Phenotype-driven genomics enhance diagnosis in children with unresolved neuromuscular diseases
Por:
Estévez-Arias B, Matalonga L, Yubero-Siles D, Polavarapu K, Codina-Bergadà A, Ortez-Gonzalez CI, Carrera-García L, Exposito-Escudero JM, Jou-Munoz C, Meyer S, Kilicarslan OA, Aleman A, Thompson R, Luknárová R, Esteve-Codina A, Gut M, Laurie S, Demidov G, Yépez VA, Beltran S, Gagneur J, Topf A, Lochmüller H, Nascimento-Osorio A, Hoenicka J, Palau F and Natera-de Benito D
Publicada:
1 mar 2025
Ahead of Print:
1 sep 2024
Resumen:
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.
Filiaciones:
Estévez-Arias B:
Neuromuscular Unit, Department of Neurology, Hospital Sant Joan de Déu, Barcelona, Spain
Laboratory of Neurogenetics and Molecular Medicine - IPER, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Matalonga L:
Centro Nacional de Análisis Genómico (CNAG), Barcelona, Spain
Universitat de Barcelona (UB), Barcelona, Spain
Yubero-Siles D:
Center for Biomedical Research Network on Rare Diseases (CIBERER), ISCIII, Barcelona, Spain
Department of Genetic and Molecular Medicine - IPER, Hospital Sant Joan de Déu and Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Polavarapu K:
Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada
Codina-Bergadà A:
Applied Research in Neuromuscular Diseases, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Department of Pathology, Hospital Sant Joan de Déu, Barcelona, Spain
Ortez-Gonzalez CI:
Neuromuscular Unit, Department of Neurology, Hospital Sant Joan de Déu, Barcelona, Spain
Center for Biomedical Research Network on Rare Diseases (CIBERER), ISCIII, Barcelona, Spain
Applied Research in Neuromuscular Diseases, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Carrera-García L:
Neuromuscular Unit, Department of Neurology, Hospital Sant Joan de Déu, Barcelona, Spain
Applied Research in Neuromuscular Diseases, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Exposito-Escudero JM:
Neuromuscular Unit, Department of Neurology, Hospital Sant Joan de Déu, Barcelona, Spain
Applied Research in Neuromuscular Diseases, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Jou-Munoz C:
Universitat de Barcelona (UB), Barcelona, Spain
Applied Research in Neuromuscular Diseases, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Department of Pathology, Hospital Sant Joan de Déu, Barcelona, Spain
Meyer S:
Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada
University Medical Center Göttingen, Department of Neurology, Göttingen, Germany
Kilicarslan OA:
Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada
Aleman A:
Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada
Division of Neurology, Department of Medicine, The Ottawa Hospital, Ottawa, ON, Canada
Thompson R:
Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada
Luknárová R:
School of Computation, Information and Technology, Technical University of Munich, Munich, Germany
Esteve-Codina A:
Centro Nacional de Análisis Genómico (CNAG), Barcelona, Spain
Universitat de Barcelona (UB), Barcelona, Spain
Gut M:
Centro Nacional de Análisis Genómico (CNAG), Barcelona, Spain
Universitat de Barcelona (UB), Barcelona, Spain
Laurie S:
Centro Nacional de Análisis Genómico (CNAG), Barcelona, Spain
Universitat de Barcelona (UB), Barcelona, Spain
Demidov G:
Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
Yépez VA:
School of Computation, Information and Technology, Technical University of Munich, Munich, Germany
Beltran S:
Centro Nacional de Análisis Genómico (CNAG), Barcelona, Spain
Universitat de Barcelona (UB), Barcelona, Spain
Gagneur J:
School of Computation, Information and Technology, Technical University of Munich, Munich, Germany
Computational Health Center, Helmholtz Center Munich, Neuherberg, Germany
Institute of Human Genetics, School of Medicine, Technical University of Munich, Munich, Germany
Topf A:
The John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
Lochmüller H:
Centro Nacional de Análisis Genómico (CNAG), Barcelona, Spain
Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada
Division of Neurology, Department of Medicine, The Ottawa Hospital, Ottawa, ON, Canada
Nascimento-Osorio A:
Neuromuscular Unit, Department of Neurology, Hospital Sant Joan de Déu, Barcelona, Spain
Center for Biomedical Research Network on Rare Diseases (CIBERER), ISCIII, Barcelona, Spain
Applied Research in Neuromuscular Diseases, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Hoenicka J:
Laboratory of Neurogenetics and Molecular Medicine - IPER, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Center for Biomedical Research Network on Rare Diseases (CIBERER), ISCIII, Barcelona, Spain
Palau F:
Laboratory of Neurogenetics and Molecular Medicine - IPER, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Center for Biomedical Research Network on Rare Diseases (CIBERER), ISCIII, Barcelona, Spain
Department of Genetic and Molecular Medicine - IPER, Hospital Sant Joan de Déu and Institut de Recerca Sant Joan de Déu, Barcelona, Spain
ERN ITHACA, Barcelona, Spain
Division of Pediatrics, Faculty of Medicine and Health Sciences, Universitat de Barcelona (UB), Barcelona, Spain
Natera-de Benito D:
Neuromuscular Unit, Department of Neurology, Hospital Sant Joan de Déu, Barcelona, Spain
Center for Biomedical Research Network on Rare Diseases (CIBERER), ISCIII, Barcelona, Spain
Applied Research in Neuromuscular Diseases, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Green Submitted, Green Accepted
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