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Maximizing Equity in Newborn Screening via Reporting Variants of Uncertain Significance (VUS)

Health Services and Implementation
  • Primary Categories:
    • Public Health Genetics
  • Secondary Categories:
    • Public Health Genetics
Introduction:
The New York State (NYS) Newborn Screening (NBS) Program tests all infants born in NYS for more than 50 conditions. Gene sequencing is performed for 9 disorders on the NYS panel as a reflex to a positive biochemical screen. Pathogenic, likely pathogenic and variants of uncertain significance (VUS) are actionable and lead to referral for clinical evaluation and diagnostic testing. The goal of this study was to determine the proportion and characteristics of infants with confirmed conditions due to VUS identified via NBS in a diverse population.

Methods:
We retrospectively identified infants confirmed to have 1 of the 9 conditions sequenced since implementation of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) guidelines for variant classification and identified all who had at least 1 VUS. Infants reported to have possible disease or to be at risk for later onset conditions after diagnostic testing were excluded from analysis; none of these cases have been reported to us as developing symptoms.

Results:
Among 981 unique variants identified by the NYS NBS Program via sequencing, 373 (38%) were classified as VUS when first reported by our Program. Overall, 16% of classified variants were not in ClinVar at last NBS Program review. The proportion of VUS varied by gene, ranging from 8-45%. Among infants confirmed to have 1 of the 9 conditions during the study period, 19 (7.2%) had 1 heterozygous VUS, 6 (2.3%) were hemizygous for a VUS, and 2 (0.8%) were homozygous for a VUS. The number and type of VUS varied by specificity of the first-tier biochemical screen, gene characteristics, availability of literature and data repositories, characteristics of the screened population including patients and unaffected individuals, time since implementation of sequencing, and prevalence of the condition. Confirmed cases with VUS were from varied ancestral backgrounds.

Conclusion:
The decision of whether to report VUS varies depending on the setting and risk of an incorrect result. In the diagnostic setting, most individuals undergoing genetic testing are already under the care of a provider and symptomatic, known to be at risk for a condition, or have a known family history. Universal newborn screening is population-based and performed for infants who have no phenotype, and individual risk is unknown. NBS programs typically implement sequencing to reduce the number of false-positive biochemical screens by resulting infants with no actionable variants as screen-negative. Ultimately, most VUS are not associated with the screened conditions, but there is insufficient evidence to justify a likely benign classification. Although reporting VUS increases the number of false-positive screens, it also is an actionable result that maximizes detection of affected infants with rare, sometimes novel variants that may be population-specific, ensuring equitable screening regardless of genetic ancestry. In conclusion, reporting VUS in the NBS setting maximizes detection of affected infants before symptom onset, when treatment is most effective.

 

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