Evidence for G6PD variant classification from multiplexed functional assays.

Area of Science:

• Biochemistry
• Genetics
• Pharmacogenomics

Background:

• Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most prevalent enzyme deficiency globally.
• It predisposes individuals to adverse reactions from specific drugs and foods.
• Over 60% of known G6PD variants are of uncertain significance, complicating clinical management.

Purpose of the Study:

• To functionally characterize a large number of G6PD variants.
• To distinguish clinically significant G6PD deficiency variants from benign ones.
• To improve genetic medicine implementation for G6PD deficiency.

Main Methods:

• Conducted high-throughput functional assays measuring G6PD activity and abundance.
• Assessed the impact of 10,674 missense, nonsense, and synonymous G6PD variants.
• Utilized variant classification based on known clinical effects.

Main Results:

• Confirmed the importance of NADP+ and G6PD dimerization for enzyme function.
• Generated evidence classifying 4,883 missense variants as contributing to G6PD deficiency.
• Classified 2,768 missense variants as unlikely to contribute to G6PD deficiency.

Conclusions:

• This study provides functional data for thousands of G6PD variants.
• The findings help resolve variants of uncertain significance, aiding clinical practice.
• Improved variant classification can prevent adverse drug reactions and guide G6PD deficiency management.