PT  - JOURNAL ARTICLE
AU  - Hong, Sung Eun
AU  - Kneissl, Jana
AU  - Cho, Anna
AU  - Kim, Man Jin
AU  - Park, Soojin
AU  - Lee, Jeongeun
AU  - Woo, Sijae
AU  - Kim, Sora
AU  - Kim, Jun-Soon
AU  - Kim, Soo Yeon
AU  - Jung, Sungwon
AU  - Kim, Jinkuk
AU  - Shin, Je-Young
AU  - Chae, Jong-Hee
AU  - Choi, Murim
TI  - Transcriptome-based variant calling and aberrant mRNA discovery enhance diagnostic efficiency for neuromuscular diseases
AID  - 10.1136/jmedgenet-2021-108307
DP  - 2022 Nov 01
TA  - Journal of Medical Genetics
PG  - 1075--1081
VI  - 59
IP  - 11
4099  - http://jmg.bmj.com/content/59/11/1075.short
4100  - http://jmg.bmj.com/content/59/11/1075.full
SO  - J Med Genet2022 Nov 01; 59
AB  - Background Whole-exome sequencing-based diagnosis of rare diseases typically yields 40%–50% of success rate. Precise diagnosis of the patients with neuromuscular disorders (NMDs) has been hampered by locus heterogeneity or phenotypic heterogeneity. We evaluated the utility of transcriptome sequencing as an independent approach in diagnosing NMDs.Methods The RNA sequencing (RNA-Seq) of muscle tissues from 117 Korean patients with suspected Mendelian NMD was performed to evaluate the ability to detect pathogenic variants. Aberrant splicing and CNVs were inspected to identify additional causal genetic factors for NMD. Aberrant splicing events in Dystrophin (DMD) were investigated by using antisense oligonucleotides (ASOs). A non-negative matrix factorisation analysis of the transcriptome data followed by cell type deconvolution was performed to cluster samples by expression-based signatures and identify cluster-specific gene ontologies.Results Our pipeline called 38.1% of pathogenic variants exclusively from the muscle transcriptomes, demonstrating a higher diagnostic rate than that achieved via exome analysis (34.9%). The discovery of variants causing aberrant splicing allowed the application of ASOs to the patient-derived cells, providing a therapeutic approach tailored to individual patients. RNA-Seq data further enabled sample clustering by distinct gene expression profiles that corresponded to clinical parameters, conferring additional advantages over exome sequencing.Conclusion The RNA-Seq-based diagnosis of NMDs achieves an increased diagnostic rate and provided pathogenic status information, which is not easily accessible through exome analysis.Data are available on reasonable request. Anonymised data not provided in the article may be shared at the request of any qualified investigator for purposes of replicating procedures and results.