Discussion:
VUS identification does not generally guide clinical management, as most VUS are ultimately determined to be benign11,12. However, these vignettes highlight how non-European underrepresentation in genomic databases may ineffectively capture clinically significant variants. This is most striking in Vignette 1, in which a VUS was formally reclassified to likely pathogenic, directly altering management, and in Vignettes 4-7, in which novel pathogenic variants were identified in patients from underrepresented backgrounds. The VUS in Vignettes 2 and 3 contrastingly remain of uncertain pathogenicity but may warrant closer investigation. In Vignette 3, the VUS was noted to be a rare variant in a disease-associated gene in another study, and in Vignette 2, the presence of HLH only in the child, despite both parent and child carrying a known pathogenic variant, along with absent perforin in the child, may suggest that the VUS is likely pathogenic.
The American College of Medical Genetics and Genomics (ACMG) has issued formal guidelines for assessing pathogenicity of sequence variants13. One of the critical factors is whether the variant has been reported previously and, if so, with what frequency. This leads to an inherent bias, given the underrepresentation of non-European genomes in reference databases. Therefore, expanding the databases to include a more diverse population should facilitate appropriate classification of more variants found predominantly in non-European patients, and should attempt to alleviate the unease experienced by families and providers when uncovering a VUS. Heightened awareness could also expedite variant reclassification if given appropriate supportive information (as in Vignette 1).
Identification of novel pathogenic variants and VUS reclassification can alter individual patient outcomes and impact the larger community by reducing healthcare disparities in underrepresented populations. Expanding genomic databases to more comprehensively incorporate patients of non-European descent will improve variant identification and classification, facilitate more informed and equitable care for all patient groups, and enhance understanding of disease pathogenesis. It is critical to coordinate multinational efforts to define the frequency and spectrum of genetic variants so that reference databases are more robust and reflect the heterogeneity of most communities.
Conflict of Interest Statement: The authors have no conflicts of interest to disclose.
Acknowledgements: N/A