Original Title: Principes et critères de sélection des gènes pour le diagnostic moléculaire des maladies en génétique constitutionnelle par séquençage de nouvelle génération (SNG)

Authors' objectives: The mandate of the Réseau québécois de diagnostic moléculaire (RQDM), of which the Centre québécois de génomique clinique (QCGC) is a part, is to meet the current and future needs of the health and social services system in the field of molecular diagnostics and personalized medicine, mainly in the areas of rare diseases and cancer. To this end, the RQDM, supported by the Ministère de la Santé et des Services sociaux (MSSS), has undertaken a provincial project to upgrade technology and to develop and repatriate tests performed by next generation sequencing (NGS). To standardize, oversee and ensure the quality of the NGS services currently being developed in Québec, representatives from the MSSS, the RQDM and the CQGC have jointly requested from the Institut national d'excellence en santé et en services sociaux (INESSS) state-of-knowledge reports on the principles and criteria for guiding the decision to perform exome sequencing instead of targeted sequencing of a limited number of genes. The principles and criteria for selecting genes to be tested, accessing sequencing data for all the genes associated with a monogenic disorder or even the entire exome, and parent-child trio testing are also among the evaluation questions. In short, the questions addressed to INESSS are intended to contribute to an overall reflection on the testing approach and the thoroughness of the genomic tests that should be proposed according to the different clinical contexts. This state-of-knowledge report specifically deals with the principles and criteria that should guide the selection of genes to be tested in the context of the molecular diagnosis of a genetic disease.

Authors' results and conclusions: RESULTS (#1 HARMONIZATION OF TERMS AND LEVELS OF EVIDENCE FOR GENE-DISEASE ASSOCIATIONS AND GENE CURATION IN CONSTITUTIONAL GENETICS): Until recently, there was a great deal of variation in the terms and the different initiatives for gene curation in the literature. It is for this reason that the Gene Curation Coalition (GenCC) was created. It brings together most of the learned societies that have proposed gene curation recommendations, criteria or initiatives in recent years and proposes the harmonization of the terms and the definitions of levels of evidence for gene-disease associations. This harmonized classification is divided into eight categories: “Definitive”, “Strong”, “Moderate”, “Limited”, “Contested”, “Refuted”, “No known relationship to disease” and “Animal model only”. The process of evaluating the evidence and classifying the clinical validity of the proposed gene-disease associations is based on the semiquantitative evaluation of the available genetic and experimental evidence. (#2 SELECTING GENES TO BE INCLUDED IN A DIAGNOSTIC NGS PANEL): The genes to be included in a diagnostic panel differ according to the learned society consulted. According to the American College of Medical Genetics and Genomics (ACMG), it is recommended that all the genes associated with a given Mendelian disease (GAD) for which the validity of the association with the disease is definitive, strong or moderate be included. On the other hand, according to Genomics England PanelApp and Gene2Phenotyp (G2P, European Bioinformatics Institute), it is recommended that only genes with a level of evidence of definitive or strong validity be included. It is also recommended to include, where appropriate, the GADs involved in the differential diagnoses to maximize the test’s sensitivity. In addition, some learned societies suggest that genes with incomplete penetrance and certain genes of uncertain significance (GUS) with limited validity, but for which new evidence has emerged, may also be included, with caution. In this case, disclosure consent explaining the possibility of inconclusive results should be requested from the patient beforehand, and the results should be clearly described and reported in a section separate from the GADs in the clinical report. When using genome-wide NGS, some learned societies recommend variant screening strategies that focus on the patient's genotype and phenotype to achieve a balance between maximizing sensitivity and reducing the number of variants to be analysed. (#3 TOOLS AND RESOURCES AVAILABLE FOR DEVELOPING DIAGNOSTIC GENE PANELS): Numerous information sources and tools for structuring and facilitating the development of gene panels are available online. Evidence of the clinical validity of genes, as documented by various resources (e.g., GenCC, OMIM, ClinGen, DECIPHER, and PanelApp), should be considered when developing and maintaining gene lists. (#4 PANEL UPDATING AND MAINTENANCE): The contents of diagnostic panels should be monitored and updated frequently. The review process may include consultations with experts in the targeted diseases, literature searches, and consulting specific resources. In addition, the laboratory's bioinformatics pipeline can be configured to flag and present all new entries in the programmed databases. ClinGen proposes time intervals for recuration procedures based on different levels of evidence of clinical validity of gene-disease associations, while the ACMG recommends a manual review every six months. (#5 REANALYSIS OF DATA AND PRODUCTION OF AN AMENDED REPORT): According to the learned societies consulted, there is no requirement for laboratories to routinely reanalyze sequencing data. Rather, it is generally recommended that requests for reanalysis be made by the patient (or their parents) through the treating clinician. However, if the laboratory learns that the status of a specific variant has been reclassified, it is good clinical practice to identify the patients concerned and generate an amended report for the requesting clinician. CONCLUSION: The present state-of-knowledge report has enabled us to gather the available relevant literature on the principles and criteria for selecting genes to be tested for the investigation of a disease in constitutional genetics. The consulted literature has made it possible to meet the main objective of this work, which is to inform the MSSS of the best strategies for selecting genes associated with genetic diseases to create or update diagnostic gene panels. The implementation of a province-wide classification system based exclusively on minimum levels of evidence of gene-disease association would harmonize practices, reporting and patient care and services.

