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Glucose-6-phosphate dehydrogenase (G6PD) is a key enzyme in the pentose phosphate pathway that generates NADPH to protect red blood cells from oxidative damage. Pathogenic variants in G6PD (HGNC:4057) cause G6PD deficiency (MONDO:0005775), an X-linked recessive disorder presenting with acute hemolytic anemia, neonatal jaundice, and rhabdomyolysis under oxidative stress. Male hemizygotes and, less frequently, heterozygous females manifest symptoms upon exposure to drugs, infections, or fava beans, with carrier females showing intermediate phenotypes in >30% of cells.
Genetic evidence for this association is definitive. Many studies report hundreds of unrelated affected individuals, including Italian Lodi cases with Asp282His and maternal segregation in three generations ([PMID:1823863]), and a Hawaiian cohort screening 4,984 subjects with 188 male probands carrying ten distinct missense variants ([PMID:8244337]). Multiple de novo and familial occurrences of variants such as c.713A>G (p.Lys238Arg) and c.1187C>G (p.Pro396Arg) confirm pathogenicity. Segregation analysis in pedigrees consistently shows co-segregation of G6PD variants with hemolytic phenotypes.
The variant spectrum encompasses >200 distinct alleles, predominantly missense substitutions clustering around substrate and NADP binding domains. Variant classes include class I (severe chronic hemolysis), class II (severe deficiency), and class III (mild deficiency). A representative variant, c.844G>C (p.Asp282His), reduces red cell enzyme activity to ~15% of normal in erythrocytes and myocytes ([PMID:1823863]). Founder and recurrent alleles (e.g., Mediterranean c.563C>T, Canton c.1376G>T) exhibit population-specific frequencies up to 20% in Laotian males ([PMID:8244337]).
Population surveys highlight high carrier rates in malaria-endemic regions: gene frequencies of 0.037 in Chinese, 0.134 in Filipinos, and 0.203 in Laotians from Hawaii ([PMID:8244337]); 5.6% Mediterranean variant prevalence in Afghan Pashtun ([PMID:24586352]); and >10% in Indian subpopulations ([PMID:15315792]). Newborn screening in China (n>10,000) identifies hotspot mutations (c.1376G>T, c.1388G>A, c.95A>G, c.1024C>T, c.871G>A) accounting for >80% of cases. Female heterozygotes frequently show intermediate activity, underscoring the need for combined genetic and enzymatic testing.
Functional and biochemical studies establish loss-of-function as the pathogenic mechanism. Recombinant A- variants show unproductive folding and decreased soluble enzyme yield ([PMID:8566536]), while class I alleles cluster near dimer interfaces, exhibiting elevated Km, heat lability, and rapid in vivo degradation ([PMID:1536798]). In vitro expression in E. coli confirms substrate binding defects for p.Arg198Cys with a 4-fold increased Km for G6P and 32-fold increased analogue utilization ([PMID:8118045]). Structural analyses reveal reduced unfolding enthalpy and disrupted tertiary contacts in A- alleles ([PMID:10734064]).
Collectively, G6PD deficiency meets all ClinGen criteria for a definitive gene-disease relationship, with strong genetic and functional concordance. Routine G6PD genotyping and enzymatic assays are crucial for diagnosing at-risk individuals, guiding safe use of oxidative drugs, and informing newborn screening and public health strategies. Key Take-home: Screening for G6PD variants informs personalized management to prevent hemolytic crises in at-risk populations.
Gene–Disease AssociationDefinitiveHundreds of unrelated cases across diverse populations; consistent X-linked inheritance and enzyme deficiency concordant with phenotype Genetic EvidenceStrong
Functional EvidenceStrongBiochemical and structural assays consistently demonstrate enzyme instability, elevated Km, and loss of activity |