逐步应用基因组学和转录组学技术提高孟德尔疾病的诊断率
Stepwise use of genomics and transcriptomics technologies increases diagnostic yield in Mendelian disorders.
摘要(中文译文)
多组学为诊断实验室提供了有价值且日益可及的技术，有助于寻找潜在的第二梯队策略来帮助未确诊的罕见病患者，尤其是临床诊断为罕见OMIM（在线人类孟德尔遗传）疾病的患者。然而，对于标准方法结果为阴性后应采用的最佳诊断照护路径，目前尚无共识。在15例临床诊断为可识别的OMIM疾病但一线遗传学结果阴性或不确定的未确诊个体中，我们探索了采用多种新型组学技术的多步骤方法用于建立分子诊断的效用。纳入标准包括临床常染色体隐性遗传病诊断且一线分析发现目标基因中单个杂合致病性变异（60%-9/15），或临床诊断为X连锁隐性或常染色体显性遗传病但未发现致病性变异（40%-6/15）。我们进行了多步骤分析，包括短读长基因组测序（srGS）以及根据GS分析结果选择的补充方法，如mRNA测序（mRNA-seq）、长读长基因组测序（lrGS）或光学基因组图谱（oGM）。单独srGS或联合其他基因组和/或转录组技术，通过识别一线靶向检测遗漏的单核苷酸变异/插入缺失、识别影响转录的变异，或有时需要lrGS或oGM才能表征的结构变异，使我们能够解决87%个体的诊断问题。假设驱动的联合组学技术实施在识别分子病因方面尤为有效。在本研究中，我们详细介绍了在一个先前已接受过检查、具有典型临床诊断但无分子病因的患者试点队列中实施基因组学和转录组学技术的经验。
Abstract
Multi-omics offer worthwhile and increasingly accessible technologies to diagnostic laboratories seeking potential second-tier strategies to help patients with unresolved rare diseases, especially patients clinically diagnosed with a rare OMIM (Online Mendelian Inheritance in Man) disease. However, no consensus exists regarding the optimal diagnostic care pathway to adopt after negative results with standard approaches. In 15 unsolved individuals clinically diagnosed with recognizable OMIM diseases but with negative or inconclusive first-line genetic results, we explored the utility of a multi-step approach using several novel omics technologies to establish a molecular diagnosis. Inclusion criteria included a clinical autosomal recessive disease diagnosis and single heterozygous pathogenic variant in the gene of interest identified by first-line analysis (60%-9/15) or a clinical diagnosis of an X-linked recessive or autosomal dominant disease with no causative variant identified (40%-6/15). We performed a multi-step analysis involving short-read genome sequencing (srGS) and complementary approaches such as mRNA sequencing (mRNA-seq), long-read genome sequencing (lrG), or optical genome mapping (oGM) selected according to the outcome of the GS analysis. SrGS alone or in combination with additional genomic and/or transcriptomic technologies allowed us to resolve 87% of individuals by identifying single nucleotide variants/indels missed by first-line targeted tests, identifying variants affecting transcription, or structural variants sometimes requiring lrGS or oGM for their characterization. Hypothesis-driven implementation of combined omics technologies is particularly effective in identifying molecular etiologies. In this study, we detail our experience of the implementation of genomics and transcriptomics technologies in a pilot cohort of previously investigated patients with a typical clinical diagnosis without molecular etiology.
如何引用
AMA
Estelle Colin, Yannis Duffourd, Martin Chevarin, Emilie Tisserant, Simon Verdez, Julien Paccaud, et al. Stepwise use of genomics and transcriptomics technologies increases diagnostic yield in Mendelian disorders.. Frontiers in cell and developmental biology. 2023; doi:10.3389/fcell.2023.1021920.
APA
Estelle Colin, Yannis Duffourd, Martin Chevarin, Emilie Tisserant, Simon Verdez, Julien Paccaud, et al (2023). Stepwise use of genomics and transcriptomics technologies increases diagnostic yield in Mendelian disorders.. Frontiers in cell and developmental biology. https://doi.org/10.3389/fcell.2023.1021920
GB/T 7714
Estelle Colin, Yannis Duffourd, Martin Chevarin, Emilie Tisserant, Simon Verdez, Julien Paccaud, et al. Stepwise use of genomics and transcriptomics technologies increases diagnostic yield in Mendelian disorders.[J]. Frontiers in cell and developmental biology, 2023 doi:10.3389/fcell.2023.1021920.
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