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Transcriptome-directed analysis for Mendelian disease diagnosis overcomes limitations of conventional genomic testing
- Source :
- J Clin Invest
- Publication Year :
- 2021
- Publisher :
- American Society for Clinical Investigation, 2021.
-
Abstract
- BACKGROUND: Transcriptome sequencing (RNA-seq) improves diagnostic rates in individuals with suspected Mendelian conditions to varying degrees, primarily by directing the prioritization of candidate DNA variants identified on exome or genome sequencing (ES/GS). Here we implemented an RNA-seq–guided method to diagnose individuals across a wide range of ages and clinical phenotypes. METHODS: One hundred fifteen undiagnosed adult and pediatric patients with diverse phenotypes and 67 family members (182 total individuals) underwent RNA-seq from whole blood and skin fibroblasts at the Baylor College of Medicine (BCM) Undiagnosed Diseases Network clinical site from 2014 to 2020. We implemented a workflow to detect outliers in gene expression and splicing for cases that remained undiagnosed despite standard genomic and transcriptomic analysis. RESULTS: The transcriptome-directed approach resulted in a diagnostic rate of 12% across the entire cohort, or 17% after excluding cases solved on ES/GS alone. Newly diagnosed conditions included Koolen–de Vries syndrome (KANSL1), Renpenning syndrome (PQBP1), TBCK-associated encephalopathy, NSD2- and CLTC-related intellectual disability, and others, all with negative conventional genomic testing, including ES and chromosomal microarray (CMA). Skin fibroblasts exhibited higher and more consistent expression of clinically relevant genes than whole blood. In solved cases with RNA-seq from both tissues, the causative defect was missed in blood in half the cases but none from fibroblasts. CONCLUSIONS: For our cohort of undiagnosed individuals with suspected Mendelian conditions, transcriptome-directed genomic analysis facilitated diagnoses, primarily through the identification of variants missed on ES and CMA. TRIAL REGISTRATION: Not applicable. FUNDING: NIH Common Fund, BCM Intellectual and Developmental Disabilities Research Center, Eunice Kennedy Shriver National Institute of Child Health & Human Development.
- Subjects :
- Adult
Male
0301 basic medicine
medicine.medical_specialty
Adolescent
Microarray
Bioinformatics
DNA sequencing
03 medical and health sciences
symbols.namesake
0302 clinical medicine
Molecular genetics
Intellectual disability
medicine
Humans
RNA-Seq
Child
Exome
Skin
business.industry
Genetic Diseases, Inborn
General Medicine
Fibroblasts
medicine.disease
030104 developmental biology
Child, Preschool
030220 oncology & carcinogenesis
Cohort
Mendelian inheritance
symbols
Female
Personalized medicine
Clinical Medicine
business
Subjects
Details
- ISSN :
- 15588238 and 00219738
- Volume :
- 131
- Database :
- OpenAIRE
- Journal :
- Journal of Clinical Investigation
- Accession number :
- edsair.doi.dedup.....a9fb813495685262f82f1c4f89ebd07e