Diagnostic utility of transcriptome sequencing for rare Mendelian diseases.,Genetics in Medicine

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Diagnostic utility of transcriptome sequencing for rare Mendelian diseases.
Genetics in Medicine ( IF 6.6 ) Pub Date : 2019-10-14 , DOI: 10.1038/s41436-019-0672-1
Hane Lee _{1,

2} , Alden Y Huang ₃ , Lee-Kai Wang ₃ , Amanda J Yoon ₂ , Genecee Renteria ₂ , Ascia Eskin ₂ , Rebecca H Signer ₂ , Naghmeh Dorrani ₄ , Shirley Nieves-Rodriguez ₂ , Jijun Wan ₂ , Emilie D Douine ₂ , Jeremy D Woods ₄ , Esteban C Dell'Angelica ₂ , Brent L Fogel _{2,

5} , Martin G Martin ₄ , Manish J Butte _{4,

6} , Neil H Parker ₇ , Richard T Wang ₂ , Perry B Shieh ₅ , Derek A Wong ₄ , Natalie Gallant _{8,

9} , Kathryn E Singh _{8,

9} , Y Jane Tavyev Asher _{4,

10,

11} , Janet S Sinsheimer _{2,

12,

13} , Deborah Krakow _{2,

4,

14,

15} , Sandra K Loo ₁₆ , Patrick Allard ₁₇ , Jeanette C Papp ₂ , , Christina G S Palmer _{2,

16,

17} , Julian A Martinez-Agosto _{2,

4,

16} , Stanley F Nelson _{1,

2,

4}

Affiliation

Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
Department of Human Genetics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
Institute for Precision Health, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
Department of Pediatrics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
Department of Neurology, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
Department of Microbiology, Immunology, and Molecular Genetics, University of California-Los Angeles, Los Angeles, CA, USA.
Department of Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
Department of Pediatrics, School of Medicine, University of California-Irvine, Irvine, CA, USA.
Miller Children's and Women's Hospital, Long Beach, CA, USA.
Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Department of Biomathematics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
Department of Biostatistics, Fielding School of Public Health, University of California-Los Angeles, Los Angeles, CA, USA.
Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
Department of Orthopaedic Surgery, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
Department of Psychiatry & Biobehavioral Sciences, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
Institute for Society and Genetics, Life Sciences, University of California-Los Angeles, Los Angeles, CA, USA.

Purpose

We investigated the value of transcriptome sequencing (RNAseq) in ascertaining the consequence of DNA variants on RNA transcripts to improve the diagnostic rate from exome or genome sequencing for undiagnosed Mendelian diseases spanning a wide spectrum of clinical indications.

Methods

From 234 subjects referred to the Undiagnosed Diseases Network, University of California–Los Angeles clinical site between July 2014 and August 2018, 113 were enrolled for high likelihood of having rare undiagnosed, suspected genetic conditions despite thorough prior clinical evaluation. Exome or genome sequencing and RNAseq were performed, and RNAseq data was integrated with genome sequencing data for DNA variant interpretation genome-wide.

Results

The molecular diagnostic rate by exome or genome sequencing was 31%. Integration of RNAseq with genome sequencing resulted in an additional seven cases with clear diagnosis of a known genetic disease. Thus, the overall molecular diagnostic rate was 38%, and 18% of all genetic diagnoses returned required RNAseq to determine variant causality.

Conclusion

In this rare disease cohort with a wide spectrum of undiagnosed, suspected genetic conditions, RNAseq analysis increased the molecular diagnostic rate above that possible with genome sequencing analysis alone even without availability of the most appropriate tissue type to assess.

中文翻译：

转录组测序对罕见孟德尔疾病的诊断效用。

目的

我们研究了转录组测序 (RNAseq) 在确定 DNA 变异对 RNA 转录本的影响方面的价值，以提高外显子组或基因组测序对跨越广泛临床适应症的未确诊孟德尔疾病的诊断率。

方法

在 2014 年 7 月至 2018 年 8 月期间，来自加州大学洛杉矶分校临床站点未确诊疾病网络的 234 名受试者中，尽管事先进行了全面的临床评估，但仍有 113 名受试者因极有可能患有罕见的未确诊、疑似遗传疾病而入组。进行了外显子组或基因组测序和 RNAseq，并将 RNAseq 数据与基因组测序数据整合，用于全基因组的 DNA 变异解释。