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Racial Disparities of VUS Results – Pediatric Neurodevelopmental Disorders

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical Genetics
  • Secondary Categories:
    • Clinical Genetics
Introduction:
Neurodevelopmental disorders (NDDs) are a group of conditions characterized by developmental deficits that alter or inhibit personal, social, academic, or occupational function and are caused by a variety of etiologies. Recent literature suggests that exome sequencing provides a 30-43% diagnostic yield among children with suspected NDDs, which led to a recommendation to consider it as a first-tier test in the workup of these conditions. However, in order to evaluate the efficacy of a genetic testing approach among a class of disorders, the utility of test application across all populations should be considered. Historical racial biases and exclusionary testing away from minority groups within genetics research has resulted in ethnic homogeneity in genetic studies and genomic databases; therefore, interpretation primarily investigates variants common to communities that were overrepresented in said genome databases compared to the general population. Consequently, racially biased genome reference databases may lead to disproportionately elevated rates of variants of uncertain significance (VUSs) among underrepresented minority groups for NDDs. This study aims to determine if such racial and ethnic disparities in VUS results exist among pediatric patients with autism spectrum disorder, intellectual disability, or developmental delay.

 

Methods:
This retrospective, quantitative, chart-review study was conducted utilizing genetic test records and electronic medical records (EMRs) from Children’s Wisconsin. Genetic tests ordered between January 2019 to May 2023 and their corresponding patient EMRs were reviewed for study participation. Specifically, exome sequencing, genome sequencing, and gene panel testing completion was a requisite for study participation. Inclusion was contingent upon reported clinical findings such as regression, developmental delay, intellectual disability, autism spectrum disorder, or other specified neurocognitive delay/disability. EMRs for pediatric participants with a clinical suspicion or diagnosis of NDDs were reviewed in order to collect demographic information, clinical indicators, diagnoses (ICD-10 codes), test results, and clinical outcomes. De-identified data was then assessed for statistical significance of VUS rates across clinical indicators/diagnoses, genetic test type, and demographic groups using statistical software (R version 4.3.1).

Results:
247 individuals met inclusion criteria for study. Participant demographic data was classified by self-reported race/ethnicity and grouped into White (71%, 173) and Non-White (29%, 71). Genetic test results were categorized by either having at least 1 VUS result (54%, 132) or 0 VUS results reported (46%, 113). While Non-White participants experienced higher rates of VUSs for all test types combined compared to White participants (63% and 49%, respectively), this data was not statistically significant. However, Non-White participants who pursued exome sequencing saw higher VUS rates than White participants (81% and 58%, respectively, p=0.026). As well, various ICD-10 codes and clinical indicators led to significantly higher VUS rates when indicated in patient records. In accordance with the literature, exome sequencing provided a diagnostic yield of 41%, while genome sequencing yielded 36.7%, and panel testing yielded 11.4%. VUS rate also significantly varied with test type: exome sequencing at 65%, genome sequencing at 42%, and panel testing at 52% (p=0.004).

Conclusion:
This study found that racial/ethnic biases exist in the VUS rate of pediatric individuals pursuing genetic testing for neurodevelopmental disorders and demonstrated significantly higher VUS rates for Non-White participants pursuing exome sequencing specifically. These results demonstrate a significant lack of representation of minority population genomes in variant reference databases. Given that VUS results are not clinically actionable, a higher rate of VUSs among specific populations can lead to shortcomings in clinical care, exacerbating existing health disparities. These results raise concerns about the utility of exome sequencing as a first-tier diagnostic modality for NDDs when applied to racially diverse populations, as well as serve as a call to action for greater diversity in reference genome databases used by clinical institutions.

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