Platt Julia, Cox Rachel, Enns Gregory M
Department of Pediatrics, Lucile Packard Children's Hospital, Stanford University, 300 Pasteur Drive, H-315, Stanford, CA, 94305, USA,
J Genet Couns. 2014 Aug;23(4):594-603. doi: 10.1007/s10897-013-9683-2. Epub 2014 Jan 8.
Mitochondrial next generation sequencing (NGS) panels offer single-step analysis of the numerous nuclear genes involved in the structure, function, and maintenance of mitochondria. However, the complexities of mitochondrial biology and genetics raise points for consideration in clinical use of these tests. To understand the current status of mitochondrial genetic testing, we assessed the gene offerings and consent forms of mitochondrial NGS panels available from seven US-based clinical laboratories. The NGS panels varied markedly in number of genes (101-1204 genes), and the proportion of genes causing "classic" mitochondrial diseases and their phenocopies ranged widely between labs (18 %-94 % of panel contents). All panels included genes not associated with classic mitochondrial diseases (6 %-28 % of panel contents), including genes causing adult-onset neurodegenerative disorders, cancer predisposition, and other genetic syndromes or inborn errors of metabolism. Five of the panels included genes that are not listed in OMIM to be associated with a disease phenotype (5 %-49 % of panel contents). None of the consent documents reviewed had options for patient preference regarding receipt of incidental findings. These findings raise points of discussion applicable to mitochondrial diagnostics, but also to the larger arenas of exome and genome sequencing, including the need to consider the boundaries between clinical and research testing, the necessity of appropriate informed consent, and the responsibilities of clinical laboratories and clinicians. Based on these findings, we recommend careful evaluation by laboratories of the genes offered on NGS panels, clear communication of the predicted phenotypes, and revised consent forms to allow patients to make choices about receiving incidental findings. We hope that our analysis and recommendations will help to maximize the considerable clinical utility of NGS panels for the diagnosis of mitochondrial disease.
线粒体下一代测序（NGS）检测板可对参与线粒体结构、功能和维持的众多核基因进行单步分析。然而，线粒体生物学和遗传学的复杂性为这些检测在临床应用中带来了一些需要考虑的问题。为了解线粒体基因检测的现状，我们评估了美国七家临床实验室提供的线粒体NGS检测板的基因项目和知情同意书。这些NGS检测板的基因数量差异显著（101 - 1204个基因），导致“经典”线粒体疾病及其拟表型的基因比例在不同实验室之间差异很大（占检测板内容的18% - 94%）。所有检测板都包含与经典线粒体疾病无关的基因（占检测板内容的6% - 28%），包括导致成人神经退行性疾病、癌症易感性以及其他遗传综合征或先天性代谢缺陷的基因。其中五个检测板包含未在《在线人类孟德尔遗传》（OMIM）中列出与疾病表型相关的基因（占检测板内容的5% - 49%）。审查的所有知情同意文件均未提供患者对接受偶然发现的偏好选项。这些发现不仅引发了适用于线粒体诊断的讨论要点，也适用于外显子组和基因组测序的更广泛领域，包括需要考虑临床检测与研究检测之间的界限、适当知情同意的必要性以及临床实验室和临床医生的责任。基于这些发现，我们建议实验室仔细评估NGS检测板上提供的基因，清晰传达预测的表型，并修订知情同意书，以便患者能够对是否接受偶然发现做出选择。我们希望我们的分析和建议将有助于最大限度地发挥NGS检测板在诊断线粒体疾病方面的巨大临床效用。
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