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