The ethnogeographic variability of genetic factors underlying G6PD deficiency.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency caused by genetic variants in the G6PD gene, constitutes the most common enzymopathy worldwide, affecting approximately 5% of the global population. While carriers are mostly asymptomatic, they are at substantial risk of acute hemolytic anemia upon certain infections or exposure to various medications. As such, information about G6PD activity status in a given patient can constitute an important parameter to guide clinical decision-making. Here, we leveraged whole genome sequencing data from 142,069 unrelated individuals across seven human populations to provide a global comprehensive map of G6PD variability. By integrating established functional classifications with stringent computational predictions using 13 partly orthogonal algorithms for uncharacterized and novel variants, we reveal the large extent of ethnogeographic variability in G6PD deficiency and highlight its population-specific genetic composition. Overall, estimated disease prevalence in males ranged between 12.2% in Africans, 2.7-3.5% across Asia and 2.1% in Middle Easterners to < 0.3% in Europeans, Finnish and Amish. In Africans, the major deficient alleles were A-202A/376 G (minor allele frequency 11.6%) and A-968 C/376 G (0.5%). In contrast, G6PD deficiency in Middle Easterners was primarily due to the Mediterranean allele (1.3%) and the population-specific Cairo variant (0.4%). In South Asia, the most prevalent deficient alleles were Mediterranean (1.7%), Kerala (1.1%), Gond (0.9%) and Orissa (0.2%), whereas in East Asian populations the Canton (1.1%), Kaiping (0.7%) and Viangchan (0.3%) variants were predominant. Combined, our analyses provide a large dataset of G6PD variability across major ethnogeographic groups and can instruct population-specific genotyping strategies to optimize genetically guided therapeutic interventions.

A greater awareness of children with glucose-6-phosphate dehydrogenase deficiency is imperative in western countries.

AIM: This national retrospective Danish study described the characteristics of children diagnosed with glucose-6-phosphate dehydrogenase (G6PD) deficiency, an inherited X-linked recessive disorder that often affects children of Middle Eastern descent. METHODS: We studied children born between 1 January 2000 and 31 December 2017 and diagnosed with G6PD deficiency. They were identified from the Danish National Hospital Discharge Register and the Danish Database of Extreme Neonatal Hyperbilirubinaemia. RESULTS: There were 113 children diagnosed with G6PD deficiency, 67% were of Middle Eastern descent and they were frequently diagnosed before the onset of symptoms, based on known heredity. Of the 67 infants born in Denmark, 10% had extreme neonatal hyperbilirubinaemia and one developed kernicterus spectrum disorder, as did one child born in the Middle East. Most (61%) of the 33 children with jaundice received phototherapy, 12% had exchange transfusions and 18% received whole blood transfusions. After the neonatal period, 23% of the cohort had blood transfusions and 4% needed intensive care for acute haemolytic anaemia. The incidence of G6PD deficiency appeared to be severely underestimated. CONCLUSION: Many families from countries where G6PD deficiency is endemic move to Denmark and other Western countries. Greater awareness is essential to avoid chronic and potentially lethal, consequences.

G6PD deficiency and severity of COVID19 pneumonia and acute respiratory distress syndrome: tip of the iceberg?

The severe pneumonia caused by the human coronavirus (hCoV)-SARS-CoV-2 has inflicted heavy casualties, especially among the elderly and those with co-morbid illnesses irrespective of their age. The high mortality in African-Americans and males, in general, raises the concern for a possible X-linked mediated process that could affect the viral pathogenesis and the immune system. We hypothesized that G6PD, the most common X-linked enzyme deficiency, associated with redox status, may have a role in severity of pneumonia. Retrospective chart review was performed in hospitalized patients with COVID19 pneumonia needing supplemental oxygen. A total of 17 patients were evaluated: six with G6PD deficiency (G6PDd) and 11 with normal levels. The two groups (normal and G6PDd) were comparable in terms of age, sex, co-morbidities, and laboratory parameters-LDH, IL-6, CRP, and ferritin, respectively. Thirteen patients needed ventilatory support ; 8 in the normal group and 5 in the G6PDd group (72% vs.83%). The main differences indicating increasing severity in normal vs. G6PDd groups included G6PD levels (12.2 vs. 5.6, P = 0.0002), PaO2/FiO2 ratio (159 vs. 108, P = 0.05), days on mechanical ventilation (10.25 vs. 21 days P = 0.04), hemoglobin level (10 vs. 8.1 P = 0.03), and hematocrit (32 vs. 26 P = 0.015). Only one patient with G6PDd died; 16 were discharged home. Our clinical series ascribes a possible biological role for G6PDd in SARS-CoV2 viral proliferation. It is imperative that further studies are performed to understand the interplay between the viral and host factors in G6PDd that may lead to disparity in outcomes. KEY POINTS: • COVID19 studies show higher mortality in men, due to severe pneumonia and ARDS, indicating possible X-linked mediated differences • G6PD, the most common X-linked enzymopathy, highly prevalent in African Americans and Italians, maintains redox homeostasis. • Preclinical studies using G6PD deficient (G6PDd) cells infected with human coronavirus (hCoV), show impaired cellular responses, viral proliferation and worsening oxidative damage. • Retrospective chart review in hospitalized patients with COVID19 pneumonia needing supplemental oxygen shows differences between the two groups (Normal and G6PDd) in hematological indices; the G6PDdgroup demonstrated prolonged PaO2/FiO2 ratio, and longer days on mechanical ventilation indicating the severity of the pneumonia.

