Original Title: État des connaissances - Panel des RASopathies par séquençage de nouvelle génération

Authors' objectives: Requests for authorization of medical laboratory services that are not available in Québec are mainly for very-high-throughput simultaneous sequencing of multiple genes using the so-called next-generation approach. The province’s laboratories have the technology and expertise to perform these tests. 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) has undertaken to quickly repatriate several tests performed outside Québec using next-generation sequencing (NGS), under the governance of the Réseau québécois de diagnostic moléculaire (RQDM). The rollout of this vast project undoubtedly entails opportunities and risks regarding the overall offer of service and requires reflection in this regard. At the MSSS’s request, the Institut national d’excellence en santé et en services sociaux (INESSS) is conducting a rapid assessment of the relevance of, the issues surrounding and, when appropriate, the optimal implementation arrangements for repatriating these tests from the overall perspective of Québec’s healthcare system. The present report deals specifically with the analysis of the NGS gene panel for the molecular diagnosis of prenatal and postnatal RASopathies.

Authors' results and conclusions: RESULTS: (#1 CLINICAL CONTEXTS AND PROPOSED TEST): RASopathies are a heterogeneous group of genetic syndromes caused by germline mutations in genes involved in the RAS-MAPK (mitogen-activated kinase) pathway. The RASopathies share several common phenotypic features, such as craniofacial dysmorphism, heart defects, skin, musculoskeletal and ocular abnormalities, neurocognitive impairment, hypotonia, and increased cancer risk. The requester is proposing that there be an offer of service that would replace several tests performed outside Québec with a panel of 28 genes associated with RASopathies and analyzed by NGS. (#2 CLINICAL VALIDITY): In hereditary genetics, the clinical validity of a multigene panel analyzed by sequencing is determined, among other things, by the association of the genes in the panel with the targeted disease. The panel should therefore include all genes for which variants have been clearly identified as being responsible for the disease (pathogenic variants). For the proposed panel, a total of 28 genes were selected. The genes were selected by the RQDM’s RASopathies working group based on the scientific literature, the PanelApp resource and panels from molecular diagnostic service providers outside Quebec. The panel includes genes associated with different RASopathies and with certain differential diagnoses. Based on the available data, the diagnostic performance varies according to the phenotypes observed in prenatal and postnatal situations.(#3 CLINICAL UTILITY): The RASopathies synthesis literature provides information on the clinical relevance of the molecular diagnosis of RASopathies. In prenatal medicine, the main objectives of this diagnosis are the molecular confirmation of the diagnosis, the identification of certain comorbidities, the provision of appropriate genetic counselling, and appropriate therapeutic management. For young children, the main objectives of postnatal analysis are to clarify the diagnosis by distinguishing, for example, between Noonan syndrome and cardio-facial-cutaneous syndrome, and to thus provide appropriate prognostic information. For older patients, the genetic investigation can put an end to unnecessary etiological searches, optimize the follow-up and genetic counselling, and better distinguish between dominant sporadic forms and recessive forms. Genetic analysis is also used to tailor patient management, in particular, to counter undernutrition in infants, to monitor growth and cardiac abnormalities, to detect medical complications early and treat them, to detect cognitive difficulties, and to organize appropriate educational programs. (#4 IMPLEMENTATION CONSIDERATIONS): The experts consulted were of the opinion that the prenatal and postnatal clinical indications proposed by the requester and the genes included in the panel are appropriate. Some experts questioned the advisability of reporting variants for the NF1 gene in the prenatal context, as they could lead to findings that are difficult to interpret and complicate the genetic counseling. The analysis and interpretation turnaround times proposed by the requester are appropriate, according to the experts consulted. In some cases, these times would constitute an improvement over the current situation. Some features of the prenatal and postnatal contexts should preferably be incorporated into a formal clinical algorithm to help prescribers properly plan molecular investigations. (#5 ECONOMIC ANALYSIS): No cost-effectiveness studies of prenatal or postnatal molecular diagnosis RASopathies by NGS were identified. It should be noted that, given the nature of the mandate given to INESSS by the MSSS, no modeling was done. The cost-effectiveness of the 11-gene panel currently sent outside Quebec has never been evaluated by INESSS. Nevertheless, considering that the clinical benefits of performing the requester’s panel are at least equivalent to those of the 11-gene panel analyzed outside Québec, this could suggest that the panel proposed by the CHUSJ is more cost-effective, since it offers a better diagnostic performance at a lower cost. With regard to the budget impact, based on the assumptions made, including the RASopathies panel in the Repertoire could generate savings of approximately $1 million over the first three years in order to provide service to patients throughout Québec. CONCLUSION: The findings and conclusion of this report are based on a rapid review of the scientific and grey literature and on contextual data and experiential knowledge. The approach is a summary risk analysis to guide the ministerial decision to repatriate tests for the molecular diagnosis of RASopathies. Although certain organizational aspects of the deployment of the repatriation of NGS testing for RASopathies were incomplete at the time of INESSS’s assessment, no other major concerns were identified, and the information gathered supports the advisability of repatriating this test. Although the experts consulted questioned the relevance of including the NF1 gene in the prenatal setting, the proposed test has the potential to improve diagnostic performance, and the turnaround time and cost compared to the panels sent outside Québec currently analyzed in this clinical context. Uncertainties related to the availability of resources and the organization of the services surrounding the use of this approach in Québec have been brought to light and should be explored to ensure optimal implementation and cost mitigation.

Authors' methods: The process included a rapid review of the scientific and grey literature for the clinical and economic aspects, a budget impact analysis, and consultations with Québec experts. Only items containing synthesis data or recommendations concerning the use of an NGS test for molecularly diagnosing RASopathies were selected. INESSS set up an advisory committee, whose members were invited to express their views on the different issues associated with the repatriation of the proposed tests. The final findings are based on the triangulation of the scientific data, the respective 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-rasopathies-par-sequencage-de-nouvelle-generation.html

Year Published: 2022

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

English language abstract: An English language summary is available

Publication Type: Other

Country: Canada

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: Gouvernement du Québec