Positivity Rates and Variant Reclassification: A Comparative Study of IRD Panels

While sponsored genetic testing panels improve access to molecular diagnosis for inherited retinal diseases (IRD), significant challenges remain, including varying positivity rates between providers, discrepancies in variant classification (especially for variants of unknown significance [VUS]), and the frequent issuance of amendments to test reports, according to a study.

This retrospective study examines the use of sponsored IRD panel tests by Invitae and Blueprint Genetics (BG), focusing on their positivity rates and variant reclassification through amendments.

A test was considered positive if it identified a pathogenic mutation in an autosomal dominant gene, 2 pathogenic mutations in an autosomal recessive gene, or a pathogenic mutation in an X-linked gene in male patients.

The positivity rates were 34.9% for Invitae (n = 109) and 42.1% for BG (n = 107). Invitae reports contained more pathogenic variants per report (0.87 vs 0.58 variants, P = 0.0038) and issued more amendments than BG (0.54 vs 0.03 amendments; P< 0.01). Of the Invitae variant classification changes, 66.2% reclassified a VUS to benign. In the BG group, 75% of variant reclassifications changed a VUS to pathogenic. Despite these amendments, 88% of the Invitae amendments did not alter the overall report result.

The researchers concluded that VUS should not be deemed pathogenic in clinical decision-making. Careful interpretation of genetic testing results is essential.

Reference
Bao YK, Situ BA, Runner M, et al. Comparison of The Results of Sponsored Genetic Testing Panels for Inherited Retinal Diseases. J Clin Med. 2024;13(11):3118. doi: 10.3390/jcm13113118. PMID: 38892829; PMCID: PMC11172676.