Original Title: Panel des syndromes polymalformatifs par séquençage de nouvelle génération

Authors' objectives: At the MSSS's request, the Institut national d'excellence en santé et en services sociaux (INESSS) is reviewing the optimal implementation of these NGS analyses within the Quebec healthcare system. This report specifically addresses the virtual panel of clinome-associated genes analyzed through whole exome sequencing (WES) for the molecular diagnosis of congenital polymalformative syndromes. The clinome, or clinical exome, is defined as the set of genes for which pathogenic variants have been associated with known human diseases.

Authors' results and conclusions: RESULTS (#1 POPULATION DIMENSION): In Quebec, the virtual gene panel analysis for congenital polymalformative syndromes is included to the Répertoire québécois et système de mesure des procédures de biologie médicale since 2022-2023. However, a significant proportion of analyses are still carried out outside Québec. Initially, molecular diagnosis of congenital polymalformative syndromes was offered only postnatally. The current service offer now covers both prenatal and postnatal settings. (#2 CLINICAL DIMENSION-CLINICAL UTILITY): Clinome analysis for congenital polymalformative syndromes enables to establish, clarify or confirm a diagnosis, assess prognosis and guide genetic counseling and patient care decisions. The recommendations of stakeholder organizations emphasize the importance of these analyses to inform parents, avoid misdiagnosis and advise on the recurrence risk for subsequent pregnancies. (#2.1 CLINICAL DIMENSION-CLINICAL VALIDITY): The included studies report a diagnostic yield of 25-45 % in the postnatal context and 26- 36 % in the prenatal context for congenital anomalies. Diagnostic yields vary significantly depending on the type of anomaly and are higher for non-isolated (multisystem) disorders. The advisory committee members suggest that the proposed approach allows for the entire exome exploration if no genetic cause is found through clinome analysis. This approach reduces the risk of missing pathological variations but increases the likelihood of discovering variants of uncertain significance. (#3 ORGANIZATIONAL DIMENSION): The lack of resources in medical genetics, laboratory technicians and genetic counselling in Quebec was highlighted by members of the advisory committee as a major challenge to the repatriation of these analyses and the development of the sequencing service offering. Adequate planning of the service offering is crucial to meet needs. The Ministry must consider the availability of resources and the impact on subsequent interventions to ensure proper medical follow-up for patients and their families. (#4 SOCIO-CULTURAL DIMENSION): Confidentiality of results, protection of personal information, informed consent and the risk of genetic discrimination are ethical and legal issues frequently raised in clinical genetics. Stakeholder organizations recommend multidisciplinary support and education for parents and patients, as well as mechanisms to ensure equitable access to genetic diagnosis across the province. (#5 ECONOMIC DIMENSION): The genome-wide sequencing efficiency for the diagnosis of congenital polymalformative syndromes is unknown. A budget impact analysis shows that repatriating analyses performed outside Quebec could generate savings of $431,000 (ranging from $388,000 to $474,000) if analyses were performed using whole exome sequencing (WES) data, or savings of $98,000 (ranging from $87,000 to $108,000) if performed using whole genome sequencing (WGS) data. Uncertainties remain regarding the costs of bioinformatics tools and data archiving, which could reduce these anticipated savings. CONCLUSION: This state of knowledge is based on a rapid review of scientific and grey literature, as well as contextual data and experiential knowledge. It aims to support the MSSS in developing and repatriating genetic analyses for the diagnosis of congenital polymalformative syndromes. Major concerns related to available resources and the organization of services in Quebec were highlighted. These concerns should be addressed to ensure the optimal deployment of the virtual panel analyzed through whole exome sequencing to establish the molecular diagnosis of congenital polymalformative syndromes in Quebec.

Authors' methods: A rapid literature review and participatory approaches to collecting contextual and experiential data were carried out.

Project Status: Completed

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

Year Published: 2025

URL for published report: https://www.inesss.qc.ca/publications/repertoire-des-publications/publication/panel-des-syndromes-polymalformatifs-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: L'Institut national d'excellence en sante et en services sociaux (INESSS)