The clinical application of genome-wide sequencing for monogenic diseases in Canada: Position Statement of the Canadian College of Medical Geneticists

Abstract

Purpose and scopeThe aim of this Position Statement is to provide recommendations for Canadian medical geneticists, clinical laboratory geneticists, genetic counsellors and other physicians regarding the use of genome-wide sequencing of germline DNA in the context of clinical genetic diagnosis. This statement has been developed to facilitate the clinical translation and development of best practices for clinical genome-wide sequencing for genetic diagnosis of monogenic diseases in Canada; it does not address the clinical application of this technology in other fields such as molecular investigation of cancer or for population screening of healthy individuals.Methods of statement developmentTwo multidisciplinary groups consisting of medical geneticists, clinical laboratory geneticists, genetic counsellors, ethicists, lawyers and genetic researchers were assembled to review existing literature and guidelines on genome-wide sequencing for clinical genetic diagnosis in the context of monogenic diseases, and to make recommendations relevant to the Canadian context. The statement was circulated for comment to the Canadian College of Medical Geneticists (CCMG) membership-at-large and, following incorporation of feedback, approved by the CCMG Board of Directors. The CCMG is a Canadian organisation responsible for certifying medical geneticists and clinical laboratory geneticists, and for establishing professional and ethical standards for clinical genetics services in Canada.Results and conclusionsRecommendations include (1) clinical genome-wide sequencing is an appropriate approach in the diagnostic assessment of a patient for whom there is suspicion of a significant monogenic disease that is associated with a high degree of genetic heterogeneity, or where specific genetic tests have failed to provide a diagnosis; (2) until the benefits of reporting incidental findings are established, we do not endorse the intentional clinical analysis of disease-associated genes other than those linked to the primary indication; and (3) clinicians should provide genetic counselling and obtain informed consent prior to undertaking clinical genome-wide sequencing. Counselling should include discussion of the limitations of testing, likelihood and implications of diagnosis and incidental findings, and the potential need for further analysis to facilitate clinical interpretation, including studies performed in a research setting. These recommendations will be routinely re-evaluated as knowledge of diagnostic and clinical utility of clinical genome-wide sequencing improves. While the document was developed to direct practice in Canada, the applicability of the statement is broader and will be of interest to clinicians and health jurisdictions internationally.

A prospective evaluation of whole-exome sequencing as a first-tier molecular test in infants with suspected monogenic disorders

“…These factors are recognized to increase diagnostic yield and/or facilitate data analysis. 23 Two small studies, of 15 and 35 patients, previously suggested high diagnostic yield in critically ill infants (73 and 55%, respectively). 7,21 In the first study, a diagnosis was obtained for 73% through whole-genome sequencing.…”

Axons to Exons: the Molecular Diagnosis of Rare Neurological Diseases by Next-Generation Sequencing

“…Similarly, the CCMG does not endorse the intentional interrogation of particular genes unrelated to the primary indication, but does provide competent adults with the option of opting in or out of receiving incidental results if they are inadvertently identified. For children, they recommend that pathogenic mutations considered medically [45]. Understandably, each laboratory will have their own policies regarding consent and reporting of these findings and it is important that they be reviewed prior to counselling patients and sending samples for testing.…”

“…Recommendations and position statements have now been written by several organizations, including the American College of Medical Genetics and Genomics (ACMG) [43], the European Society of Human Genetics (ESHG) [44], and the Canadian College of Medical Geneticists (CCMG) [45], to help guide their respective memberships. The ACMG recommends that patients be counselled and given the option of receiving results for a prescriptive list of 56 Bactionable^genes in which mutations greatly increase risk of serious, but treatable, diseases [43].…”

Findings made in gene panel to whole genome sequencing: data, knowledge, ethics – and consequences?

“…This shall result in the patient consenting to the testing process as well as to the consequences the data might induce [100,101]. The patient will likely have the current disease condition in focus and take for granted that potential risks that she/he should consent to are directly connected to related findings and their immediate consequences for her-or himself.…”