Recent advances in understanding the molecular genetic basis of mitochondrial disease
Recent advances in understanding the molecular genetic basis of mitochondrial disease
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DOI：
10.1002/jimd.12104
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发表时间：
2020-01-01
影响因子：
4.2
通讯作者：
Taylor, Robert W.
中科院分区：
文献类型：
--
作者：
Thompson, Kyle;Collier, Jack J.;Taylor, Robert W.
线粒体疾病在相关的临床表现和潜在的遗传原因方面是非常不同的，目前描述了300多个疾病基因的致病变异。其中大约一半是在过去十年中被发现的，这是由于下一代测序技术的日益广泛的应用，特别是无偏的完整外显子组-以及后来的全基因组测序。这些技术允许从线粒体疾病患者那里收集更多的遗传数据，不断提高临床诊断的成功率。尽管取得了这些重大进展，但一些患者仍然没有明确的基因诊断。包含许多未知意义的变体的大数据集已经成为下一代测序策略的主要挑战，这些策略需要重要的功能验证来确认致病性。诊断和研究之间的这种接口对于继续扩大已知致病变异的列表并同时增强我们对线粒体生物学的知识至关重要。全外显子组测序、全基因组测序和其他“组学”技术，如转录组和蛋白质组学，将产生更多的数据，并使进一步询问和验证遗传原因，包括编码区以外的原因。这将进一步提高诊断产量，并强调对变异因果关系的功能评估在这一过程中发挥的不可或缺的作用--这是本审查的主要重点。
Mitochondrial disease is hugely diverse with respect to associated clinical presentations and underlying genetic causes, with pathogenic variants in over 300 disease genes currently described. Approximately half of these have been discovered in the last decade due to the increasingly widespread application of next generation sequencing technologies, in particular unbiased, whole exome-and latterly, whole genome sequencing. These technologies allow more genetic data to be collected from patients with mitochondrial disorders, continually improving the diagnostic success rate in a clinical setting. Despite these significant advances, some patients still remain without a definitive genetic diagnosis. Large datasets containing many variants of unknown significance have become a major challenge with next generation sequencing strategies and these require significant functional validation to confirm pathogenicity. This interface between diagnostics and research is critical in continuing to expand the list of known pathogenic variants and concomitantly enhance our knowledge of mitochondrial biology. The increasing use of whole exome sequencing, whole genome sequencing and other "omics" techniques such as transcriptomics and proteomics will generate even more data and allow further interrogation and validation of genetic causes, including those outside of coding regions. This will improve diagnostic yields still further and emphasizes the integral role that functional assessment of variant causality plays in this process-the overarching focus of this review.