focuses on analyzing patients\' gene assets, offering new light on the complex interplay between genetics and disease presentation. Integrating this approach into clinical practices could significantly enhance the management of patients with rare genetic disorders.
摘要：
尽管医学实践不可避免地转向通过多基因分析更深入地了解疾病的病因和进展，孟德尔疾病的深刻历史影响不容忽视。这些疾病,如囊性纤维化和地中海贫血，特征是单个基因中的单个变异导致临床疾病，并显著塑造了我们的医学知识和治疗方法。在这方面,单基因方法不可避免地导致下一代测序(NGS)数据的利用不足。在这里，进行了一项回顾性研究，以评估32个具有特定表型特征的先证者（患有自身炎症和免疫失调的患者，N=20；诊断为溶血性尿毒综合征的患者N=9；以及Waldenström巨球蛋白血症的患者，N=3)。使用*进行基因富集分析。SOPHIA-DDM-v4生成的VCF文件。该分析选择了包含具有常染色体显性遗传(AD)遗传的致病性或可能的致病性变体的基因子集。此外,包括所有不确定意义（VUS）的变体，按AD继承模式过滤，复合杂合子的存在，和0.05%的次要等位基因频率(MAF)截止值。这里描述的管道的目的是基于一种视角转变，专注于分析患者的基因资产，为遗传学和疾病表现之间复杂的相互作用提供了新的思路。将这种方法纳入临床实践可以显着提高罕见遗传疾病患者的管理。
