Diagnostic utility of transcriptome sequencing for rare Mendelian diseases

Hane Lee; Alden Y Huang; Lee-Kai Wang; Amanda J Yoon; Genecee Renteria; Ascia Eskin; Rebecca H Signer; Naghmeh Dorrani; Shirley Nieves-Rodriguez; Jijun Wan; Emilie D Douine; Jeremy D Woods; Esteban C Dell'Angelica; Brent L Fogel; Martin G Martin; Manish J Butte; Neil H Parker; Richard T Wang; Perry B Shieh; Derek A Wong; Natalie Gallant; Kathryn E Singh; Y Jane Tavyev Asher; Janet S Sinsheimer; Deborah Krakow; Sandra K Loo; Patrick Allard; Jeanette C Papp; Undiagnosed Diseases Network; Christina G S Palmer; Julian A Martinez-Agosto; Stanley F Nelson

doi:10.1038/s41436-019-0672-1

Diagnostic utility of transcriptome sequencing for rare Mendelian diseases

Genet Med. 2020 Mar;22(3):490-499. doi: 10.1038/s41436-019-0672-1. Epub 2019 Oct 14.

Authors

Hane Lee^{1

2}, Alden Y Huang³, Lee-Kai Wang³, Amanda J Yoon², Genecee Renteria², Ascia Eskin², Rebecca H Signer², Naghmeh Dorrani⁴, Shirley Nieves-Rodriguez², Jijun Wan², Emilie D Douine², Jeremy D Woods⁴, Esteban C Dell'Angelica², Brent L Fogel^{2

5}, Martin G Martin⁴, Manish J Butte^{4

6}, Neil H Parker⁷, Richard T Wang², Perry B Shieh⁵, Derek A Wong⁴, 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 Loo¹⁶, Patrick Allard¹⁷, Jeanette C Papp²; Undiagnosed Diseases Network; Christina G S Palmer^{2

16

17}, Julian A Martinez-Agosto^{2

4

16}, Stanley F Nelson^{18

19

20}

Affiliations

¹ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
² Department of Human Genetics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
³ Institute for Precision Health, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
⁴ Department of Pediatrics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
⁵ Department of Neurology, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
⁶ Department of Microbiology, Immunology, and Molecular Genetics, University of California-Los Angeles, Los Angeles, CA, USA.
⁷ Department of Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
⁸ Department of Pediatrics, School of Medicine, University of California-Irvine, Irvine, CA, USA.
⁹ Miller Children's and Women's Hospital, Long Beach, CA, USA.
¹⁰ Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹¹ Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹² Department of Biomathematics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
¹³ Department of Biostatistics, Fielding School of Public Health, University of California-Los Angeles, Los Angeles, CA, USA.
¹⁴ Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
¹⁵ Department of Orthopaedic Surgery, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
¹⁶ Department of Psychiatry & Biobehavioral Sciences, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
¹⁷ Institute for Society and Genetics, Life Sciences, University of California-Los Angeles, Los Angeles, CA, USA.
¹⁸ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA. [email protected].
¹⁹ Department of Human Genetics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA. [email protected].
²⁰ Department of Pediatrics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA. [email protected].

Abstract

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.

Keywords: exome sequencing; genome sequencing; molecular diagnosis; transcriptome sequencing; undiagnosed rare Mendelian diseases.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Exome / genetics
Exome Sequencing / standards
Genetic Diseases, Inborn / diagnosis*
Genetic Diseases, Inborn / genetics
Genetic Testing / standards
Humans
Mutation / genetics
Pathology, Molecular*
RNA-Seq / standards
Rare Diseases / diagnosis*
Rare Diseases / genetics
Sequence Analysis, DNA / standards
Transcriptome / genetics*
Whole Genome Sequencing / standards

Abstract

Publication types

MeSH terms

Grants and funding