Evaluation of the Diagnostic Accuracy of the CareStart™ Glucose-6-Phosphate Dehydrogenase Deficiency Rapid Diagnostic Test among Chinese Newborns.

Previous studies have shown that the CareStart™ G6PD Deficiency rapid diagnostic test has high diagnostic accuracy on G6PD deficiency in Africa and Thailand, but not in China. As there are regional differences of G6PD genotype distribution, we are attending to verify the effectiveness of the kit in Chinese population. The study cohort included 247 newborns admitted to our hospital for jaundice. The quantitative detection of G6PD enzyme activity and G6PD gene mutations analysis was used to classify the status of G6PD deficiency. The performance of CareStart™ assays was verified by calculating the sensitivity, specificity and area under the receiver operating characteristic curve (AUC) based on the corrected G6PD deficiency status. In male newborns, the sensitivity of the CareStart™ assay was 98.9%, the specificity was 94.2% and the AUC was 0.97. In female newborns, the sensitivity was 58.5% when the cutoff value of residual enzyme activity was 100%; however, the sensitivity was 100% when the cutoff value was 60%. Therefore, the CareStart™ test can effectively screen G6PD deficiency in male newborns and female infants with less than 60% residual enzyme activity, female infants with residual enzyme activities of 60-100% are more likely to be missed diagnosed among Chinese newborns.

G6PD A- is the major cause of G6PD deficiency among the Siddis of Karnataka, India.

Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human erythroenzymopathy affecting more than 400 million people worldwide. G6PD deficiency was reported in India more than 50 years ago and the prevalence rate varies from 5.7% to 27.9% in different caste and tribal groups.Aim: To study the prevalence of, and the mutations causing, G6PD deficiency among the Siddis of Karnataka.Subjects and methods: A total of 755 individuals were screened using the DPIP dye decolorisation method and the deficiency was further confirmed by quantitative assay. Molecular characterisation was performed by PCR-RFLP method and DNA sequencing. Biochemical characterisation was performed as per WHO criteria.Results: Of the 755 individuals, 71 individuals (9.4%) were found to be G6PD deficient with an enzyme activity ranging from 0.02 to 3.83 IU/gm Hb. Mutational analysis could be performed on 49 G6PD deficient individuals and 45 (91.8%) of them showed the presence of the G6PD A- variant while the remaining 4 (8.2%) had the G6PD Kerala-Kalyan mutation. Microsatellite analysis in G6PD A- individuals showed the presence of 166/195 bp, AC/CTT alleles.Conclusions: G6PD deficiencies among the Siddis are predominantly due to G6PD A- mutation. Furthermore, biochemical parameters and the microsatellite repeat markers in the Siddi A- chromosome confirmed they are African descendants with Indian admixture.

[Increasing prevalence of G6PD deficiency in the Netherlands]. / Steeds meer mensen met G6PD-deficiëntie in Nederland.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked enzyme deficiency with a high prevalence in Sub-Saharan countries and countries in the Middle East. Due to increased migration in the past decennium, the prevalence of this disorder has increased in the Netherlands. Here we present three patients with acute haemolysis due to G6PD deficiency: a male neonate with severe hyperbilirubinaemia leading to kernicterus; a 3-year-old girl with a severe acute haemolysis due to an infection; and a 5-year-old boy with acute haemolysis with no clear cause. These cases serve to trigger the awareness of all caregivers of the increased prevalence of this disorder, and of the limited health literacy of many immigrants.

