Five novel glucose-6-phosphate dehydrogenase deficiency haplotypes correlating with disease severity

Abstract

BackgroundGlucose-6-phosphate dehydrogenase (G6PD, EC 1.1.1.49) deficiency is caused by one or more mutations in the G6PD gene on chromosome X. An association between enzyme levels and gene haplotypes remains to be established.MethodsIn this study, we determined G6PD enzyme levels and sequenced the coding region, including the intron-exon boundaries, in a group of individuals (163 males and 86 females) who were referred to the clinic with suspected G6PD deficiency. The sequence data were analysed by physical linkage analysis and PHASE haplotype reconstruction.ResultsAll previously reported G6PD missense changes, including the AURES, MEDITERRANEAN, A-, SIBARI, VIANGCHAN and ANANT, were identified in our cohort. The AURES mutation (p.Ile48Thr) was the most common variant in the cohort (30% in males patients) followed by the Mediterranean variant (p.Ser188Phe) detectable in 17.79% in male patients. Variant forms of the A- mutation (p.Val68Met, p.Asn126Asp or a combination of both) were detectable in 15.33% of the male patients. However, unique to this study, several of such mutations co-existed in the same patient as shown by physical linkage in males or PHASE haplotype reconstruction in females. Based on 6 non-synonymous variants of G6PD, 13 different haplotypes (13 in males, 8 in females) were identified. Five of these were previously unreported (Jeddah A, B, C, D and E) and were defined by previously unreported combinations of extant mutations where patients harbouring these haplotypes exhibited severe G6PD deficiency.ConclusionsOur findings will help design a focused population screening approach and provide better management for G6PD deficiency patients.

Genotype–Phenotype Correlations of Glucose-6-Phosphate–Deficient Variants Throughout an Activity Distribution

“…Finding class II variants (<10% normal activity) such as Union, Mediterranean, Santa Maria, and Canton in the very deficient region was expected (4, 7) because our reference interval is 9.9 to 16.6 U/g Hb (median, 13.2). However, 1 older review mentions both class II and III activities for the Canton variant (21), and a more recent article shows a range of activities for Mediterranean heterozygous females similar to what they observed for heterozygous female A− variants (22). The single Asahi variant in our study had a G6PD activity of 4.2 U/g Hb (31% of the reference interval median).…”

Glucose-6-Phosphate Dehydrogenase Deficiency in Individuals Infected with Human Immunodeficiency Virus at the Aminu Kano Teaching Hospital Kano, North Western Nigeria

“…[9], reported a 20% prevalence of G-6-PD deficiency in his study in Nigeria. In other parts of Africa, the prevalence of G-6-PD deficiency has been reported to be 22.5% in Congo (Brazzaville), 15.7% in Mali (Bamako), 13.0% in Uganda and 9.0-15.5% in Gabon [15]. The higher number of G-6-PD deficient females compared with the males was unexpected as G-6-PD deficiency has been reported to be sex linked with male preponderance.…”

A novel flow cytometry‐based method of analyzing Heinz bodies

“…This result may be due to variance in the severity of patients’ G6PD deficiency. Previous research has shown variation among patients in clinical settings ranging from asymptomatic to severely anemic . Therefore, further study should use flow cytometry to assess the relationship between the clinical severity of patients’ G6PD deficiency and the number of RBCs positive for Heinz bodies.…”