AUTHOR=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 , Doco-Fenzy Martine , Uguen Kevin , Chatron Nicolas , Aral Bernard , Marle Nathalie , Kuentz Paul , Boland Anne , Olaso Robert , Deleuze Jean-François , Sanlaville Damien , Callier Patrick , Philippe Christophe , Thauvin-Robinet Christel , Faivre Laurence , Vitobello Antonio
TITLE=Stepwise use of genomics and transcriptomics technologies increases diagnostic yield in Mendelian disorders
JOURNAL=Frontiers in Cell and Developmental Biology
VOLUME=11
YEAR=2023
URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2023.1021920
DOI=10.3389/fcell.2023.1021920
ISSN=2296-634X
ABSTRACT=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.