1. Introduction Glucose-6-phosphate-dehydrogenase (G6PD) deficiency is one of the most common enzyme disorders, affecting as much as 5% of the world’s population.1 The G6PD gene is located on the X chromosome; therefore, males inherit one G6PD allele and females inherit two G6PD alleles. The population frequency of G6PD deficiency varies by gender and race, affecting males more than females. It is more prevalent among individuals of African, South-East Asian, and Mediterranean descent.2 G6PD reduces nicotinamide adenine dinucleotide phosphate (NADPH) and is the sole defense mechanism of red blood cells (RBC) against oxidative stress. People who are G6PD deficient are particularly susceptible to hemolytic events during infections or after exposure to certain foods and medications,3 such as rasburicase.4 Identification of patients with G6PD deficiency can be achieved by two different methods: G6PD activity testing and G6PD genotyping.5 The current gold standard for assigning G6PD phenotype is by activity; however, this test is not without limitations.6 G6PD activity test results are affected by various hematologic parameters which require an assessment for interfering factors before interpretation. Four known interferences include: 1) critically low hemoglobin, 2) recent RBC transfusion, 3) elevated reticulocyte count, and 4) elevated white blood cell (WBC) count.7-9 Thus, for many groups of patients (those with cancer, anemia, infections), G6PD activity test results may not be reliable. The gene coding for G6PD is highly polymorphic, with over 200 known variant alleles;10 however, the A-(202A_376G) variant accounts for the vast majority of low function alleles in African American populations.2,11 With growing use of clinical whole exome and whole genome sequencing, as well as pharmacogenetic arrays, G6PD genotype results will be increasingly available for patients. In cases where G6PD activity test results have also been generated, it is necessary to reconcile G6PD genotyping with any measured phenotypes. We herein describe how two laboratory tests (G6PD genotyping and G6PD activity) can be used in combination to assign G6PD phenotype. We also describe algorithms to assess for possible interferences with the G6PD activity test and to incorporate genotype to assign a more informed G6PD phenotype, especially in those with abnormal hematologic parameters, thereby properly guiding medication selection and improving patient safety.
2. Methods