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