Genetic diagnosis of Mendelian disorders via RNA sequencing.
Genetic diagnosis of Mendelian disorders via RNA sequencing.
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DOI：
10.1038/ncomms15824
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发表时间：
2017-06-12
影响因子：
16.6
通讯作者：
Prokisch H
中科院分区：
文献类型：
--
作者：
Kremer LS;Bader DM;Mertes C;Kopajtich R;Pichler G;Iuso A;Haack TB;Graf E;Schwarzmayr T;Terrile C;Koňaříková E;Repp B;Kastenmüller G;Adamski J;Lichtner P;Leonhardt C;Funalot B;Donati A;Tiranti V;Lombes A;Jardel C;Gläser D;Taylor RW;Ghezzi D;Mayr JA;Rötig A;Freisinger P;Distelmaier F;Strom TM;Meitinger T;Gagneur J;Prokisch H
在各种孟德尔疾病中，大约50-75%的患者没有接受通过外显子组测序的遗传诊断，表明非编码区中的致病变体。虽然基因组测序原则上揭示了所有的遗传变异，但它们的数量庞大和注释较差，使得优先排序具有挑战性。在这里，我们展示了转录组测序的力量，以分子诊断10%（48例中的5例）的乳腺癌患者，并确定其余的候选基因。我们发现了一个异常表达基因的中位数，五个异常剪接事件和六个单等位基因表达的罕见变异的患者来源的成纤维细胞，并建立每种致病作用。私有外显子通常产生于隐蔽的剪接位点，为变体优先化提供了重要线索。一个这样的事件是发现在复合物I组装因子TIMMDC 1建立一个新的疾病相关基因。总之，我们的研究扩展了用于检测非外显子变异的诊断工具，并提供了具有病理相关性的内含子功能丧失变异的实例。单靠基因组测序无法为许多孟德尔疾病患者提供遗传诊断。在这里，作者利用RNA测序来补充罕见线粒体疾病患者的基因分型，通过检测异常RNA表达，剪接和等位基因特异性表达。
Across a variety of Mendelian disorders, ∼50–75% of patients do not receive a genetic diagnosis by exome sequencing indicating disease-causing variants in non-coding regions. Although genome sequencing in principle reveals all genetic variants, their sizeable number and poorer annotation make prioritization challenging. Here, we demonstrate the power of transcriptome sequencing to molecularly diagnose 10% (5 of 48) of mitochondriopathy patients and identify candidate genes for the remainder. We find a median of one aberrantly expressed gene, five aberrant splicing events and six mono-allelically expressed rare variants in patient-derived fibroblasts and establish disease-causing roles for each kind. Private exons often arise from cryptic splice sites providing an important clue for variant prioritization. One such event is found in the complex I assembly factor TIMMDC1 establishing a novel disease-associated gene. In conclusion, our study expands the diagnostic tools for detecting non-exonic variants and provides examples of intronic loss-of-function variants with pathological relevance. Genome sequencing alone fails to provide a genetic diagnosis for many Mendelian disorder patients. Here, the authors utilize RNA sequencing to complement genotyping of patients with a rare mitochondrial disease by detecting aberrant RNA expression, splicing and allele-specific expression.