Independent origin of single and double mutations in the human glucose 6-phosphate dehydrogenase gene

Vulliamy, Tom; Rovira, Ana; Yusoff, Nazarah; Colomer, Dolors; Luzzatto, Lucio; Corrons, Joan Lluís Vives i

doi:10.1002/(sici)1098-1004(1996)8:4<311::aid-humu3>3.0.co;2-a

Cited by 19 publications

(6 citation statements)

References 27 publications

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“…This includes rarer alleles such as A-968 (c.[376A>G;968T>C]), which has previously only been reported with anemia in three individuals, one homozygote and two heterozygotes. 36,37 Three missense variants in G6PD (c.202G>A, c.376A>G, and c.563C>T) were significantly enriched in All of Us alleles from participants with a diagnosis of G6PD deficiency (p-values < 0.0001) (Table 2). Occurrence of common A-202 variant c.[202G>A;376A>G] in both G6PD-deficient individuals who are asymptomatic and who have AHA is in agreement with other reports (Supplemental Table 3).…”

Section: Resultsmentioning

confidence: 99%

Functional interpretation, cataloging, and analysis of 1,341 known and new glucose-6-phosphate dehydrogenase variants

Geck

Powell

Dunham

2022

Preprint

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Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency affects over 500 million individuals who can experience anemia in response to oxidative stressors such as certain foods and drugs. Recently, the World Health Organization (WHO) called for revisiting G6PD variant classification as a priority to implement genetic medicine in low- and middle-income countries. Towards this goal, we sought to collect reports of G6PD variants and provide interpretations. We identified 1,341 G6PD variants in population and clinical databases. Using the ACMG standards and guidelines for the interpretation of sequence variants, we provided interpretations for 268 variants, including 186 variants that were not reported or of uncertain significance in ClinVar, bringing the total number of variants with non-conflicting interpretations to 400. For 414 variants with functional or clinical data, we analyzed associations between activity, stability, and current classification systems, including the new 2022 WHO Classification. We corroborated known challenges with classification systems, including phenotypic variation, emphasizing the importance of comparing variant effects across patients and studies. Biobank data made available by All of Us illustrate the benefit of large-scale sequencing and phenotyping by adding additional support connecting variants to G6PD-deficient anemia. By leveraging available data and interpretation guidelines, we created a repository for information on G6PD variants and nearly doubled the number of variants with clinical interpretations. These tools enable better interpretation of G6PD variants for the implementation of genetic medicine.

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Section: Resultsmentioning

confidence: 99%

Functional interpretation, cataloging, and analysis of 1,341 known and new glucose-6-phosphate dehydrogenase variants

Geck

Powell

Dunham

2022

Preprint

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“…G6PD Santiago de Cuba 1339A was identified in an 8year-old male patient who was referred for presenting a previous hemolytic event, osmotic fragility test was negative, blood smear was normal, and thalassemia was ruled out; this variant was first described in a Cuban boy with chronic anemia and later observed in Japanese and Chinese patients. G6PD Kamiube 1387T was observed in a 1year-old male patient whose newborn screening test suggested G6PD deficiency, osmotic fragility test, blood smear, and other hematological parameters were normal; this variant was firstly detected in a Japanese boy (Vulliamy et al, 1996;Hirono et al, 1997), suggesting an Asian origin of both variants. G6PD A +376G , typically classified as an asymptomatic class IV G6PD deficiency variant (Luzzatto et al, 2020), was recently considered a class III variant.…”

Section: G6pd Variants In Mexicansmentioning

confidence: 97%

Hematological and molecular analysis of patients with G6PD deficiency revealed coexistent hereditary spherocytosis and alpha thalassemia

Herrera-Tirado

Hernández-Peña

Ibarra-Cortés

et al. 2021

Annals of Human Genetics

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Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency, hereditary spherocytosis (HS), and alpha thalassemia (α-thal) are frequent erythrocyte pathologies with different geographic distributions worldwide. Our aim is to report hematological and molecular findings of G6PD deficient Mexican patients in coinheritance with suggestive hereditary spherocytosis (sHS) and α-thal. Methods: We studied 78 G6PD deficiency patients. Hematological parameters, acidified glycerol lysis test, erythrocyte morphology, electrophoresis, and hemoglobin quantification were obtained. G6PD and HBA2/HBA1 variants were identified using ARMS-PCR, Gap-PCR, or Sanger sequencing.Results: Nine G6PD variants were identified; A -202A/376G , A -376G/968C , and A +376G as the most frequent. G6PD Santiago de Cuba 1339A and Kamiube 1387T were detected in Mexicans for first time. Hematological analysis revealed additional erythrocyte pathologies in 52 patients, 32 with positive osmotic fragility test and spherocytes in blood smear (suggestive hereditary spherocytosis, sHS), 12 with microcytosis and 8 with all three defects who had the most severe phenotype, with significantly lower hematological parameters (Hb, PCV, MCV, and MCH). α-thal variants (α Hph α, α -59C>T α and -α 3.7 ) were observed in 65% of patients with microcytosis. Conclusion:Additional erythrocyte defects were observed in 69.3% of G6PD deficiency patients. We stress the importance of searching for the presence of additional erythrocyte hereditary diseases in patients with G6PD deficiency.

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“…G6PD exons 2 to 13 were amplified by the polymerase chain reaction (PCR) using appropriate oligonucleotide primers, as previously described. [18][19][20] Molecular studies of the G6PD gene were performed by direct Sanger sequencing of all the exons and adjacent intronic regions and 3'UTR regions. The three most common mutations were analyzed by PCR-RFLP.…”

Section: Molecular Studiesmentioning

confidence: 99%

Heterogeneidade Molecular da Deficiência em Glicose-6-Fosfato Desidrogenase (G6PD) na População Portuguesa

et al. 2022

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Introduction: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzyme defect in the world, affecting more than 500 million people. In Portugal, the average frequency of G6PD deficiency in males was estimated at about 0.5% and since the year 2000 several G6PD-deficient alleles have been identified. The main goal of this study was to improve the knowledge on the molecular heterogeneity of G6PD deficiency in the Portuguese population.Material and Methods: A retrospective analysis of the mutational profile of 138 unrelated Portuguese individuals (101 males; 37 females), with no known sub-Saharan ancestry, who had been diagnosed with G6PD deficiency between 1994 and 2020 at the Molecular Hematology Unit of Centro Hospitalar e Universitário de Coimbra. The molecular study was done by direct Sanger sequencing or PCR-RFLP analysis.Results: Twenty-one different pathogenic mutations were found. Among them, 20 were missense, causing the amino acid change, and one was an in-frame deletion in exon 10. The three most frequent mutations belong to the G6PD c.376A>G African background haplotype, namely the G6PD variants: A- (c.202G>A; p.68Val>Met) (58.6%), Betica (c.968T>C; p.323Leu>Pro) (12.1%) and Santamaria (c.542A>T; p.181Asp>Val) (4.3%).Conclusion: There is a wide molecular heterogeneity of G6PD deficiency in the Portuguese population.

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Independent origin of single and double mutations in the human glucose 6-phosphate dehydrogenase gene

Cited by 19 publications

References 27 publications

Functional interpretation, cataloging, and analysis of 1,341 known and new glucose-6-phosphate dehydrogenase variants

Functional interpretation, cataloging, and analysis of 1,341 known and new glucose-6-phosphate dehydrogenase variants

Hematological and molecular analysis of patients with G6PD deficiency revealed coexistent hereditary spherocytosis and alpha thalassemia

Heterogeneidade Molecular da Deficiência em Glicose-6-Fosfato Desidrogenase (G6PD) na População Portuguesa

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