Open Access Research

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

Ashraf Dallol2, Huda Banni12, Mamdooh A Gari2, Mohammed H Al-Qahtani2, Adel M Abuzenadeh2, Fatin Al-Sayes3, Adeel G Chaudhary2, Jeffrey Bidwell1 and Wael Kafienah1*

Author Affiliations

1 School of Cellular and Molecular Medicine, Medical Sciences Building, University of Bristol, University Walk, Bristol, BS8 1TD, UK

2 Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia

3 Department of Hematology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia

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Journal of Translational Medicine 2012, 10:199  doi:10.1186/1479-5876-10-199

Published: 24 September 2012

Abstract

Background

Glucose-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.

Methods

In 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.

Results

All 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.

Conclusions

Our findings will help design a focused population screening approach and provide better management for G6PD deficiency patients.

Keywords:
Glucose-6-phosphate dehydrogenase; Haemolytic anaemia; DNA sequencing; Haplotype; PHASE reconstruction; Linkage analysis; Gene mutation