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Colin, Estelle; Duffourd, Yannis; Chevarin, Martin; Tisserant, Emilie; Verdez, Simon; Paccaud, Julien; Bruel, Ange-Line; Tran Mau-Them, Frédéric; Denommé-Pichon, Anne-Sophie; Thevenon, Julien; Safraou, Hana; Besnard, Thomas; Goldenberg, Alice; Cogné, Benjamin; Isidor, Bertrand; Delanne, Julian; Sorlin, Arthur; Moutton, Sébastien; Fradin, Mélanie; Dubourg, Christèle; Gorce, Magali; Bonneau, Dominique; El Chehadeh, Salima; Debray, François-Guillaume; [...]

Stepwise use of genomics and transcriptomics technologies increases diagnostic yield in Mendelian disorders

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  • Medientyp: E-Artikel
  • Titel: Stepwise use of genomics and transcriptomics technologies increases diagnostic yield in Mendelian disorders
  • Beteiligte: Colin, Estelle; Duffourd, Yannis; Chevarin, Martin; Tisserant, Emilie; Verdez, Simon; Paccaud, Julien; Bruel, Ange-Line; Tran Mau-Them, Frédéric; Denommé-Pichon, Anne-Sophie; Thevenon, Julien; Safraou, Hana; Besnard, Thomas; Goldenberg, Alice; Cogné, Benjamin; Isidor, Bertrand; Delanne, Julian; Sorlin, Arthur; Moutton, Sébastien; Fradin, Mélanie; Dubourg, Christèle; Gorce, Magali; Bonneau, Dominique; El Chehadeh, Salima; Debray, François-Guillaume; [...]
  • Erschienen: Frontiers Media SA, 2023
  • Erschienen in: Frontiers in Cell and Developmental Biology
  • Sprache: Nicht zu entscheiden
  • DOI: 10.3389/fcell.2023.1021920
  • ISSN: 2296-634X
  • Schlagwörter: Cell Biology ; Developmental Biology
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:p><jats:bold>Purpose:</jats:bold> Multi-omics offer worthwhile and increasingly accessible technologies to diagnostic laboratories seeking potential second-tier strategies to help patients with unresolved rare diseases, especially patients clinically diagnosed with a rare OMIM (Online Mendelian Inheritance in Man) disease. However, no consensus exists regarding the optimal diagnostic care pathway to adopt after negative results with standard approaches.</jats:p><jats:p><jats:bold>Methods:</jats:bold> In 15 unsolved individuals clinically diagnosed with recognizable OMIM diseases but with negative or inconclusive first-line genetic results, we explored the utility of a multi-step approach using several novel omics technologies to establish a molecular diagnosis. Inclusion criteria included a clinical autosomal recessive disease diagnosis and single heterozygous pathogenic variant in the gene of interest identified by first-line analysis (60%–9/15) or a clinical diagnosis of an X-linked recessive or autosomal dominant disease with no causative variant identified (40%–6/15). We performed a multi-step analysis involving short-read genome sequencing (srGS) and complementary approaches such as mRNA sequencing (mRNA-seq), long-read genome sequencing (lrG), or optical genome mapping (oGM) selected according to the outcome of the GS analysis.</jats:p><jats:p><jats:bold>Results:</jats:bold> SrGS alone or in combination with additional genomic and/or transcriptomic technologies allowed us to resolve 87% of individuals by identifying single nucleotide variants/indels missed by first-line targeted tests, identifying variants affecting transcription, or structural variants sometimes requiring lrGS or oGM for their characterization.</jats:p><jats:p><jats:bold>Conclusion:</jats:bold> Hypothesis-driven implementation of combined omics technologies is particularly effective in identifying molecular etiologies. In this study, we detail our experience of the implementation of genomics and transcriptomics technologies in a pilot cohort of previously investigated patients with a typical clinical diagnosis without molecular etiology.</jats:p>
  • Zugangsstatus: Freier Zugang