Current address: Sequenom Inc, San Diego, CA.
Towards an evidence-based process for the clinical interpretation of copy number variation
Article first published online: 13 DEC 2011
© 2011 John Wiley & Sons A/S
Volume 81, Issue 5, pages 403–412, May 2012
How to Cite
Riggs, E., Church, D., Hanson, K., Horner, V., Kaminsky, E., Kuhn, R., Wain, K., Williams, E., Aradhya, S., Kearney, H., Ledbetter, D., South, S., Thorland, E. and Martin, C. (2012), Towards an evidence-based process for the clinical interpretation of copy number variation. Clinical Genetics, 81: 403–412. doi: 10.1111/j.1399-0004.2011.01818.x
- Issue published online: 11 APR 2012
- Article first published online: 13 DEC 2011
- Accepted manuscript online: 19 NOV 2011 02:17AM EST
- Received 16 September 2011, revised and accepted for publication 16 November 2011
- DNA copy number variation;
- evidence-based practice;
- gene dosage;
- oligonucleotide array sequence analysis
Riggs ER, Church DM, Hanson K, Horner VL, Kaminsky EB, Kuhn RM, Wain KE, Williams ES, Aradhya S, Kearney HM, Ledbetter DH, South ST, Thorland EC, Martin CL. Towards an evidence-based process for the clinical interpretation of copy number variation.
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.