Towards an evidence‐based process for the clinical interpretation of copy number variation

Abstract

The evidence-based review (EBR) process has been widely used to develop standards for medical decision-making and to explore complex clinical questions. This approach can be applied to genetic tests, such as chromosomal microarrays, in order to assist in the clinical interpretation of certain copy number variants (CNVs), particularly those that are rare, and guide array design for optimal clinical utility. To address these issues, the International Standards for Cytogenomic Arrays Consortium has established an EBR Work Group charged with building a framework to systematically assess the potential clinical relevance of CNVs throughout the genome. This group has developed a rating system enumerating the evidence supporting or refuting dosage sensitivity for individual genes and regions that considers the following criteria: number of causative mutations reported; patterns of inheritance; consistency of phenotype; evidence from large-scale case-control studies; mutational mechanisms; data from public genome variation databases; and expert consensus opinion. The system is designed to be dynamic in nature, with regions being reevaluated periodically to incorporate emerging evidence. The evidence collected will be displayed within a publically available database, and can be used in part to inform clinical laboratory CNV interpretations as well as to guide array design.

Types of array findings detectable in cytogenetic diagnosis: a proposal for a generic classification

“…Overall, 42% of the children said they were not asked for their opinion on participation, whereas 39% of the children felt that both parents and children should be asked for permission and another 33% thought that children of their age should always give permission. 3 This study is an excellent illustration of children who have, unfortunately, not been involved in the decision-making process and it underscores our notion of assent. We agree with Waligora that in order to foster and safeguard the engagement of children in the decision-making process, practical guidance is needed.…”

“…A CNV (copy number variant) classification is already proposed and published by several authors. [1][2][3] However, none of these proposals defined any subcategories of clinically significant findings. We think that defining subcategories is a crucial basis for developing generic consent, if the patients may choose the kind of information they wish to be informed about.…”

Identification of an NPHP1 deletion causing adult form of nephronophthisis

“…The other rearrangements were found among individuals with intellectual deficiency or developmental delay. They correspond to copy number changes inherited from unaffected parents and their causative effects are still in discussion [27,28].…”

Mechanisms of Origin, Phenotypic Effects and Diagnostic Implications of Complex Chromosome Rearrangements

“…jsp), DECIPHER (https://decipher.sanger.ac.uk/), ISCA (http://clinicalgenome.org/), and PubMed should be consulted for each of the disrupted genes to determine whether such a gene disruption has previously been discovered in a patient with a similar phenotype [Feenstra et al, 2006;Firth et al, 2009;Kaminsky et al, 2011;South and Brothman, 2011;de Leeuw et al, 2012;Riggs et al, 2012]. The Database of Genomic Variants (http://dgv.…”