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Estévez-Arias, B.* ; Matalonga, L.* ; Yubero, D.* ; Polavarapu, K.* ; Codina, A.E.* ; Ortez, C.* ; Carrera-García, L.* ; Expósito-Escudero, J.* ; Jou, C.* ; Meyer, S.* ; Kilicarslan, O.A.* ; Aleman, A.* ; Thompson, R.* ; Luknárová, R.* ; Esteve-Codina, A.* ; Gut, M.* ; Laurie, S.* ; Demidov, G.* ; Yépez, V.A.* ; Beltran, S.* ; Gagneur, J. ; Töpf, A.* ; Lochmüller, H.* ; Nascimento, A.* ; Hoenicka, J.* ; Palau, F.* ; Natera-de Benito, D.*

Phenotype-driven genomics enhance diagnosis in children with unresolved neuromuscular diseases.

Eur. J. Hum. Genet., DOI: 10.1038/s41431-024-01699-4 (2024)
DOI PMC
: Publ. Version/Full Text online available 10/2025
Establishing a molecular diagnosis remains challenging in half of individuals with childhood-onset neuromuscular diseases (NMDs) despite exome sequencing. This study evaluates the diagnostic utility of combining genomic approaches in undiagnosed NMD patients. We performed deep phenotyping of 58 individuals with unsolved childhood-onset NMDs that have previously undergone inconclusive exome studies. Genomic approaches included trio genome sequencing and RNASeq. Genetic diagnoses were reached in 23 out of 58 individuals (40%). Twenty-one individuals carried causal single nucleotide variants (SNVs) or small insertions and deletions, while 2 carried pathogenic structural variants (SVs). Genomic sequencing identified pathogenic variants in coding regions or at the splice site in 17 out of 21 resolved cases, while RNA sequencing was additionally required for the diagnosis of 4 cases. Reasons for previous diagnostic failures included low coverage in exonic regions harboring the second pathogenic variant and involvement of genes that were not yet linked to human diseases at the time of the first NGS analysis. In summary, our systematic genetic analysis, integrating deep phenotyping, trio genome sequencing and RNASeq, proved effective in diagnosing unsolved childhood-onset NMDs. This approach holds promise for similar cohorts, offering potential improvements in diagnostic rates and clinical management of individuals with NMDs.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Muscular-dystrophy; Variants
ISSN (print) / ISBN 1018-4813
e-ISSN 1476-5438
Journal European Journal of Human Genetics
Publisher Nature Publishing Group
Publishing Place Campus, 4 Crinan St, London, N1 9xw, England
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Computational Biology (ICB)
Grants European Union Seventh Framework Programme (FP7/2007-2013)
Instituto de Salud Carlos III
AGAUR
Fundacion Ramon Areces
EU Horizon Europe Health Programme
CIBERER
Spanish State Research Agency (AEI)
Instituto de Salud Carlos III, Spain
IRSJD Carmen de Torres 2023 grant
Torro Solidari-RAC1 i Torrons Vicens
Canadian Institutes of Health Research (CIHR)
European Union's Horizon 2020 research and innovation programme
Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)
Government of Canada Canada First Research Excellence Fund (CFREF)
Canada Research Coordinating Committee New Frontiers in Research Fund
European Commission
CIHR
Canada Research Chairs program
Canada Foundation for Innovation
European Union