Germline Genetic Variant Classification Requires More Equitable Reference Database Representation
Year: 2025
Type: article
Study design: Case Report
Abstract: Germline genetic testing can aid diagnostic workups but may reveal variants of unknown significance (VUS). VUS do not provide definitive diagnoses and may worsen patient and family stress. VUS are more prevalent in populations that are underrepresented in large genomic databases. We describe 7 pediatric hematology-oncology patients from the highly diverse Bronx County for whom VUS, novel, or rare pathogenic variant identification influenced clinical management and outcomes. For these cases, further investigation and/or variant reclassification ultimately led to diagnoses of von Hippel-Lindau syndrome, hemophagocytic lymphohistiocytosis, atypical hemolytic uremic syndrome, severe combined immunodeficiency, and Fanconi anemia. Through discussion of these cases, we illustrate how providers may gain insight into the pathogenicity of VUS and highlight the importance of incorporating underrepresented populations into genomic databases to improve variant characterization and address health care disparities.
Source: PEDIATRICS
Authors: Shana Burstein, Eva Spier, Janki Patel, William Jerome, Miranda Di Biase, Thelma Alessandra Sugrañes, Hailey Reisert, David M. Loeb, Daniel A. Weiser
Language: English
Topic: Genomics and Rare Diseases
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4408212166