[Neonatal screening for glucose-6-phosphate dehydrogenase (G6PD) deficiency in Mauritania]. / Dépistage néonatal du déficit en glucose 6 phosphate déshydrogénase (G6PD) en Mauritanie.

INTRODUCTION: We conducted a cross-sectional descriptive study aiming to identify risk factors associated with G6PD deficiency, its frequency and geographic distribution in Nouakchott, in order to provide useful informations to monitor it. As this disease has never previously been studied in Mauritania, we tried to define the epidemiological profile and the burden of morbidity related to G6PD deficiency in a newborn population in two health structures in the city of Nouakchott. METHODS: This study was conducted in two hospitals in Nouakchott, at the Maternity and Infant Hospital and at the Health Center in Sebkha between August and October 2015. A sampling of 523 newborns having different sexes was enrolled in the study. Screening was based on BinaxNow G6PD test, followed by quantitative confirmation in positive patients. Statistical analysis was performed using SPSS20. RESULTS: G6PD deficiency was higher in male newborns (15% vs 7% p = 0.007) and, in particular, in black children (15% vs 8% p = 0.001). The prevalence of G6PD deficiency in the study population was 11.09% (58/523). CONCLUSION: To our knowledge, this is the first study on G6PD deficiency in the Mauritanian population. It provides important informations on the epidemiological features of G6PD deficiency in the region of Nouakchott. A degree of variability exists in the occurrence of G6PD deficiency in the ethnic groups.

Validation of the quantitative point-of-care CareStart biosensor for assessment of G6PD activity in venous blood.

INTRODUCTION: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymopathy in the human population affecting an estimated 8% of the world population, especially those living in areas of past and present malaria endemicity. Decreased G6PD enzymatic activity is associated with drug-induced hemolysis and increased risk of severe neonatal hyperbilirubinemia leading to brain damage. The G6PD gene is on the X chromosome therefore mutations cause enzymatic deficiency in hemizygote males and homozygote females while the majority of heterozygous females have an intermediate activity (between 30-80% of normal) with a large distribution into the range of deficiency and normality. Current G6PD qualitative tests are unable to diagnose G6PD intermediate activities which could hinder wide use of 8-aminoquinolines for Plasmodium vivax elimination. The aim of the study was to assess the diagnostic performances of the new Carestart G6PD quantitative biosensor. METHODS: A total of 150 samples of venous blood with G6PD deficient, intermediate and normal phenotypes were collected among healthy volunteers living along the north-western Thailand-Myanmar border. Samples were analyzed by complete blood count, by gold standard spectrophotometric assay using Trinity kits and by the latest model of Carestart G6PD biosensor which analyzes both G6PD and hemoglobin. RESULTS: Bland-Altman comparison of the CareStart normalized G6PD values to that of the gold standard assay showed a strong bias in values resulting in poor area under-the-curve values for both 30% and 80% thresholds. Performing a receiver operator curve identified threshold values for the CareStart product equivalent to the 30% and 80% gold standard values with good sensitivity and specificity values, 100% and 92% (for 30% G6PD activity) and 92% and 94% (for 80% activity) respectively. CONCLUSION: The Carestart G6PD biosensor represents a significant improvement for quantitative diagnosis of G6PD deficiency over previous versions. Further improvements and validation studies are required to assess its utility for informing radical cure decisions in malaria endemic settings.

Cytochemical flow analysis of intracellular G6PD and aggregate analysis of mosaic G6PD expression.

BACKGROUND: Medicines that exert oxidative pressure on red blood cells (RBC) can cause severe hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Due to X-chromosome inactivation, females heterozygous for G6PD with 1 allele encoding a G6PD-deficient protein and the other a normal protein produce 2 RBC populations each expressing exclusively 1 allele. The G6PD mosaic is not captured with routine G6PD tests. METHODS: An open-source software tool for G6PD cytofluorometric data interpretation is described. The tool interprets data in terms of % bright RBC, or cells with normal G6PD activity in specimens collected from 2 geographically and ethnically distinct populations, an African American cohort (USA) and a Karen and Burman ethnic cohort (Thailand) comprising 242 specimens including 89 heterozygous females. RESULTS: The tool allowed comparison of data across 2 laboratories and both populations. Hemizygous normal or deficient males and homozygous normal or deficient females cluster at narrow % bright cells with mean values of 96%, or 6% (males) and 97%, or 2% (females), respectively. Heterozygous females show a distribution of 10-85% bright cells and a mean of 50%. The distributions are associated with the severity of the G6PD mutation. CONCLUSIONS: Consistent cytofluorometric G6PD analysis facilitates interlaboratory comparison of cellular G6PD profiles and contributes to understanding primaquine-associated hemolytic risk.

