ArticleAmerican journal of human genetics2022
MRSD: A quantitative approach for assessing suitability of RNA-seq in the investigation of mis-splicing in Mendelian disease.
Article in American journal of human genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 27 citations in OpenAlex.
- Translating transcriptomics analysis into diagnostic workflows: clinical variant identification and interpretation in hypothesis-driven and hypothesis-free approaches.EBioMedicine · 2026Article
- The utility of ultra-deep RNA sequencing in Mendelian disorder diagnostics.American journal of human genetics · 2025Article
- Cracking rare disorders: a new minimally invasive RNA-seq protocol.NPJ genomic medicine · 2025Article
- Identification of diagnostic candidates in Mendelian disorders using an RNA sequencing-centric approach.Genome medicine · 2024Article
- RNA variant assessment using transactivation and transdifferentiation.American journal of human genetics · 2024Article
- CRISPR activation to characterize splice-altering variants in easily accessible cells.American journal of human genetics · 2024Article
- Splicing defects in rare diseases: transcriptomics and machine learning strategies towards genetic diagnosis.Briefings in bioinformatics · 2023Review
- A homozygous POLR1A variant causes leukodystrophy and affects protein homeostasis.Brain : a journal of neurology · 2023Article
- Web-accessible application for identifying pathogenic transcripts with RNA-seq: Increased sensitivity in diagnosis of neurodevelopmental disorders.American journal of human genetics · 2023Article
- Rapid genome sequencing for pediatrics.Human mutation · 2022Review
- Transcriptome analysis provides critical answers to the "variants of uncertain significance" conundrum.Human mutation · 2022Review
- Recommendations for clinical interpretation of variants found in non-coding regions of the genome.Genome medicine · 2022Article
- Targeted RNAseq Improves Clinical Diagnosis of Very Early-Onset Pediatric Immune Dysregulation.Journal of personalized medicine · 2022Article
- Clinical implementation of RNA sequencing for Mendelian disease diagnostics.Genome medicine · 2022Article
- Splicing in the Diagnosis of Rare Disease: Advances and Challenges.Frontiers in genetics · 2021Review
- Strategies to Uplift Novel Mendelian Gene Discovery for Improved Clinical Outcomes.Frontiers in genetics · 2021Review
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Authors and funding
14 authors at 5 institutions in 1 country.
Funding
Abstract
Variable levels of gene expression between tissues complicates the use of RNA sequencing of patient biosamples to delineate the impact of genomic variants. Here, we describe a gene- and tissue-specific metric to inform the feasibility of RNA sequencing. This overcomes limitations of using expression values alone as a metric to predict RNA-sequencing utility. We have derived a metric, minimum required sequencing depth (MRSD), that estimates the depth of sequencing required from RNA sequencing to achieve user-specified sequencing coverage of a gene, transcript, or group of genes. We applied MRSD across four human biosamples: whole blood, lymphoblastoid cell lines (LCLs), skeletal muscle, and cultured fibroblasts. MRSD has high precision (90.1%-98.2%) and overcomes transcript region-specific sequencing biases. Applying MRSD scoring to established disease gene panels shows that fibroblasts, of these four biosamples, are the optimum source of RNA for 63.1% of gene panels. Using this approach, up to 67.8% of the variants of uncertain significance in ClinVar that are predicted to impact splicing could be assayed by RNA sequencing in at least one of the biosamples. We demonstrate the utility and benefits of MRSD as a metric to inform functional assessment of splicing aberrations, in particular in the context of Mendelian genetic disorders to improve diagnostic yield.
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