biostudies-literatureEstevez-Arias BCanada Foundation for Innovation (Fondation canadienne pour l'innovation)Ministry of Economy and Competitiveness | Instituto de Salud Carlos IIICanada Research Chairs (Chaires de recherche du Canada)Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)Canada Research ChairsMinistry of Economy and Competitiveness | Instituto de Salud Carlos III (Institute of Health Carlos III)Deutsche ForschungsgemeinschaftDeutsche Forschungsgemeinschaft (German Research Foundation)Ministry of Economy and Competitiveness | Agencia Estatal de Investigación (Spanish Agencia Estatal de Investigación)Canada Foundation for InnovationMinistry of Economy and Competitiveness | Agencia Estatal de InvestigaciónGovernment of Catalonia | Agència de Gestió d'Ajuts Universitaris i de Recerca (Agency for Management of University and Research Grants)Gouvernement du Canada | Canadian Institutes of Health ResearchGovernment of Catalonia | Agència de Gestió d'Ajuts Universitaris i de Recerca239-247https://www.ebi.ac.uk/biostudies/studies/S-EPMC11840105biostudies-literatureUnknown33(2)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 reEuropean journal of human genetics : EJHGPhenotype-driven genomics enhance diagnosis in children with unresolved neuromuscular diseases.PMC11840105CP22/00141FDN-167281950-232279PI22-00680CFI-JELF 38412ACCI2021-20PID2020-114655RB-1004135016502024 FI-1 000752021-SGR-01610Kilicarslan OAHoenicka JGagneur JBeltran SLuknarova RCodina AEstevez-Arias BGut MPalau FOrtez CMeyer SExposito-Escudero JCarrera-Garcia LJou CAleman ATopf AYubero DLochmuller HMatalonga LPolavarapu KEsteve-Codina AThompson RYepez VANascimento ANatera-de Benito DLaurie SDemidov GfalsePhenotype-driven genomics enhance diagnosis in children with unresolved neuromuscular diseases.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 re2025-01-01T00:00:00Z2025 Mar2026-07-16T23:31:54.174Z2026-07-12T03:11:16.285ZS-EPMC118401053933342910.1038/s41431-024-01699-4