Germline Genetic Variant Classification Requires More Equitable Reference Database Representation.

Area of Science:

• Genetics
• Pediatric Hematology-Oncology
• Genomic Medicine

Background:

• Germline genetic testing aids diagnosis but can yield variants of unknown significance (VUS).
• VUS complicate diagnoses, increase patient/family stress, and are more common in underrepresented populations.
• Genomic databases often lack diversity, impacting variant interpretation.

Purpose of the Study:

• To illustrate how VUS and rare variants impact clinical management in pediatric hematology-oncology.
• To highlight the diagnostic utility of further investigation for VUS in diverse patient cohorts.
• To emphasize the need for broader representation in genomic databases.

Main Methods:

• Case series of 7 pediatric hematology-oncology patients from a diverse urban setting.
• Review of germline genetic testing results, including VUS, novel, and rare variants.
• Clinical correlation and outcomes following variant reclassification and further investigation.

Main Results:

• Identification of VUS, novel, or rare pathogenic variants influenced clinical management.
• Diagnoses included von Hippel-Lindau syndrome, hemophagocytic lymphohistiocytosis, atypical hemolytic uremic syndrome, severe combined immunodeficiency, and Fanconi anemia.
• Further investigation and reclassification of variants were crucial for diagnosis.

Conclusions:

• Detailed case analysis can provide insights into VUS pathogenicity.
• Incorporating diverse populations into genomic databases is essential for accurate variant characterization.
• Addressing health care disparities requires improved genomic data for underrepresented groups.