Authors' recommendations: RESULTS (#1 HARMONIZATION OF TERMS AND LEVELS OF EVIDENCE FOR GENE-DISEASE ASSOCIATIONS AND GENE CURATION IN CONSTITUTIONAL GENETICS): Until recently, there was a great deal of variation in the terms and the different initiatives for gene curation in the literature. It is for this reason that the Gene Curation Coalition (GenCC) was created. It brings together most of the learned societies that have proposed gene curation recommendations, criteria or initiatives in recent years and proposes the harmonization of the terms and the definitions of levels of evidence for gene-disease associations. This harmonized classification is divided into eight categories: “Definitive”, “Strong”, “Moderate”, “Limited”, “Contested”, “Refuted”, “No known relationship to disease” and “Animal model only”. The process of evaluating the evidence and classifying the clinical validity of the proposed gene-disease associations is based on the semiquantitative evaluation of the available genetic and experimental evidence. (#2 SELECTING GENES TO BE INCLUDED IN A DIAGNOSTIC NGS PANEL): The genes to be included in a diagnostic panel differ according to the learned society consulted. According to the American College of Medical Genetics and Genomics (ACMG), it is recommended that all the genes associated with a given Mendelian disease (GAD) for which the validity of the association with the disease is definitive, strong or moderate be included. On the other hand, according to Genomics England PanelApp and Gene2Phenotyp (G2P, European Bioinformatics Institute), it is recommended that only genes with a level of evidence of definitive or strong validity be included. It is also recommended to include, where appropriate, the GADs involved in the differential diagnoses to maximize the test’s sensitivity. In addition, some learned societies suggest that genes with incomplete penetrance and certain genes of uncertain significance (GUS) with limited validity, but for which new evidence has emerged, may also be included, with caution. In this case, disclosure consent explaining the possibility of inconclusive results should be requested from the patient beforehand, and the results should be clearly described and reported in a section separate from the GADs in the clinical report. When using genome-wide NGS, some learned societies recommend variant screening strategies that focus on the patient's genotype and phenotype to achieve a balance between maximizing sensitivity and reducing the number of variants to be analysed. (#3 TOOLS AND RESOURCES AVAILABLE FOR DEVELOPING DIAGNOSTIC GENE PANELS): Numerous information sources and tools for structuring and facilitating the development of gene panels are available online. Evidence of the clinical validity of genes, as documented by various resources (e.g., GenCC, OMIM, ClinGen, DECIPHER, and PanelApp), should be considered when developing and maintaining gene lists. (#4 PANEL UPDATING AND MAINTENANCE): The contents of diagnostic panels should be monitored and updated frequently. The review process may include consultations with experts in the targeted diseases, literature searches, and consulting specific resources. In addition, the laboratory's bioinformatics pipeline can be configured to flag and present all new entries in the programmed databases. ClinGen proposes time intervals for recuration procedures based on different levels of evidence of clinical validity of gene-disease associations, while the ACMG recommends a manual review every six months. (#5 REANALYSIS OF DATA AND PRODUCTION OF AN AMENDED REPORT): According to the learned societies consulted, there is no requirement for laboratories to routinely reanalyze sequencing data. Rather, it is generally recommended that requests for reanalysis be made by the patient (or their parents) through the treating clinician. However, if the laboratory learns that the status of a specific variant has been reclassified, it is good clinical practice to identify the patients concerned and generate an amended report for the requesting clinician. CONCLUSION: The present state-of-knowledge report has enabled us to gather the available relevant literature on the principles and criteria for selecting genes to be tested for the investigation of a disease in constitutional genetics. The consulted literature has made it possible to meet the main objective of this work, which is to inform the MSSS of the best strategies for selecting genes associated with genetic diseases to create or update diagnostic gene panels. The implementation of a province-wide classification system based exclusively on minimum levels of evidence of gene-disease association would harmonize practices, reporting and patient care and services.

Authors' methods: This state-of-knowledge report is a synthesis of the results of a rapid literature review that INESSS carried out on the principles and criteria for guiding the choice of genes to be tested according to their clinical relevance in constitutional genetic diseases. Publications were selected according to PIPOH1 criteria previously established by two scientific professionals. These publications include health technology assessment reports, systematic or nonsystematic reviews with or without meta-analysis, guidance documents, clinical practice guidelines, and learned society recommendations or positions on the topic of interest. A preliminary version of the report was read by two RQDM expert members to check the direction of the work and to ensure that it meets the MSSS’s and RQDM’s needs

Project Status: Completed

URL for project: https://www.inesss.qc.ca/publications/repertoire-des-publications/publication/principes-et-criteres-de-selection-des-genes-pour-le-diagnostic-moleculaire-des-maladies-en-genetique-constitutionnelle-par-sequencage-de-nouvelle-generation-sng.html

Year Published: 2023

URL for published report: https://www.inesss.qc.ca/publications/repertoire-des-publications/publication/principes-et-criteres-de-selection-des-genes-pour-le-diagnostic-moleculaire-des-maladies-en-genetique-constitutionnelle-par-sequencage-de-nouvelle-generation-sng.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)