Abstract and Introduction
Abstract
Purpose and scope The 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 development Two 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 conclusions Recommendations 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.
Introduction
There are approximately 7000 individually rare monogenic diseases that, as a group, affect 1 in 50 individuals and collectively contribute to significant morbidity, mortality and healthcare costs. Despite extensive investigations to identify the specific cause of a rare disease, the underlying aetiology remains unidentified for many patients. The diagnostic process employed by most medical geneticists in Canada involves clinical assessment followed by sequential laboratory testing. Recent advances, such as chromosomal microarray analyses and multigene panel DNA tests, have increased diagnostic yield, but the diagnosis remains elusive for the majority of patients in whom there is a presumed monogenic aetiology.
In recent years, the cost of DNA sequencing has declined rapidly. Next-generation sequencing (NGS) technologies have made it possible to interrogate a patient's genome in a cost-effective and efficient manner. While genome-wide sequencing in Canada has been performed on a research basis for several years, clinical diagnostic services based on these technologies are just now becoming available and are increasingly being requested. Ensuring that patients with genetic disease have appropriate access to these diagnostic tests has, therefore, become important. This document addresses the clinical use of genome-wide sequencing of germline DNA in the diagnosis of monogenic disease in Canada, but does not address the use of genome-wide sequencing in other medical contexts, such as molecular investigation of cancer or for population screening of healthy individuals. While the document was developed to direct practice in Canada, the applicability of the statement is not confined to Canadian borders and will be of interest to clinicians and health jurisdictions internationally.
The Canadian College of Medical Geneticists (CCMG) is a Canadian professional organisation comprised of clinically trained medical and laboratory geneticists that establishes professional standards of clinical genetics practice across the country. This Position Statement provides recommendations on clinical genome-wide sequencing for those providing clinical genetic services in Canada. The statement was developed by two multidisciplinary working groups, one focusing on clinical indications and one on incidental findings. It was posted on the CCMG website on 14 January 2015 for comment by the membership and approved by the CCMG Board of Directors on 22 March 2015.