Rapid Fire Presentation 8th International Conference on Plasmodium vivax Research 2022

G6PD deficiency: genotype/phenotype associations and implications for diagnostics (#324)

Gonzalo Domingo 1 , Germana Bancone 2 , David G Grenache 3 , Mallika Imwong 4 , Michael Kalnoky 1 , Kamonlak Leecharoenkiat 5 , Didier Menard 6 , Issarang Nuchprayoon 7 , Duangdao Palasuwan 5 , Anna-Linda Peters 8 , Ari Winasti Satyagraha 9 , Rob van Zwieten 10
  1. PATH, Seattle, WASHINGTON, United States
  2. Shoklo Malaria Research Institute, Mae Sot, Thailand
  3. TriCore Reference Laboratories, , Albuquerque, , New Mexico, , USA
  4. Department of Molecular Tropical Medicine and Genetics,, Faculty of Tropical Medicine, Mahidol University, , Bangkok, , Thailand
  5. Oxidation in Red Cell Disorders Research Unit, Department of Clinical Microscopy, , Faculty of Allied Health Sciences, Chulalongkorn University, , Bangkok, , Thailand
  6. Unité Génétique du Paludisme et Résistance, INSERM U1201, Département de Parasites et Insectes Vecteurs, , Institut Pasteur, , Paris, , France
  7. Department of Pediatrics, Faculty of Medicine, , Chulalongkorn University, , Bangkok, , Thailand
  8. Department of Anesthesiology, Division of Vital Functions, , University Medical Center Utrecht, , Utrecht, , The Netherlands.
  9. Red Blood Cell Enzymes and Membrane Disorders Laboratory, , Eijkman Institute of Molecular Biology,, Jakarta, , Indonesia
  10. Laboratory of Red Blood Cell Diagnostics, , Department of Blood Cell Research, Sanquin Blood Supply Organisation, , Amsterdam, , The Netherlands.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked genetic disorder. Males are either hemizygous G6PD deficient or normal, and females carrying two alleles can be homozygous for two deficient or two normal alleles, as well as heterozygous with one normal and one deficient allele. While males mostly exhibit either low G6PD enzyme levels (< 30% activity) or higher G6PD enzyme levels (> 60%), G6PD activity in females can spread across the full dynamic range. This study explores the influence of these different relationships on the performance of diagnostic tests for G6PD deficiency.

Multiple datasets for which there was genotype and associated phenotype information were compiled, resulting in an empirical dataset of 197 hemizygous deficient males, 427 hemizygous normal males, 99 homozygous deficient females, 491 heterozygous females, and 590 homozygous normal females. G6PD activity distributions for a population of 10,000 at different G6PD deficient allele prevalence was generated by using the Hardy-Weinberg equilibrium to establish the frequency of each genotype, and then random sampling the empirical dataset to generate the associated G6PD activity profiles. Receiver operating characteristic and area under the curve analysis was used to explore the implications of G6PD activity distributions on the performance of a point-of-care test for G6PD deficiency. The trends observed in this study are compared to those observed in clinical studies evaluating the performance of a point-of-care test for G6PD deficiency.

The G6PD phenotype/genotype distributions indicate that at an 80% G6PD activity upper threshold to define intermediate females, homozygous normal females will constitute the majority of intermediate cases. This is also true at the 70% G6PD activity threshold but less so, and as such, may be a more appropriate threshold for defining females with intermediate G6PD activity. The G6PD activity distribution also dictates the performance of a test at different thresholds assuming typical imprecisions.