Browsing by Author "Dunham, Maitreya J."

Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    Functional analysis of G6PD variants associated with low G6PD activity in the All of Us Research Program
    (Oxford University Press, 2024-11-28) Powell, Nicholas R.; Geck, Renee C.; Lai, Dongbing; Shugg, Tyler; Skaar, Todd C.; Dunham, Maitreya J.; Medicine, School of Medicine
    The glucose-6-phosphate dehydrogenase (G6PD) enzyme protects red blood cells against oxidative damage. Individuals with G6PD-impairing polymorphisms are at risk of hemolytic anemia from oxidative stressors. Prevention of G6PD deficiency-related hemolytic anemia is achievable by identifying affected individuals through G6PD genetic testing. However, accurately predicting the clinical consequence of G6PD variants is limited by over 800 G6PD variants which remain of uncertain significance (VUS). There also remains inconsistency in which deficiency-causing variants are included in genetic testing arrays: many institutions only test c.202G > A, though dozens of other variants can cause G6PD deficiency. Here, we improve G6PD genotype interpretations using the All of Us Research Program data and a yeast functional assay. We confirm that G6PD coding variants are the main contributor to decreased G6PD activity and that 13% of individuals in the All of Us data with deficiency-causing variants would be missed by only genotyping for c.202G > A. We expand clinical interpretation for G6PD VUS, reporting that c.595A > G ("Dagua" or "Açores") and the novel variant c.430C > G reduce activity sufficiently to lead to G6PD deficiency. We also provide evidence that 5 missense VUS are unlikely to lead to G6PD deficiency, and we applied the new World Health Organization (WHO) guidelines to recommend classifying 2 synonymous variants as WHO Class C. In total, we provide new or updated clinical interpretations for 9 G6PD variants. We anticipate these results will improve the accuracy, and prompt increased use, of G6PD genetic tests through a more complete clinical interpretation of G6PD variants.
  • Thumbnail Image
    Item
    Functional interpretation, cataloging, and analysis of 1,341 glucose-6-phosphate dehydrogenase variants
    (Elsevier, 2023) Geck, Renee C.; Powell, Nicholas R.; Dunham, Maitreya J.; Medicine, School of Medicine
    Glucose-6-phosphate dehydrogenase (G6PD) deficiency affects over 500 million individuals who can experience anemia in response to oxidative stressors such as certain foods and drugs. Recently, the World Health Organization (WHO) called for revisiting G6PD variant classification as a priority to implement genetic medicine in low- and middle-income countries. Toward this goal, we sought to collect reports of G6PD variants and provide interpretations. We identified 1,341 G6PD variants in population and clinical databases. Using the ACMG standards and guidelines for the interpretation of sequence variants, we provided interpretations for 268 variants, including 186 variants that were not reported or of uncertain significance in ClinVar, bringing the total number of variants with non-conflicting interpretations to 400. For 414 variants with functional or clinical data, we analyzed associations between activity, stability, and current classification systems, including the new 2022 WHO classification. We corroborated known challenges with classification systems, including phenotypic variation, emphasizing the importance of comparing variant effects across individuals and studies. Biobank data made available by All of Us illustrate the benefit of large-scale sequencing and phenotyping by adding additional support connecting variants to G6PD-deficient anemia. By leveraging available data and interpretation guidelines, we created a repository for information on G6PD variants and nearly doubled the number of variants with clinical interpretations. These tools enable better interpretation of G6PD variants for the implementation of genetic medicine.
  • Thumbnail Image
    Item
    Response to Luzzatto et al.
    (Elsevier, 2023) Geck, Renee C.; Powell, Nicholas R.; Dunham, Maitreya J.; Medicine, School of Medicine