Institute of Human Genetics, Technische Universität München, Trogerstrasse 32, 81675, Munich, Germany.
Institute of Human Genetics, Helmholtz Zentrum München, Munich, Germany.
J Inherit Metab Dis. 2018 May;41(3):525-532. doi: 10.1007/s10545-017-0133-4. Epub 2018 Jan 25.
Exome wide sequencing techniques have revolutionized molecular diagnostics in patients with suspected inborn errors of metabolism or neuromuscular disorders. However, the diagnostic yield of 25-60% still leaves a large fraction of individuals without a diagnosis. This indicates a causative role for non-exonic regulatory variants not covered by whole exome sequencing. Here we review how systematic RNA-sequencing analysis (RNA-seq, "transcriptomics") lead to a molecular diagnosis in 10-35% of patients in whom whole exome sequencing failed to do so. Importantly, RNA-sequencing based discoveries cannot only guide molecular diagnosis but might also unravel therapeutic intervention points such as antisense oligonucleotide treatment for splicing defects as recently reported for spinal muscular atrophy.
外显子组测序技术在疑似先天性代谢错误或神经肌肉疾病患者的分子诊断中引发了革命。然而，25-60%的诊断率仍然让很大一部分人无法得到诊断。这表明外显子组测序未涵盖的非外显子调控变异可能起致病作用。在这里，我们回顾了系统的 RNA 测序分析（RNA-seq，“转录组学”）如何在全外显子组测序未能做出诊断的 10-35%的患者中实现分子诊断。重要的是，基于 RNA 测序的发现不仅可以指导分子诊断，还可以揭示治疗干预点，例如最近报道的用于脊髓性肌萎缩症的剪接缺陷的反义寡核苷酸治疗。
