Original Title: État des connaissances - Panels de la déficience intellectuelle et du retard global du développement 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. Yet, the province’s laboratories have the technology and expertise to perform such 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 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 with respect to the overall offer of services 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 mechanisms for the repatriation of 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 identifying molecular causes of intellectual disability and global developmental delay.

Authors' results and conclusions: RESULTS: (#1 CLINICAL CONTEXTS AND PROPOSED TESTS): Intellectual disability (ID) and global developmental delay (GDD) are a heterogeneous group of conditions that are most often acquired but may be inherited. ID is characterized by a significant deficit in intellectual functions and adaptive behaviour that appears before the age of 18 years, while GDD is a temporary diagnosis reserved for children under 5 years of age who present with significant developmental limitations. ID/GDD causes 2 limitations in several areas of daily living and social life. Given its phenotypic heterogeneity, diagnosis and etiological determination are difficult. To provide more information to patients and their families, to facilitate access to different specialized resources, or to support informed decision-making during family planning or regarding the continuation or termination of a pregnancy in progress, one must look for the molecular causes of ID and GDD. Thus, the requester proposes the rollout of an offer of services that includes a virtual panel of ID/GDD-associated genes analyzed from exome sequencing data. (#2 VALIDITY AND CLINICAL UTILITY): In hereditary genetics, the clinical validity of a multigene panel analyzed by sequencing is, among other things, determined by the correspondence of the genes in the panel with the target disease. The panel should therefore include all the genes for which variants have been clearly identified as being responsible for the disease (pathogenic variants). The proposed panel consists primarily of the genes identified by the ID/GDD Panel App initiative (2,677 genes). Based on the available data, the diagnostic performance of the proposed tests is between 11% and 56%. Few treatments are available for ID and GDD. The gene panel is therefore mainly for diagnostic and prognostic purposes. The identification of a genetic cause in severe pediatric cases will also be of use when providing prenatal diagnostic services. Six items published by learned societies support the clinical utility of the NGS test in the diagnostic investigation of ID/GDD. It is noted that gene panel or exome sequencing plays a crucial role in the diagnosis of ID and GDD. It can have a significant psychological impact by putting an end to the diagnostic odyssey. (#3 IMPLEMENTATION CONSIDERATIONS): Information from the literature and that from the expert consultations are in agreement that genetic testing should be prioritized based on a combination of data concerning the clinical presentation and from the clinical examination and the family history. In this regard, to support the rollout of this offer of services and the optimal use of these tests, a clinical algorithm is presented. A medical genetics or pediatric neurology consultation is a prerequisite for the test. In light of the consultations conducted, the offer of services for the molecular diagnosis of ID/GDD generally appears to be in line with the needs. Nevertheless, some experts feel that it is important to proceed in stages during diagnosis to avoid overordering, while at the same time ensuring access for patients with a suggestive clinical presentation. Concerns of a more general nature that do not specifically pertain to ID or GDD panels were raised during the consultations. Some of the experts feel that the quality of the molecular diagnostic service and the turnaround time should be comparable to those currently offered by outside laboratories and be uniform across the province. There are concerns about the importance of developing clear policies on the management and disclosure of variants of uncertain significance, access to exome sequencing data in the event of a negative panel result, and the disclosure of incidental or secondary findings. Indeed, depending on the thoroughness of the analytical method used, there is a risk of discovering uncertain or unexpected variants, which can complicate genetic counselling. (#4 ECONOMIC ANALYSIS): Although no economic evaluation in the Québec context was performed, the results of evaluations carried out in other jurisdictions suggest that whole-exome sequencing, used as a follow-up to standard diagnostic tests or early in the diagnostic process in combination with comparative genomic hybridization, is cost-effective. According to the assumptions made, including virtual panels of ID/GDD-associated genes in the Répertoire could generate savings of nearly $900,000 over the first three years in the context of providing services to patients throughout Quebec. CONCLUSION: The findings and conclusions of this report are based on a rapid review of the scientific and grey literature and on the gathered contextual data and experiential knowledge. The process consisted of a brief risk analysis for guiding the MSSS’s decision regarding the repatriation of gene panels for the molecular diagnosis of ID and GDD. In this exercise, no major concerns were identified in this regard, and the information gathered supports the appropriateness of repatriating these tests. However, some uncertainties regarding the availability of the resources and the organization of the services surrounding this initiative in Québec were identified and should be explored to ensure an optimal implementation.

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 identifying molecular causes of intellectual disability and global developmental delay 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 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/panels-de-la-deficience-intellectuelle-et-du-retard-global-du-developpement-par-sequencage-de-nouvelle-generation.html

Year Published: 2023

URL for published report: https://www.inesss.qc.ca/publications/repertoire-des-publications/publication/panels-de-la-deficience-intellectuelle-et-du-retard-global-du-developpement-par-sequencage-de-nouvelle-generation.html

English language abstract: An English language summary is available

Publication Type: Other

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: Gouvernement du Québec