Examination of Hydroxychloroquine Use and Hemolytic Anemia in G6PDH-Deficient Patients.

OBJECTIVE: Some sources urge caution when prescribing hydroxychloroquine (HCQ) to patients with G6PDH deficiency, presumably due to a risk of hemolytic anemia. There are limited published data, however, to support this risk. Additionally, not all patients with G6PDH deficiency are at similar risk for hemolysis, and people with the African variant are at particularly low risk. Through a retrospective chart review, we aimed to quantify the frequency of G6PDH-deficient patients with hemolysis attributed to HCQ. METHODS: We identified Duke University Medical Center rheumatology patients with HCQ use and a measured G6PDH level. A retrospective chart review was performed, recording demographics, G6PDH levels, episodes of anemia, laboratory values consistent with hemolysis, and HCQ use. RESULTS: Of the 275 patients reviewed, 84% were female; 46% were African American and 48% were white. The leading diagnoses were systemic lupus erythematosus (32%), rheumatoid arthritis (29%), and inflammatory arthritis (14%). Only 4% of patients were G6PDH deficient (all African American). Two G6PDH-deficient patients had hemolysis during severe lupus flares that occurred while not taking HCQ. There were no reported episodes of hemolysis in more than 700 months of HCQ exposure among the 11 G6PDH-deficient patients. CONCLUSION: This is the largest study to date evaluating G6PDH deficiency with concurrent use of HCQ. Of 11 patients with G6PDH deficiency, 2 had episodes of hemolysis, but these did not occur during HCQ therapy. These data do not support routine measurement of G6PDH levels or withholding HCQ therapy among African American patients with G6PDH deficiency.

Further Molecular Analysis of G6PD Deficiency Variants in Southern Vietnam and a Novel Variant Designated as G6PD Ho Chi Minh (173 A>G; 58 Asp>Gly): Frequency Distributions of Variants Compared with Those in Other Southeast Asian Countries.

We conducted a survey of glucose-6-phosphate dehydrogenase (G6PD) deficiency among newborn babies at Tu Du Hospital, Ho Chi Minh, southern Vietnam. A total of 90 deficient babies were detected, including 85 in the Kinh ethnic group, 4 Chinese, and 1 in the K'Ho minority group. In the Kinh ethnic group, G6PD variants such as G6PD Viangchan (n=32), Kaiping (n=11), Canton (n=8), Chinese-5 (n=7), Union (n=5) and Quing Yuan (n=4) were detected. A variant with silent mutations at 1311 C>T and IVS11 nt 93 T>C was also detected in 17 cases. A novel mutation (173 A>G) in exon 4 with a predicted amino acid change of 58 Asp>Gly was also found in a Kinh newborn girl and her father, and it was designated as G6PD Ho Chi Minh. These findings demonstrated that the Kinh ethnic group in southern Vietnam has 8 different G6PD variants, indicating that the members of this group have many ancestors in terms of G6PD variants from Southeast Asia, China, and Oceania. We compared the frequency distribution of G6PD variants in the Kinh population with those of other Southeast Asian populations, and the Kinh population's distribution was quite similar to that in the Thai population, but differed from it by the absence of G6PD Mahidol.

