Back to Search Start Over

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

Authors :
Colin E
Duffourd Y
Chevarin M
Tisserant E
Verdez S
Paccaud J
Bruel AL
Tran Mau-Them F
Denommé-Pichon AS
Thevenon J
Safraou H
Besnard T
Goldenberg A
Cogné B
Isidor B
Delanne J
Sorlin A
Moutton S
Fradin M
Dubourg C
Gorce M
Bonneau D
El Chehadeh S
Debray FG
Doco-Fenzy M
Uguen K
Chatron N
Aral B
Marle N
Kuentz P
Boland A
Olaso R
Deleuze JF
Sanlaville D
Callier P
Philippe C
Thauvin-Robinet C
Faivre L
Vitobello A
Source :
Frontiers in cell and developmental biology [Front Cell Dev Biol] 2023 Feb 28; Vol. 11, pp. 1021920. Date of Electronic Publication: 2023 Feb 28 (Print Publication: 2023).
Publication Year :
2023

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.<br />Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.<br /> (Copyright © 2023 Colin, Duffourd, Chevarin, Tisserant, Verdez, Paccaud, Bruel, Tran Mau-Them, Denommé-Pichon, Thevenon, Safraou, Besnard, Goldenberg, Cogné, Isidor, Delanne, Sorlin, Moutton, Fradin, Dubourg, Gorce, Bonneau, El Chehadeh, Debray, Doco-Fenzy, Uguen, Chatron, Aral, Marle, Kuentz, Boland, Olaso, Deleuze, Sanlaville, Callier, Philippe, Thauvin-Robinet, Faivre and Vitobello.)

Details

Language :
English
ISSN :
2296-634X
Volume :
11
Database :
MEDLINE
Journal :
Frontiers in cell and developmental biology
Publication Type :
Academic Journal
Accession number :
36926521
Full Text :
https://doi.org/10.3389/fcell.2023.1021920