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PMID: 22097934 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Review

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

Clinical genetics ·Vol. 81 ·No. 5 ·2012-05-00 ·Pages 403-12

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

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.

MeSH Terms
DNA Copy Number Variations/genetics Evidence-Based Medicine Gene Dosage Genome, Human Humans Phenotype
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Riggs E R
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
Church D M
Hanson K
Horner V L
Kaminsky E B
Kuhn R M
Wain K E
Williams E S
Aradhya S
Kearney H M
Ledbetter D H
South S T
Thorland E C
Martin C L
Conflict of Interest

S. A. is employed by GeneDx (a subsidiary of Bioreference Laboratories, Inc.). S. S. is the Medical Director at ARUP Laboratories, a not-for-profit organization owned by the University of Utah offering among other tests genomic microarray. She also serves as a consultant to Lineagen, Inc., a for-profit company, which offers genomic microarray testing. Dr S. S. has received honoraria for speaking engagements on behalf of Affymetrix Inc. D. L. is a consultant for Roche Nimblegen. The other authors declare no conflict of interest.

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Article Info
Journal
Clinical genetics
Abbr.
Clin Genet
ISSN
1399-0004
DOI
10.1111/j.1399-0004.2011.01818.x
Published
2012-05-00
Epub
2011-00-13
Pages
403-12
Language
English
Region
Denmark
NLM ID
0253664
PMCID
PMC5008023
Subset
IM
Grants
NICHD NIH HHS · RC2 HD064525 · United States
NHGRI NIH HHS · U41 HG002371 · United States
Intramural NIH HHS · United States
NICHD NIH HHS · HD064525 · United States
External Links
PubMed source DOI: 10.1111/j.1399-0004.2011.01818.x PMC Full Text View journal details
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