Co-inheritance of glucose-6-phosphate dehydrogenase deficiency mutations and hemoglobin E in a Kachin population in a malaria-endemic region of Southeast Asia.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency and hemoglobin E (HbE, ß26 Glu-Lys) are two common red cell disorders in Southeast Asia. G6PD deficiency produces hemolytic anemia, which can be triggered by certain drugs or infections. HbE is asymptomatic or is manifested as microcytic, minimally hemolytic anemia. The association between G6PD deficiency and HbE is little understood. This study aimed to investigate G6PD deficiency and HbE in a Kachin ethnic group in the China-Myanmar border area. G6PD enzyme activity was measured using a quantitative G6PD assay, G6PD variants genotyped by the SNaPshot assay, and an HbE gene mutation identified by an amplification refractory mutation system and subsequently confirmed by using a reverse dot blot hybridization assay from 100 unrelated individuals in the study area. G6PD enzyme activity ranged from 0.4 to 24.7 U/g Hb, and six males had severe G6PD deficiency (<0.12-1.2 U/g Hb), while six males and 12 females had mild G6PD deficiency (>1.2-4.5 U/g Hb). Among the 24 G6PD-deficient subjects, 22 (92%) had the Mahidol 487G>A mutation (12 male hemizygotes, one female homozygote, and nine female heterozygotes), while the G6PD genotypes in two female subjects were unknown. HbE was identified in 39 subjects (20 males and 19 females), including 15 HbEE (seven males and eight females) and 24 HbAE (13 males and 11 females). Twenty-three subjects co-inherited both G6PD deficiency and HbE (22 with HbAE and one with HbEE). Whereas mean Hb levels were not significantly different between the HbA and HbE groups, G6PD-deficient males had significantly lower Hb levels than G6PD-normal males (P < 0.05, t-test). However, it is noteworthy that two G6PD-deficient hemizygous males with HbAE were severely anemic with Hb levels below 50 g/L. This study revealed high prevalence of co-inheritance of G6PD deficiency with HbAE in the Kachin ethnicity, and a potential interaction of the G6PD Mahidol 487G>A and HbAE in males leading to severe anemia. The presence of 6% males with severe G6PD deficiency raised a major concern in the use of primaquine for radical cure of vivax malaria.

A Comparison of Three Quantitative Methods to Estimate G6PD Activity in the Chittagong Hill Tracts, Bangladesh.

BACKGROUND: Glucose-6-phosphate-dehydrogenase-deficiency (G6PDd) is a major risk factor for primaquine-induced haemolysis. There is a need for improved point-of-care and laboratory-based G6PD diagnostics to unsure safe use of primaquine. METHODS: G6PD activities of participants in a cross-sectional survey in Bangladesh were assessed using two novel quantitative assays, the modified WST-8 test and the CareStart™ G6PD Biosensor (Access Bio), The results were compared with a gold standard UV spectrophotometry assay (Randox). The handheld CareStart™ Hb instrument (Access Bio) is designed to be a companion instrument to the CareStart™ G6PD biosensor, and its performance was compared to the well-validated HemoCue™ method. All quantitative G6PD results were normalized with the HemoCue™ result. RESULTS: A total of 1002 individuals were enrolled. The adjusted male median (AMM) derived by spectrophotometry was 7.03 U/g Hb (interquartile range (IQR): 5.38-8.69), by WST-8 was 7.03 U/g Hb (IQR: 5.22-8.16) and by Biosensor was 8.61 U/g Hb (IQR: 6.71-10.08). The AMM between spectrophotometry and WST-8 did not differ (p = 1.0) but differed significantly between spectrophotometry and Biosensor (p<0.01). Both, WST-8 and Biosensor were correlated with spectrophotometry (rs = 0.5 and rs = 0.4, both p<0.001). The mean difference in G6PD activity was -0.12 U/g Hb (95% limit of agreement (95% LoA): -5.45 to 5.20) between spectrophotometry and WST-8 and -1.74U/g Hb (95% LoA: -7.63 to 4.23) between spectrophotometry and Biosensor. The WST-8 identified 55.1% (49/89) and the Biosensor 19.1% (17/89) of individuals with G6PD activity <30% by spectrophotometry. Areas under the ROC curve did not differ significantly for the WST-8 and Biosensor irrespective of the cut-off activity applied (all p>0.05). Sensitivity and specificity for detecting G6PD activity <30% was 0.55 (95% confidence interval (95%CI): 0.44-0.66) and 0.98 (95%CI: 0.97-0.99) respectively for the WST-8 and 0.19 (95%CI: 0.12-0.29) and 0.99 (95%CI: 0.98-0.99) respectively for the Biosensor. Hb concentrations measured by HemoCue™ and CareStart™ Hb were strongly correlated (rs = 0.8, p<0.001, mean difference = 0.09 g Hb/dL, 95% LoA: -2.15 to 2.34). CONCLUSION: WST-8 and the CareStart™ G6PD Biosensor represent advances in G6PD diagnostics in resource poor settings, but will require further development before clinical deployment. The CareStart™ Hb instrument produced a precise measure of haemoglobin concentration.

