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

• DOI: 10.3389/fcell.2023.1021920
• Publication Date: 2023-03-06T17:24:30Z
• Authors: Estelle Colin; Yannis Duffourd; Martin Chevarin; Emilie Tisserant; Simon Verdez; Julien Paccaud; Ange-Line Bruel; Frédéric Tran Mau...; Anne-Sophie Denom...; Julien Thevenon; Hana Safraou; Thomas Besnard; Alice Goldenberg; Benjamin Cogné; Bertrand Isidor; Julian Delanne; Arthur Sorlin; Sébastien Moutton; Mélanie Fradin; Christèle Dubourg; Magali Gorce; Dominique Bonneau; Salima El Chehadeh; François-Guillaum...; Martine Doco-Fenzy; Kevin Uguen; Nicolas Chatron; Bernard Aral; Nathalie Marle; Paul Kuentz; Anne Boland; Robert Olaso; Jean-François Del...; Damien Sanlaville; Patrick Callier; Christophe Philippe; Christel Thauvin-...; Laurence Faivre; Antonio Vitobello
• Keywords: Mendelian inheritance; Indel; Omics

Purpose: Multi-omics offer worthwhile and increasingly accessible technologies to diagnostic laboratories seeking potential second-tier strategies help patients with unresolved rare diseases, especially clinically diagnosed a OMIM (Online Mendelian Inheritance in Man) disease. However, no consensus exists regarding the optimal care pathway adopt after negative results standard approaches. Methods: In 15 unsolved individuals recognizable diseases but or inconclusive first-line genetic results, we explored utility of multi-step approach using several novel omics establish molecular diagnosis. Inclusion criteria included clinical autosomal recessive disease diagnosis single heterozygous pathogenic variant gene interest identified by analysis (60%-9/15) an X-linked dominant causative (40%-6/15). We performed involving short-read genome sequencing (srGS) complementary approaches such as mRNA (mRNA-seq), long-read (lrG), optical mapping (oGM) selected according outcome GS analysis. Results: SrGS alone combination additional genomic and/or transcriptomic allowed us resolve 87% identifying nucleotide variants/indels missed targeted tests, variants affecting transcription, structural sometimes requiring lrGS oGM for their characterization. Conclusion: Hypothesis-driven implementation combined is particularly effective etiologies. this study, detail our experience genomics transcriptomics pilot cohort previously investigated typical without etiology.