How Experts Make a Call: Copy Number Variation Analysis in Unusual/Rare Case Scenarios

Cytogenetic microarray (CMA) has brought a revolution in the field of cytogenetics by improving resolution by 500 times that of traditional karyotyping. Analysis and interpretation of whole genome copy number variations (CNVs) is quite a challenging task for clinicians. Some software packages and databases are available which are based on algorithm. However, there is no clear rule to decide the pathogenicity.

To formulate a step-wise approach to evaluate the interpretation of a CNV and to help the clinicians to interpret the CNV reported by a laboratory with help of four representative cases of different phenotypes.

CMA was done using AffymetrixCytoscan 750K array in four cases from different families. Analysis was done based on the proposed approach.

The prediction of the effect of these CNVs depends on multiple factors and can change over time as the databases are expanded. CMA in four cases from different families revealed, a rare co-occurrence of 22q13.3 duplication and 22q13.3 deletion in a proband, a deletion along with mosaicism on 10q21.2 and 10p15.3, respectively, in the second case. Third case resulted in one variant of unknown significance of 1.2 Kb deletion on 10q11.22 and the fourth case showed a benign CNV. All CNVs were analyzed based on the proposed approach and helped in subsequent management and counselling of the families. The results indicate the effectiveness of a principled, feature-based, statistical framework for uncharacterized CNV interpretation, which future studies can expand upon to construct more reliable classifiers.