Frontiers in Cell and Developmental Biology (Feb 2023)

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

  • Estelle Colin,
  • Estelle Colin,
  • Yannis Duffourd,
  • Martin Chevarin,
  • Martin Chevarin,
  • Emilie Tisserant,
  • Simon Verdez,
  • Julien Paccaud,
  • Ange-Line Bruel,
  • Ange-Line Bruel,
  • Frédéric Tran Mau-Them,
  • Frédéric Tran Mau-Them,
  • Anne-Sophie Denommé-Pichon,
  • Anne-Sophie Denommé-Pichon,
  • Julien Thevenon,
  • Hana Safraou,
  • Hana Safraou,
  • Thomas Besnard,
  • Thomas Besnard,
  • Alice Goldenberg,
  • Alice Goldenberg,
  • Benjamin Cogné,
  • Benjamin Cogné,
  • Bertrand Isidor,
  • Julian Delanne,
  • Julian Delanne,
  • Arthur Sorlin,
  • Arthur Sorlin,
  • Sébastien Moutton,
  • Sébastien Moutton,
  • Mélanie Fradin,
  • Christèle Dubourg,
  • Christèle Dubourg,
  • Magali Gorce,
  • Dominique Bonneau,
  • Salima El Chehadeh,
  • François-Guillaume Debray,
  • Martine Doco-Fenzy,
  • Martine Doco-Fenzy,
  • Kevin Uguen,
  • Kevin Uguen,
  • Nicolas Chatron,
  • Bernard Aral,
  • Nathalie Marle,
  • Paul Kuentz,
  • Paul Kuentz,
  • Anne Boland,
  • Robert Olaso,
  • Robert Olaso,
  • Jean-François Deleuze,
  • Jean-François Deleuze,
  • Damien Sanlaville,
  • Patrick Callier,
  • Patrick Callier,
  • Christophe Philippe,
  • Christophe Philippe,
  • Christel Thauvin-Robinet,
  • Christel Thauvin-Robinet,
  • Christel Thauvin-Robinet,
  • Laurence Faivre,
  • Laurence Faivre,
  • Antonio Vitobello,
  • Antonio Vitobello

DOI
https://doi.org/10.3389/fcell.2023.1021920
Journal volume & issue
Vol. 11

Abstract

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Purpose: 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.Methods: 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.Results: 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.Conclusion: 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.

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