Interpretation

When interpreting results, the following factors need to be considered:

Copy number variation is found in all individuals, including patients with abnormal phenotypes and normal populations. Therefore, determining the clinical significance of a rare or novel copy number change can be challenging. Parental testing may be necessary to further assess the potential pathogenicity of a copy number change.

While most copy number changes observed by chromosomal microarray testing can readily be characterized as pathogenic or benign, there are limited data available to support definitive classification of a subset into either of these categories. In these situations, a number of considerations are taken into account to help interpret results including the size and gene content of the imbalance, whether the change is a deletion or duplication, the inheritance pattern, and the clinical and/or developmental history of a transmitting parent.

All copy number variants within the limit of detection classified as pathogenic or likely pathogenic will be reported regardless of size. This includes but is not limited to incidental findings currently recommended for reporting by the American College of Medical Genetics and Genomics.(1) Copy number changes with unknown significance will be reported when at least one protein-coding gene is involved in a deletion greater than 200 kilobases or a duplication greater than 1 megabase (Mb).

The detection of excessive homozygosity may suggest the need for additional clinical testing to confirm uniparental disomy (UPD) or to test for variants in genes associated with autosomal recessive disorders consistent with the patient's clinical presentation that are present in regions of homozygosity. Interstitial regions with absence of heterozygosity (AOH) of unknown significance will be reported when greater than 10 Mb on UPD-associated chromosomes, and greater than 15 Mb on non-imprinted chromosomes. Terminal AOH will be reported when greater than 5 Mb. Whole genome AOH will be reported when greater than 2% of the genome.

The continual discovery of novel copy number variation and published clinical reports means that the interpretation of any given copy number change may evolve with increased scientific understanding.

Families benefit from hearing genetic information multiple times and in multiple ways. A referral to a clinical genetics professional is appropriate for individuals and families to discuss the results of chromosomal microarray testing.