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

Autor:	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 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 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 C; 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., Expósito-Escudero J; 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 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 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. francesc.palau@sjd.es.; Center for Biomedical Research Network on Rare Diseases (CIBERER), ISCIII, Barcelona, Spain. francesc.palau@sjd.es.; Department of Genetic and Molecular Medicine - IPER, Hospital Sant Joan de Déu and Institut de Recerca Sant Joan de Déu, Barcelona, Spain. francesc.palau@sjd.es.; ERN ITHACA, Barcelona, Spain. francesc.palau@sjd.es.; Division of Pediatrics, Faculty of Medicine and Health Sciences, Universitat de Barcelona (UB), Barcelona, Spain. francesc.palau@sjd.es., Natera-de Benito D; Neuromuscular Unit, Department of Neurology, Hospital Sant Joan de Déu, Barcelona, Spain. daniel.natera@sjd.es.; Center for Biomedical Research Network on Rare Diseases (CIBERER), ISCIII, Barcelona, Spain. daniel.natera@sjd.es.; Applied Research in Neuromuscular Diseases, Institut de Recerca Sant Joan de Déu, Barcelona, Spain. daniel.natera@sjd.es.
Jazyk:	angličtina
Zdroj:	European journal of human genetics : EJHG [Eur J Hum Genet] 2024 Sep 27. Date of Electronic Publication: 2024 Sep 27.
DOI:	10.1038/s41431-024-01699-4
Abstrakt:	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. Competing Interests: Competing interests: The authors declare no competing interests. Ethical approval: Data were collected and analyzed following the ethics guidelines of Hospital Sant Joan de Déu (PIC 98-20). The family provided written informed consent for the study. (© 2024. The Author(s), under exclusive licence to European Society of Human Genetics.)
Databáze:	MEDLINE
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