Improving genetic diagnosis in Mendelian disease with transcriptome sequencing.
Improving genetic diagnosis in Mendelian disease with transcriptome sequencing.
复制标题
DOI：
10.1126/scitranslmed.aal5209
复制
发表时间：
2017-04-19
影响因子：
17.1
通讯作者：
MacArthur DG
中科院分区：
文献类型：
--
作者：
Cummings BB;Marshall JL;Tukiainen T;Lek M;Donkervoort S;Foley AR;Bolduc V;Waddell LB;Sandaradura SA;O'Grady GL;Estrella E;Reddy HM;Zhao F;Weisburd B;Karczewski KJ;O'Donnell-Luria AH;Birnbaum D;Sarkozy A;Hu Y;Gonorazky H;Claeys K;Joshi H;Bournazos A;Oates EC;Ghaoui R;Davis MR;Laing NG;Topf A;Genotype-Tissue Expression Consortium;Kang PB;Beggs AH;North KN;Straub V;Dowling JJ;Muntoni F;Clarke NF;Cooper ST;Bönnemann CG;MacArthur DG
外显子组和全基因组测序正日益成为孟德尔疾病诊断中的常规方法。尽管他们取得了成功，但目前对各种罕见疾病的基因组分析的诊断率约为25%至50%。我们探索了转录组测序[RNA测序(RNA-seq)]作为一种补充诊断工具在50例遗传未诊断的罕见肌肉疾病患者队列中的应用。我们描述了一种分析患者肌肉RNA-seq的集成方法，利用一个分析框架，与180多个对照骨骼肌样本相比，该分析框架专注于检测患者特有的转录水平变化。我们展示了RNA-SEQ在验证候选剪接破坏突变和识别外显子和深层内含子区域的剪接改变变体方面的能力，产生了35%的总体诊断率。我们还报告了在COL6A1中发现的一个高度重复的从头开始内含子突变，它导致了一个主要作用的剪接获得事件，扰乱了三螺旋结构域的关键甘氨酸重复基序。我们在外部VI型胶原样营养不良队列中总共27名遗传未解决的患者中发现了这种致病变异，从而解释了临床上提示患有VI型胶原营养不良的患者中约25%的患者先前的基因分析为阴性。总体而言，这项研究代表了转录组测序在罕见疾病诊断中的大规模系统应用，并强调了它在检测和解释当前标准诊断方法遗漏的变异方面的有效性。
Exome and whole-genome sequencing are becoming increasingly routine approaches in Mendelian disease diagnosis. Despite their success, the current diagnostic rate for genomic analyses across a variety of rare diseases is approximately 25 to 50%. We explore the utility of transcriptome sequencing [RNA sequencing (RNA-seq)] as a complementary diagnostic tool in a cohort of 50 patients with genetically undiagnosed rare muscle disorders. We describe an integrated approach to analyze patient muscle RNA-seq, leveraging an analysis framework focused on the detection of transcript-level changes that are unique to the patient compared to more than 180 control skeletal muscle samples. We demonstrate the power of RNA-seq to validate candidate splice-disrupting mutations and to identify splice-altering variants in both exonic and deep intronic regions, yielding an overall diagnosis rate of 35%. We also report the discovery of a highly recurrent de novo intronic mutation in COL6A1 that results in a dominantly acting splice-gain event, disrupting the critical glycine repeat motif of the triple helical domain. We identify this pathogenic variant in a total of 27 genetically unsolved patients in an external collagen VI–like dystrophy cohort, thus explaining approximately 25% of patients clinically suggestive of having collagen VI dystrophy in whom prior genetic analysis is negative. Overall, this study represents a large systematic application of transcriptome sequencing to rare disease diagnosis and highlights its utility for the detection and interpretation of variants missed by current standard diagnostic approaches.
登录
查看更多内容
影响因子：
14.9
作者：
Desmet FO;Hamroun D;Lalande M;Collod-Béroud G;Claustres M;Béroud C
通讯作者：
Béroud C
影响因子：
5.2
作者：
Kiiski, Kirsi;Lehtokari, Vilma-Lotta;Pelin, Katarina
通讯作者：
Pelin, Katarina
DOI：
10.1126/science.1262110
发表时间：
2015-05-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
GTEx Consortium
通讯作者：
GTEx Consortium
影响因子：
5.4
作者：
Begay RL;Graw S;Sinagra G;Merlo M;Slavov D;Gowan K;Jones KL;Barbati G;Spezzacatene A;Brun F;Di Lenarda A;Smith JE;Granzier HL;Mestroni L;Taylor M;Familial Cardiomyopathy Registry
通讯作者：
Familial Cardiomyopathy Registry
影响因子：
30.8
作者：
Jung-, Hyunchul;Lee, Donghoon;Lee, Eunjung
通讯作者：
Lee, Eunjung