Quantitative Enzymatic
Polymerase Chain Reaction/Sequencing
- Preferred test for individuals of high-risk ethnic backgrounds other than those of African descent
- Appropriate test for symptomatic individuals of African descent who do not carry the A- allele
- Detects most G6PD deficiency-causing gene variants
Polymerase Chain Reaction/TaqMAN
- Preferred test for individuals of African descent
- Detects the single most common pathogenic G6PD variant (the A- allele) in individuals of African descent
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymatic disorder of red blood cells (RBCs) mainly affecting males. G6PD generates NADPH and protects RBCs from oxidative injury. G6PD deficiency can result in RBC hemolysis.
The most common condition associated with G6PD deficiency is hemolytic anemia, which can be triggered by bacterial or viral infections, by certain antibiotics and malaria medications, and by consumption of fava beans or inhaling fava pollen (called favism).
G6PD deficiency can also be a significant cause of mild to severe jaundice in newborns.
Disease Overview
Prevalence
400 million worldwide; varies by ethnicity
- 7/10 Kurdish Jewish males
- 1/6-10 African American males
- 1/7-9 Arabic males
- 1/6-16 Southeast Asian males
Symptoms
Most symptomatic individuals have ~10% residual enzyme activity.
Presentation varies by sex
- Males
- Hemizygotes – variably affected
- Females
- Heterozygotes – may experience symptoms even in the presence of normal enzyme levels
- Homozygotes – may be seen in populations where the G6PD-deficient allele is common
May present variably
- Acute hemolytic anemia in response to oxidative stress
- Neonatal jaundice
- Chronic nonspherocytic hemolytic anemia in the absence of oxidative stressors
Physiology
- G6PD protects red blood cell proteins from oxidative damage
- Decreased activity is associated with acute hemolytic anemia when individual is exposed to oxidative stress
- Certain antibiotics and malaria medications (eg, primaquine)
- Nondrug etiologies
- Diabetic ketoacidosis
- Infections
- Fava bean consumption
- Severe decreases in enzyme activity (<10%) associated with chronic nonspherocytic hemolytic anemia in the absence of oxidative stressors
Genetics
Gene
G6PD
Inheritance
X-linked recessive
Penetrance
Depends on variant; generally low
De novo Variants
Rare
Variants
- 400 allelic variants known
- >170 sequence variants in exons 2-13 are known to cause G6PD deficiency
Test Interpretation
Glucose-6-Phosphate Dehydrogenase
Clinical Sensitivity
99%
Results
Positive
- Class I – severe enzyme deficiency
- Associated with chronic nonspherocytic hemolytic anemia
- Class II – severe enzyme deficiency with <10% of normal activity
- Associated with acute hemolytic anemia
- Class III – mild to moderate enzyme deficiency (10-60% of normal activity)
- Most common class
- Class IV – very mild to almost normal enzyme activity (>60% of normal activity)
- No clinical consequences
Limitations
- Reduced sensitivity for detection of G6PD deficiency in
- Presence of hemolytic crises
- Neonates
- Presence of high reticulocyte count
- After blood transfusion
- Heterozygous females
- Diagnostic errors can occur due to rare sequence variations
Glucose-6-Phosphate Dehydrogenase Deficiency (G6PD) Sequencing
Sensitivity/Specificity
Results
- Positive
- Pathogenic variant(s) detected
- Negative
- No pathogenic variant detected
Limitations
- Sequencing may detect variants of unknown clinical significance
- Diagnostic errors can occur due to rare sequence variations
- Not detected by sequencing
- Deep intronic or regulatory region variants
- Large deletions or duplications
Glucose-6-Phosphate Dehydrogenase (G6PD) 2 Mutations
Sensitivity/Specificity
Results
Positive
- A- allele
- Male hemizygotes and female homozygotes are predicted to be affected by G6PD deficiency
- Female heterozygotes may be at risk for enzyme deficiency
- A+ allele
- Not associated with G6PD deficiency phenotype
Limitations
- Variants other than c.376A>G and c.202G>A will not be detected
- Diagnostic errors can occur due to rare sequence variations
References
-
27941691
Gómez-Manzo S, Marcial-Quino J, Vanoye-Carlo A, et al. Glucose-6-phosphate dehydrogenase: update and analysis of new mutations around the world. Int J Mol Sci. 2016;17(12):2069.
PubMed -
17978087
Beutler E, Duparc S, G6PD Deficiency Working Group. Glucose-6-phosphate dehydrogenase deficiency and antimalarial drug development. Am J Trop Med Hyg. 2007;77(4):779-789.
PubMed
Preferred initial screening test for G6PD deficiency