Beyond the exome: What’s next in diagnostic testing for Mendelian conditions,American Journal of Human Genetics

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Beyond the exome: What’s next in diagnostic testing for Mendelian conditions
American Journal of Human Genetics ( IF 9.8 ) Pub Date : 2023-08-03 , DOI: 10.1016/j.ajhg.2023.06.009
Monica H Wojcik ₁ , Chloe M Reuter ₂ , Shruti Marwaha ₂ , Medhat Mahmoud ₃ , Michael H Duyzend ₄ , Hayk Barseghyan ₅ , Bo Yuan ₆ , Philip M Boone ₄ , Emily E Groopman ₄ , Emmanuèle C Délot ₇ , Deepti Jain ₈ , Alba Sanchis-Juan ₉ , , Lea M Starita ₁₀ , Michael Talkowski ₁₁ , Stephen B Montgomery ₁₂ , Michael J Bamshad ₁₃ , Jessica X Chong ₁₄ , Matthew T Wheeler ₂ , Seth I Berger ₁₅ , Anne O'Donnell-Luria ₄ , Fritz J Sedlazeck ₁₆ , Danny E Miller ₁₇

Affiliation

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Division of Newborn Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
Center for Genetics Medicine Research, Children's National Research Institute, Children's National Hospital, Washington, DC 20010, USA; Department of Genomics and Precision Medicine, School of Medicine and Health Sciences, George Washington University, Washington, DC 20037, USA.
Department of Molecular and Human Genetics and Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Department of Genomics and Precision Medicine, School of Medicine and Health Sciences, George Washington University, Washington, DC 20037, USA; Center for Genetics Medicine Research, Children's National Research and Innovation Campus, Washington, DC, USA; Department of Pediatrics, George Washington University, School of Medicine and Health Sciences, George Washington University, Washington, DC 20037, USA.
Department of Biostatistics, School of Public Health, University of Washington, Seattle, WA 98195, USA.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
Brotman Baty Institute for Precision Medicine, University of Washington, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Brotman Baty Institute for Precision Medicine, University of Washington, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA 98195, USA.
Brotman Baty Institute for Precision Medicine, University of Washington, Seattle, WA 98195, USA; Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA 98195, USA.
Center for Genetics Medicine Research and Rare Disease Institute, Children's National Hospital, Washington, DC 20010, USA.
Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Computer Science, Rice University, 6100 Main Street, Houston, TX 77005, USA.
Brotman Baty Institute for Precision Medicine, University of Washington, Seattle, WA 98195, USA; Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA 98195, USA; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA.

Despite advances in clinical genetic testing, including the introduction of exome sequencing (ES), more than 50% of individuals with a suspected Mendelian condition lack a precise molecular diagnosis. Clinical evaluation is increasingly undertaken by specialists outside of clinical genetics, often occurring in a tiered fashion and typically ending after ES. The current diagnostic rate reflects multiple factors, including technical limitations, incomplete understanding of variant pathogenicity, missing genotype-phenotype associations, complex gene-environment interactions, and reporting differences between clinical labs. Maintaining a clear understanding of the rapidly evolving landscape of diagnostic tests beyond ES, and their limitations, presents a challenge for non-genetics professionals. Newer tests, such as short-read genome or RNA sequencing, can be challenging to order, and emerging technologies, such as optical genome mapping and long-read DNA sequencing, are not available clinically. Furthermore, there is no clear guidance on the next best steps after inconclusive evaluation. Here, we review why a clinical genetic evaluation may be negative, discuss questions to be asked in this setting, and provide a framework for further investigation, including the advantages and disadvantages of new approaches that are nascent in the clinical sphere. We present a guide for the next best steps after inconclusive molecular testing based upon phenotype and prior evaluation, including when to consider referral to research consortia focused on elucidating the underlying cause of rare unsolved genetic disorders.

中文翻译：

超越外显子组：孟德尔病症诊断测试的下一步是什么

尽管临床基因检测取得了进展，包括引入外显子组测序(ES)，但超过 50% 的疑似孟德尔病症患者缺乏精确的分子诊断。临床评估越来越多地由临床遗传学以外的专家进行，通常以分层方式进行，通常在 ES 之后结束。目前的诊断率反映了多种因素，包括技术限制、对变异致病性的不完全理解、缺失基因型-表型关联、复杂的基因-环境相互作用以及临床实验室之间的报告差异。对于非遗传学专业人士来说，保持对 ES 之外快速发展的诊断测试格局及其局限性的清晰了解是一项挑战。短读长基因组或 RNA 测序等较新的测试可能难以订购，而光学基因组作图和长读长DNA 测序等新兴技术在临床上尚不可用。此外，在不确定的评估之后，对于下一步的最佳步骤没有明确的指导。在这里，我们回顾为什么临床遗传评估可能呈阴性，讨论在这种情况下要提出的问题，并为进一步研究提供框架，包括临床领域新兴新方法的优点和缺点。我们根据表型和先前的评估提供了在不确定的分子测试后下一步最佳步骤的指南，包括何时考虑转介到专注于阐明罕见的未解决的遗传性疾病的根本原因的研究联盟。

更新日期：2023-08-03

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