Abstract
This study aimed to evaluate inter-laboratory classification concordance for copy number variants (CNVs) with a semiquantitative point-based scoring metric recommended by the American College of Medical Genetics and Genomics (ACMG) and Clinical Genome Resources (ClinGen). A total of 234 CNVs distributed by the National Center of Clinical Laboratories (NCCLs), and 72 CNVs submitted by different laboratories, were distributed to nine clinical laboratories performing routine clinical CNV testing in China and independently classified across laboratories. The overall inter-laboratory complete classification concordance rate of the 234 distributed CNVs increased from 18% (41/234) to 76% (177/234) using the scoring metric compared to the laboratory's previous method. The overall inter-laboratory complete classification concordance rate of the 72 submitted CNVs was 65% (47/72) using the scoring metrics. The 82 variants that initially did not reach complete concordance classification and 1 additional CNV deletion were reviewed; 34 reached complete agreement, and the overall post-review complete concordance rate was 85% (260/306). Additionally, the overall percentage of classification discordance possibly impacting medical management [i.e., pathogenic (P) or likely pathogenic (LP) vs. variant of uncertain significance (VUS)] was 11% (35/306). The causes of initial and final discordance in the classification were identified. The ACMG-ClinGen framework has promoted consistency in interpreting the clinical significance of CNVs. Continuous training among laboratories, further criteria and additional clarification of the standards, sharing classifications and supporting evidence through public database, and ongoing work for dosage sensitive genes/regions curation will be beneficial for harmonization of CNVs classification.
Highlights
Copy number variants (CNVs) are a class of human genetic variations comprising gains, losses, or complex rearrangements
After the 193 copy number variants (CNVs) with discrepant classifications based on the original clinical laboratory classification were re-evaluated using the ACMG-Clinical Genome Resources (ClinGen) scoring metrics by all nine laboratories, an additional 136 variants showed agreement of classifications, and the complete five-category concordance rate increased to 76% (177/234); the variant of uncertain significance (VUS)-category concordance rate was the highest (44%, 104/234)
This may be attributable to the fact that the participating laboratories have implemented scoring metrics for a certain period, familiarity and systems are constantly evolving, and such aspects are imperative for classification concordance
Summary
Copy number variants (CNVs) are a class of human genetic variations comprising gains (duplications and triplications), losses (deletions), or complex rearrangements. CNVs can disrupt the coding region or alter gene dosage and contribute to a broad range of genetic disorders, including intellectual disability (ID) and other neurodevelopmental disorders (NDDs), as well as multiple congenital anomalies (Nowakowska et al, 2017; Riggs et al, 2020a). In patients with several other diseases, such as deafness, renal disorder, blindness, and complex phenotype, CNV Interpretation Concordance. There are a proportion of benign CNVs in the human genome which are not enriched in individuals with abnormal phenotype and are repeatedly found in normal control populations (Tsuchiya et al, 2009; Nowakowska et al, 2017). Understanding the potential clinical significance of CNVs is crucial for their medical management. The frequency data of CNVs from healthy individuals remains limited, and novel CNVs are continually discovered; accurate and consistent determination of the clinical significance of individual rare CNVs across laboratories is challenging (Kearney et al, 2011)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
