Translating Muscle RNAseq Into the Clinic for the Diagnosis of Muscle Diseases

ObjectiveApproximately half of patients with hereditary myopathies remain without a definitive genetic diagnosis after DNA next-generation sequencing (NGS). Here, we implemented transcriptome analysis of muscle biopsies as a complementary diagnostic tool for patients with muscle disease but no defin...

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Detalles Bibliográficos
Autores: Segarra-Casas, A, Domínguez-González, C, Natera-de Benito, D, Kapetanovic, S, Hernández-Laín, A, Estévez-Arias, B, Llansó, L, Ortez, C, Jou, C, Martí-Carrera, I, López-Márquez, A, Rodríguez, MJ, González-Mera, L, Nedkova, V, Fernández-Torrón, R, Rodríguez-Santiago, B, Jimenez-Mallebrera, C, Juntas-Morales, R, López-de Munain, A, Surrallés, J, Nascimento, A, Gallardo, E, Olivé, M, Gallano, P, González-Quereda, L
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repositorio:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:oai:iibsantpau.fundanetsuite.com:p19749
Acceso en línea:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=19749
Access Level:acceso abierto
Palabra clave:alternative splicing
congenital myopathy
genetic diagnosis
muscular dystrophy
neuromuscular diseases
RNA sequencing
transcriptomics
Descripción
Sumario:ObjectiveApproximately half of patients with hereditary myopathies remain without a definitive genetic diagnosis after DNA next-generation sequencing (NGS). Here, we implemented transcriptome analysis of muscle biopsies as a complementary diagnostic tool for patients with muscle disease but no definitive genetic diagnosis after exome sequencing.MethodsIn total, 70 undiagnosed cases with suspected genetic muscular dystrophies or congenital myopathies were included in the study. Muscle RNAseq comprised the analysis of aberrant splicing, aberrant expression, and monoallelic expression. In addition, existing NGS data or variant calling from RNAseq were reanalyzed, and genome sequencing was performed in selected cases. Four aberrant splicing open-source tools were compared and assessed.ResultsRNAseq established a diagnosis in 10/70 patients (14.3%) by identifying aberrant transcripts produced by single nucleotide variants (7/10) or copy number variants (3/10). Reanalysis of NGS data allowed the diagnosis in 9/70 individuals (12.9%). Based on this cohort, FRASER was the tool that reported more splicing outlier events per sample while showing the highest accuracy (81.26%).ConclusionsWe demonstrate the utility of RNAseq in identifying causative variants in muscle diseases. Evaluation of four aberrant splicing tools allowed efficient identification of most pathogenic splicing events, obtaining a manageable number of candidate events for manual inspection, demonstrating feasibility for translation into a clinical setting. We also show how the integration of omic technologies reduces the turnaround time to identify causative variants.

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