American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants

Abstract

Genomic microarrays used to assess DNA copy number are now recommended as first-tier tests for the postnatal evaluation of individuals with intellectual disability, autism spectrum disorders, and/or multiple congenital anomalies. Application of this technology has resulted in the discovery of widespread copy number variation in the human genome, both polymorphic variation in healthy individuals and novel pathogenic copy number imbalances. To assist clinical laboratories in the evaluation of copy number variants and to promote consistency in interpretation and reporting of genomic microarray results, the American College of Medical Genetics has developed the following professional guidelines for the interpretation and reporting of copy number variation. These guidelines apply primarily to evaluation of constitutional copy number variants detected in the postnatal setting.

Variants of unknown significance on chromosomal microarray analysis: parental perspectives

“…This method of copy number variation (CNV) detection is currently recommended as a first-tier test by the American College of Medical Genetics for individuals with developmental delay (DD), intellectual disability (ID), and/or autism spectrum disorder (ASD), as well as multiple congenital anomalies that are not specific to a recognizable syndrome (Manning and Hudgins 2010;Miller et al 2010). Even though this is a standard genetic test for individuals with DD/ID/ASD, there is much variability in laboratory interpretation and reporting of various CNVs (Bell et al 2008;Kearney et al 2011;Tsuchiya et al 2009). …”

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

“…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.…”

“…16 We suggest using a uniform name for disease-causing array findings, namely, pathogenic, which means that 'the CNV is documented as clinically significant in multiple peer-reviewed publications, even if penetrance and expressivity of the CNV are known to be variable' . 1 Based on our experience we recommend using three subcategories of pathogenic array findings: causative array findings, unexpected diagnoses and susceptibility loci for neurodevelopmental disorders (Table 1).…”

Assessing the utility of confirmatory studies following identification of large-scale genomic imbalances by microarray

“…[5][6][7][8][9] Genomic imbalances meeting reportable criteria were flagged for confirmatory studies.…”