Copy Number Variants of Uncertain Significance by Chromosome Microarray Analysis from Consecutive Pediatric Patients: Reevaluation Following Current Guidelines and Reanalysis by Genome Sequencing.

BACKGROUND

Copy number variants of uncertain significance (CNVus) from chromosome microarray analysis (CMA) presents unresolved challenges for clinical geneticists, genetic counselors, and patients. We performed a systematic reevaluation of reported CNVus and reanalysis of selected CNVus by whole genome sequencing (WGS) to assess the diagnostic value and clinical impact on CNVus reclassification.

METHODS

We retrospectively reviewed 5277 consecutive pediatric cases by CMA from the Yale Clinical Cytogenetics Laboratory over a 13-year period. Reevaluation was performed on all reported CNVus following current ACMG/ClinGen guidelines. Reanalysis by WGS was applied to selected cases for reclassification of CNVus.

RESULTS

A total of 567 CNVus from 480 cases were reported, which accounted for 9.1% of pediatric cases. A total of 4 CNVus in 4 cases (0.8%, 4/480) were reclassified to pathogenic/likely pathogenic CNVs (pCNVs/lpCNVs); while 23 CNVus in 23 cases (4.8%, 23/480) were reclassified to benign/likely benign CNVs (bCNVs/lbCNVs). The overall rate of reclassification was 5.6%. WGS performed on selected cases further defined breakpoints and ruled out additional causative genetic variants.

CONCLUSIONS

The results from this study demonstrated the diagnostic value of periodic reevaluation of CNVus and reanalysis by WGS in an interval of 3-5 years and provided evidence to support standardized laboratory reevaluation and reanalysis.