Molecular Epidemiological Survey of Glucose-6-Phosphate Dehydrogenase Deficiency and Thalassemia in Uygur and Kazak Ethnic Groups in Xinjiang, Northwest China.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency and thalassemia occur frequently in tropical and subtropical regions, while the prevalence of relationship between the two diseases in Xinjiang has not been reported. We aimed to determine the prevalence of these diseases and clarify the relationship between genotypes and phenotypes of the two diseases in the Uygur and Kazak ethnic groups in Xinjiang. We measured G6PD activity by G6PD:6PGD (glucose acid-6-phosphate dehydrogenase) ratio, identified the gene variants of G6PD and α- and ß-globin genes by polymerase chain reaction (PCR)-DNA sequencing and gap-PCR and compared these variants in different ethnic groups in Xinjiang with those adjacent to it. Of the 149 subjects with molecular analysis of G6PD deficiency conducted, a higher prevalence of the combined mutations c.1311C > T/IVSXI + 93T > C and IVSXI + 93T > C, both with normal enzymatic activities, were observed in the Uygur and Kazak subjects. A case of rare mutation HBB: c.135delC [codon 44 (-C) in the heterozygous state], a heterozygous case of HBB: c.68A > G [Hb G-Taipei or ß22(B4)Glu→Gly] and several common single nucleotide polymorphisms (SNPs) were found on the ß-globin gene. In conclusion, G6PD deficiency with pathogenic mutations and three common α-thalassemia (α-thal) [- -(SEA), -α(3.7) (rightward), -α(4.2) (leftward)] deletions and point mutations of the α-globin gene were not detected in the present study. The average incidence of ß-thalassemia (ß-thal) in Uygurs was 1.45% (2/138) in Xinjiang. The polymorphisms of G6PD and ß-globin genes might be useful genetic markers to trace the origin and migration of the Uygur and Kazak in Xinjiang.

[Molecular epidemiology of G6PD deficiency in Chaozhou area of eastern Guangdong Province].

OBJECTIVE: To determine the incidence and molecular characteristics of G6PD deficiency in Chaozhou region of eastern Guangdong Province. METHODS: G6PD enzyme activity was assayed with an auto-bioanalyzer. Reverse dot blotting (RDB) was used for detecting 6 common G6PD mutations. Samples with no mutation detected by RDB were further sequenced for unknown mutations. RESULTS: The rate of G6PD deficiency was 3.36% (142/4224). 2.33% (47/2013) of males and 4.3% (95/2208) of females were affected. 12 mutations were detected among the 142 patients, which included c.1376G>T, c.1388G>A, c.1024C>T, c.392G>T, c.871G>A, c.95A>G, c.517T>C, c.131C>G, c.1376G>T/c.517T>C, c.871G>A/IVS-1193T>C/c.1311C>T, c.1376G>T/IVS-11, 93T>C/c.1311C>T and c.1376G>T/c.486_34delT (rs3216174). CONCLUSION: The incidence of G6PD deficiency in Chaozhou region was lower than that of the Hakka population of Guangdong Province, and the mutation types were diversely distributed in this region. c.1376G>T, c.1388G>A and c.1024C>T were the most common mutations, which was followed by c.517T>C. In addition, c.131C>G has been first discovered in the Chinese population. c.1376G>T/c.517T>C and c.1376G>T/c.486_34delT(rs3216174) were new types of compound heterozygous mutations in females.

Severe G6PD Deficiency Due to a New Missense Mutation in an Infant of Northern European Descent.

We report a term male infant born to parents of Danish descent, who on the second day of life developed jaundice peaking at 67 hours and decreasing on applied double-sided phototherapy. In the weeks following, the infant showed signs of ongoing hemolysis. Laboratory tests showed very low glucose-6-phosphate dehydrogenase (G6PD) enzymatic activity, and sequencing of the G6PD gene revealed a previously uncharacterized missense mutation c. 592 C>A (Arg198Ser). Oral DNA from the infant had the same G6PD mutation, suggesting a spontaneous maternal germline mutation as the mutation was not observed in leukocytes from the mother.

The Changing Epidemiology of Pediatric Hemoglobinopathy Patients in Northern Alberta, Canada.

