Original Title: Panel des maladies mitochondriales par séquençage de nouvelle génération

Authors' objectives: Most requests for authorization for medical biology services not available in Quebec involve very high throughput sequencing of several genes simultaneously, using a socalled next-generation approach. However, the province’s laboratories have the technology and expertise to perform these analyses. With a view to achieving economies of scale and promoting more judicious use of this technology, the Ministère de la Santé et des Services Sociaux (MSSS), in collaboration with the Réseau québécois de diagnostic moléculaire (RQDM), has undertaken to rapidly repatriate several analyses performed using next-generation sequencing (NGS). At the request of the MSSS, the Institut national d’excellence en santé et en services sociaux (INESSS) is carrying out a rapid assessment of the relevance, challenges and, where appropriate, optimal implementation methods associated with the repatriation of these analyses, from the overall perspective of the Quebec healthcare system. This report deals specifically with the panel of nuclear genes analyzed by NGS for the molecular diagnosis of mitochondrial diseases.

Authors' results and conclusions: The literature search identified six publications from learned societies and review papers relating to the use of NGS in the molecular diagnosis of mitochondrial diseases. In 2014, INESSS published an evaluation report recommending the introduction of mtDNA sequencing for the diagnosis of mitochondrial diseases. According to the Mitochondrial Medicine Society (MMS), the use of parallel massive NGS techniques are recommended for mtDNA analysis. In the event of a negative blood mtDNA result, mtDNA from other tissues should be analyzed to avoid the possibility of missing tissue-specific mutations or low levels of heteroplasmy in blood. NGS methods providing complete coverage of nuclear genes associated with mitochondrial diseases should also be employed. WES should be considered in case of negative results by targeted panel. RESULTS (#1 POPULATION AND CLINICAL DIMENSIONS): Given the high phenotypic heterogeneity and overlap with other genetic conditions, the experts consulted stressed the importance of being able to run several virtual panels simultaneously, or of having faster access to exome data. Some recognize the importance of exploratory analyses in the event of a negative result, and of enhancing the search for new genes. NGS services outside of Quebec currently provide access to data for emerging genes. Therefore, it would be important that the service offered by the RQDM included the analysis of these genes. Some experts also stress the importance of having access to reanalysis of sequence data when new evidence becomes available. (#2 ORGANIZATIONAL DIMENSION): The importance of adequately planning the need for resources in genetic counseling, genetic medicine and metabolic diseases was also stressed, as the system does not have the capacity to supply the demand with the current volume. (#3 ETHICAL, SOCIAL AND LEGAL DIMENSIONS): Policies on access to exome sequencing data, information management and disclosure of incidental findings would need to be developed to guide clinicians’ possible requests for access to exome sequencing data. (#4 ECONOMIC ANALYSIS): A review of the economic literature suggests that genome-wide approaches would be dominant compared to conventional approaches for the diagnosis of mitochondrial diseases. WGS would not be efficient compared to WES and mtDNA analysis. Based on budget impacts, the use of WES with simultaneous mtDNA capture could generate savings of $23,500 ($21,155 to $191,700) over the first three years. The use of WGS could increase expenses by $707,484 ($636,735 to $1.3 million) over the first three years. The budgetary impact remains uncertain due to difficulties in estimating the exact number of analyses planned and the costs of bioinformatics tools (licenses, data archiving). CONCLUSION: The findings and conclusions of this report are based on a quick review of the scientific and gray literature, as well as on the contextual data and experiential knowledge gathered. The approach consists of a summary risk analysis to guide the ministerial decision to repatriate the nuclear gene panel intended for the molecular diagnosis of mitochondrial diseases. In the present exercise, no major concerns were identified in this respect, and the information gathered supports the appropriateness of repatriating these analyses. However, uncertainties related to the availability of resources, the choice of analytical approach and the organization of services surrounding the implementation of this approach in Quebec have been highlighted and should be explored to ensure optimal implementation. Conclusions on potential savings also call for caution, but the possible use of a simultaneous nuclear exome and mitochondrial genome capture kit could improve efficiency.

Authors' methods: The process included a quick review of the scientific and gray literature for the clinical and economic aspects, a budget impact analysis, and consultations with Quebec experts. Only documents presenting synthesis data or recommendations associated with the use of a NGS test to establish the diagnosis of mitochondrial diseases were retained. INESSS set up an advisory committee where members were invited to express their views on the various issues surrounding repatriation of the proposed tests. The final findings are based on a triangulation of scientific data, the positions of the main learned societies consulted, and the contextual data and experiential knowledge gathered.

Project Status: Completed

URL for project: https://www.inesss.qc.ca/publications/repertoire-des-publications/publication/panel-des-maladies-mitochondriales-par-sequencage-de-nouvelle-generation.html

Year Published: 2024

URL for published report: https://www.inesss.qc.ca/publications/repertoire-des-publications/publication/panel-des-maladies-mitochondriales-par-sequencage-de-nouvelle-generation.html

English language abstract: An English language summary is available

Publication Type: Not Assigned

Country: Canada

Province: Quebec

Organisation Name: Institut national d'excellence en sante et en services sociaux

Contact Address: L'Institut national d'excellence en sante et en services sociaux (INESSS) , 2021, avenue Union, bureau 10.083, Montreal, Quebec, Canada, H3A 2S9;Tel: 1+514-873-2563, Fax: 1+514-873-1369

Contact Name: demande@inesss.qc.ca

Contact Email: demande@inesss.qc.ca

Copyright: L'Institut national d'excellence en sante et en services sociaux (INESSS)