In the era of next-generation sequencing, clinicians frequently encounter VUS on genetic tests for MODY. Pathogenicity ascertainment of those variants may have substantial impact on optimal diabetes care. We aimed to determine the usefulness of reanalyzing previous VUS results in MODY. We performed a retrospective chart review to identify subjects with a VUS on a MODY genetic test performed > 3 years before the study and requested reanalysis of their genetic data at Athena Diagnostics. We identified 10 subjects with at least one VUS on MODY genetic testing (mean age at diagnosis: 13.4 ± 3.4 years, 60% female, 60% Hispanic, 20% African American and 20% non-Hispanic White). After reanalysis, 50% were recategorized to a different category: 30% “likely pathogenic” and 20% “benign”. All newly reclassified pathogenic variants were in HNF1A, and benign variants were in HNF1B and PDX1. The median time to reclassification since MODY testing was 8 years (range 4-10 years). The mean random C-peptide at diagnosis was 1.17 ± 0.17, 2.24 ± 0.8 and 2.96 ± 1.4 ng/mL for those with variants reclassified as benign, likely pathogenic and those who remained as VUS, respectively. In sum, periodic reanalysis of the genetic data of cases with a VUS on MODY tests may provide high-yield diagnostic information. Further studies are warranted to identify the optimal time and frequency for such analyses.


G.Alarcon: None. M.J.Redondo: None. M.Tosur: Advisory Panel; Provention Bio, Inc.

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