Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency

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

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

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

• Clinical sensitivity: >98% 
• Analytical sensitivity/specificity: 99%

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

• Clinical sensitivity: 99% in individuals of African descent 
• Analytical sensitivity/specificity: 99%

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