Mitochondrial Research Group, Institute for Ageing and Health, The Medical School, Newcastle University, UK.
Hum Mutat. 2011 Nov;32(11):1319-25. doi: 10.1002/humu.21575. Epub 2011 Sep 19.
Distinguishing pathogenic from polymorphic changes poses significant problems for geneticists and despite 30 years of postgenomic experience this remains the case in mitochondrial genetics. Base substitutions in mitochondrial tRNA (mt-tRNA) genes are particularly difficult, but important, because they are common causes of pathology and associated with high rates of transmission. Providing accurate genetic advice to patients and their families is of paramount importance in disease prevention, and brings into sharp focus the factors used to distinguish pathogenic from polymorphic variants. We have reevaluated our pathogenicity scoring system for mt-tRNA mutations following a considerable increase in the number reported since the system was devised in 2004. This allowed us to address notable issues including the underestimation of "definitely pathogenic" mutations resulting from insufficient data collection. We illustrate the robustness of our revised scoring system using novel pathogenic and previously reported polymorphic changes and conclude that while clear evidence from single-fiber and/or trans-mitochondrial cybrid studies remains the gold standard for assigning pathogenicity, our scoring system is valuable for deciding which mt-tRNA mutations to investigate further using these labor-intensive techniques.
区分致病性和多态性变化对遗传学家来说是一个重大问题，尽管有 30 年的后基因组经验，但在线粒体遗传学中仍然如此。线粒体 tRNA(mt-tRNA)基因中的碱基替换特别困难，但也很重要，因为它们是导致疾病的常见原因，并且与高的传递率有关。为患者及其家属提供准确的遗传咨询对于预防疾病至关重要，并且使用于区分致病性和多态性变体的因素变得非常重要。自 2004 年制定该系统以来，我们报道的 mt-tRNA 突变数量显著增加，因此我们重新评估了我们的致病性评分系统。这使我们能够解决一些值得注意的问题，包括由于数据收集不足而低估“肯定致病性”突变的问题。我们使用新的致病性和以前报道的多态性变化来说明我们修订后的评分系统的稳健性，并得出结论，虽然来自单纤维和/或跨线粒体杂种细胞研究的明确证据仍然是确定致病性的金标准，但我们的评分系统对于决定使用这些劳动密集型技术进一步研究哪些 mt-tRNA 突变非常有用。