BACKGROUND: Hemoglobinopathies are associated with significant morbidity and mortality. Accurate epidemiologic data reflecting the number of hemoglobinopathy patients are lacking in Canada. Immigration patterns are shifting such that regions where these diseases were rare are seeing a rapid population expansion, revealing a gap in the health care system and the need for a public health response. METHODS: To understand the epidemiology of pediatric hemoglobinopathy patients given the provincial population growth and immigration patterns, a retrospective chart review was conducted at the Stollery Children's Hospital from January 2004 to July 2014. RESULTS: A total of 88% of patients had sickle cell disease; 55% of patients were Canadian born and 63% of families originated from Africa. There was a 3.5-fold increase in patient numbers with acceleration in patient accrual over the study period and a delay in diagnosis in 70% of patients. There was a significant increase in the number of hospitalizations over the study period. Thirteen percent required at least 1 exchange transfusion, 16% received chronic transfusions, and 30% of patients developed at least 1 severe complication related to their diagnosis. CONCLUSIONS: It is imperative to demonstrate the growing hemoglobinopathy population and changing health care requirements to advocate for appropriate resources, educate health care providers, and increase awareness.

Glucose-6-phosphate dehydrogenase polymorphisms and susceptibility to mild malaria in Dogon and Fulani, Mali.

BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is associated with protection from severe malaria, and potentially uncomplicated malaria phenotypes. It has been documented that G6PD deficiency in sub-Saharan Africa is due to the 202A/376G G6PD A-allele, and association studies have used genotyping as a convenient technique for epidemiological studies. However, recent studies have shown discrepancies in G6PD202/376 associations with severe malaria. There is evidence to suggest that other G6PD deficiency alleles may be common in some regions of West Africa, and that allelic heterogeneity could explain these discrepancies. METHODS: A cross-sectional epidemiological study of malaria susceptibility was conducted during 2006 and 2007 in the Sahel meso-endemic malaria zone of Mali. The study included Dogon (n = 375) and Fulani (n = 337) sympatric ethnic groups, where the latter group is characterized by lower susceptibility to Plasmodium falciparum malaria. Fifty-three G6PD polymorphisms, including 202/376, were genotyped across the 712 samples. Evidence of association of these G6PD polymorphisms and mild malaria was assessed in both ethnic groups using genotypic and haplotypic statistical tests. RESULTS: It was confirmed that the Fulani are less susceptible to malaria, and the 202A mutation is rare in this group (<1% versus Dogon 7.9%). The Betica-Selma 968C/376G (~11% enzymatic activity) was more common in Fulani (6.1% vs Dogon 0.0%). There are differences in haplotype frequencies between Dogon and Fulani, and association analysis did not reveal strong evidence of protective G6PD genetic effects against uncomplicated malaria in both ethnic groups and gender. However, there was some evidence of increased risk of mild malaria in Dogon with the 202A mutation, attaining borderline statistical significance in females. The rs915942 polymorphism was found to be associated with asymptomatic malaria in Dogon females, and the rs61042368 polymorphism was associated with clinical malaria in Fulani males. CONCLUSIONS: The results highlight the need to consider markers in addition to G6PD202 in studies of deficiency. Further, large genetic epidemiological studies of multi-ethnic groups in West Africa across a spectrum of malaria severity phenotypes are required to establish who receives protection from G6PD deficiency.

Prevalence and molecular characterization of glucose-6-phosphate dehydrogenase deficiency in northern Thailand.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is one of the most common inherited enzymopathies in endemic areas of malaria including Southeast Asia. The molecular features of G6PD deficiency are similar among Southeast Asian population, with differences in the type of the prominent variants in each region. This study determined the prevalence and molecular characteristics of G6PD deficiency in northern Thailand. Quantitative assay of G6PD activity was conducted in 566 neonatal cord blood samples and 6 common G6PD mutations were determined by PCR-restriction fragment length polymorphism method on G6PD complete and intermediate deficiency samples. Ninety newborns had G6PD deficiency, with prevalence in male newborns of 17% and that of female newborns having an intermediate and complete deficiency of 13% and 2%, respectively. From 95 G6PD alleles tested, G6PD Mahidol, G6PD Kaiping, G6PD Canton, G6PD Viangchan, G6PD Union, and G6PD Chinese-5 was detected in 19, 17, 15, 13, 7, and 2 alleles, respectively. Our study shows that the prevalence of G6PD deficiency in northern Thai population is high and combination of the common Chinese mutations is the majority, a distribution different from central and southern Thailand where G6PD Viangchan is the prominent variant. These findings suggest a higher proportion of assimilated Chinese ethnic group in the northern Thai population.