Genetic variants causing G6PD deficiency: Clinical and biochemical data support new WHO classification

• Published in: British journal of haematology Vol. 202; no. 5; pp. 1024 - 1032
• Main Authors: Nannelli, Caterina, Bosman, Andrea, Cunningham, Jane, Dugué, Pierre‐Antoine, Luzzatto, Lucio
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.09.2023
• Subjects: Anemia; Erythrocytes; G6PD deficiency; Gene frequency; Genetic diversity; Glucosephosphate dehydrogenase; Glucosephosphate Dehydrogenase - genetics; Glucosephosphate Dehydrogenase Deficiency - genetics; glucose‐6‐phosphate dehydrogenase; haemolytic anaemia; Hematology; Hemolysis; Hemolytic anemia; Humans; Infant, Newborn; Jaundice; Literature reviews; Male; Neonates; Polymorphism, Genetic; Substrate preferences; WHO classification; World Health Organization; haemolytic anaemia; glucose-6-phosphate dehydrogenase; WHO classification; G6PD deficiency
• ISSN: 0007-1048; 1365-2141; 1365-2141
• DOI: 10.1111/bjh.18943

Summary Glucose‐6‐phosphate dehydrogenase (G6PD) deficiency in erythrocytes causes acute haemolytic anaemia upon exposure to fava beans, drugs, or infection; and it predisposes to neonatal jaundice. The polymorphism of the X‐linked G6PD gene has been studied extensively: allele frequencies of up to 25% of different G6PD deficient variants are known in many populations; variants that cause chronic non‐spherocytic haemolytic anaemia (CNSHA) are instead all rare. WHO recommends G6PD testing to guide 8‐aminoquinolines administration to prevent relapse of Plasmodium vivax infection. From a literature review focused on polymorphic G6PD variants we have retrieved G6PD activity values of 2291 males, and for the mean residual red cell G6PD activity of 16 common variants we have obtained reliable estimates, that range from 1.9% to 33%. There is variation in different datasets: for most variants most G6PD deficient males have a G6PD activity below 30% of normal. There is a direct relationship between residual G6PD activity and substrate affinity (KmG6P), suggesting a mechanism whereby polymorphic G6PD deficient variants do not entail CNSHA. Extensive overlap in G6PD activity values of individuals with different variants, and no clustering of mean values above or below 10% support the merger of class II and class III variants. Genetic variants of G6PD causing G6PD deficiency make red cells vulnerable to oxidative damage. From a literature review we have compiled data on 2291 G6PD deficient male subjects and determined the residual G6PD activity associated with 17 common variants of G6PD: the values range from 2 to 33% of normal. With respect to the WHO classification of G6PD variants, our data support the merger of class II and class III.