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

[en] 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.

Disciplines :

Genetics & genetic processes

Author, co-author :

Colin, Estelle; UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR1231 GAD "Génétique des Anomalies du Développement", FHUTRANSLAD, Dijon, France ; Service de Génétique Médicale, CHU d'Angers, Angers, France

Duffourd, Yannis; UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR1231 GAD "Génétique des Anomalies du Développement", FHUTRANSLAD, Dijon, France

Chevarin, Martin; UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR1231 GAD "Génétique des Anomalies du Développement", FHUTRANSLAD, Dijon, France ; Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France

Tisserant, Emilie; UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR1231 GAD "Génétique des Anomalies du Développement", FHUTRANSLAD, Dijon, France

Verdez, Simon; UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR1231 GAD "Génétique des Anomalies du Développement", FHUTRANSLAD, Dijon, France

Paccaud, Julien; UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR1231 GAD "Génétique des Anomalies du Développement", FHUTRANSLAD, Dijon, France

Bruel, Ange-Line; UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR1231 GAD "Génétique des Anomalies du Développement", FHUTRANSLAD, Dijon, France ; Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France

Tran Mau-Them, Frédéric; UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR1231 GAD "Génétique des Anomalies du Développement", FHUTRANSLAD, Dijon, France ; Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France

Denommé-Pichon, Anne-Sophie; UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR1231 GAD "Génétique des Anomalies du Développement", FHUTRANSLAD, Dijon, France ; Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France

Thevenon, Julien; UFR Des Sciences de Santé, INSERM-Université de Bourgogne UMR1231 GAD "Génétique des Anomalies du Développement", FHUTRANSLAD, Dijon, France

More authors (29 more)

Language :

English

Title :

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

Publication date :

2023

Journal title :

Frontiers in Cell and Developmental Biology

eISSN :

2296-634X

Publisher :

Frontiers, Switzerland

Volume :

Pages :

1021920

Peer reviewed :

Peer Reviewed verified by ORBi

Additional URL :

https://www.frontiersin.org/articles/10.3389/fcell.2023.1021920/full

Funding text :

This work was supported by grants from Dijon University Hospital, the ISITE-BFC (PIA ANR), the European Union through the FEDER programs (PERSONALISE), and the Burgundy-Franche Comté regional council (INTEGRA). The sequencing performed at the CNRGH was supported by the France Génomique National infrastructure, funded as part of the “Investissements d’Avenir” program managed by the Agence Nationale pour la Recherche (contract ANR-10-INBS-09).

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