A Novel Variant in &lt;b&gt;&lt;i&gt;G6PD&lt;/i&gt;&lt;/b&gt; (c.1375C&amp;#x3e;G) Identified from a Hispanic Neonate with Extreme Hyperbilirubinemia and Low G6PD Enzymatic Activity

Bahr, Timothy M.; Lozano-Chinga, Michell; Agarwal, Archana; Meznarich, Jessica; Yost, Christian C.; Reading, N. Scott; Prchal, Josef T.; Christensen, Robert D.

doi:10.1159/000510300

Cited by 6 publications

(4 citation statements)

References 9 publications

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“…Furthermore, of the 201 variants with nucleotide substitutions, 200 were missense variants instead of nonsense variants, meaning that the mutations cause a change in amino acid rather than a premature termination of translation. Since then, many more novel variants were reported, either through case reports from symptomatic patients [c.1375C > G; ( 26 )] or genetic screening [c.1118T > C; ( 27 )]. Other studies involving genetic analyses also reported 2 and 7 novel mutations in Malaysia and Qatar, respectively ( 28 , 29 ).…”

Section: Classes Of Mutation and Spectrum Of Deficiencymentioning

confidence: 99%

Glucose-6-Phosphate Dehydrogenase Deficiency and Neonatal Hyperbilirubinemia: Insights on Pathophysiology, Diagnosis, and Gene Variants in Disease Heterogeneity

et al. 2022

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Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a prevalent condition worldwide and is caused by loss-of-function mutations in the G6PD gene. Individuals with deficiency are more susceptible to oxidative stress which leads to the classical, acute hemolytic anemia (favism). However, G6PD deficiency in newborn infants presents with an increased risk of hyperbilirubinemia, that may rapidly escalate to result in bilirubin induced neurologic dysfunction (BIND). Often with no overt signs of hemolysis, G6PD deficiency in the neonatal period appears to be different in the pathophysiology from favism. This review discusses and compares the mechanistic pathways involved in these two clinical presentations of this enzyme disorder. In contrast to the membrane disruption of red blood cells and Heinz bodies formation in favism, G6PD deficiency causing jaundice is perhaps attributed to the disruption of oxidant-antioxidant balance, impaired recycling of peroxiredoxin 2, thus affecting bilirubin clearance. Screening for G6PD deficiency and close monitoring of affected infants are important aspects in neonatal care to prevent kernicterus, a permanent and devastating neurological damage. WHO recommends screening for G6PD activity of all infants in countries with high prevalence of this deficiency. The traditional fluorescent spot test as a screening tool, although low in cost, misses a significant proportion of cases with moderate deficiency or the partially deficient, heterozygote females. Some newer and emerging laboratory tests and diagnostic methods will be discussed while developments in genomics and proteomics contribute to increasing studies that spatially profile genetic mutations within the protein structure that could predict their functional and structural effects. In this review, several known variants of G6PD are highlighted based on the location of the mutation and amino acid replacement. These could provide insights on why some variants may cause a higher degree of phenotypic severity compared to others. Further studies are needed to elucidate the predisposition of some variants toward certain clinical manifestations, particularly neonatal hyperbilirubinemia, and how some variants increase in severity when co-inherited with other blood- or bilirubin-related genetic disorders.

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Section: Classes Of Mutation and Spectrum Of Deficiencymentioning

confidence: 99%

Glucose-6-Phosphate Dehydrogenase Deficiency and Neonatal Hyperbilirubinemia: Insights on Pathophysiology, Diagnosis, and Gene Variants in Disease Heterogeneity

et al. 2022

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“…Although higher incidence among black neonates has been recognized and confirmed by more recent prospective cohort studies in newborn population [8]; recent clinical reports [25,26] report adverse clinical consequences of neonatal hyperbilirubinemia that are not limited to specific race or ethnicity alone. As a first step to assist the clinicians, we generated estimates of G6PD deficient neonates classified by maternal race and state of birth-based that were easily accessed from available relevant epidemiological data.…”

Section: Discussionmentioning

confidence: 92%

“…23 Even though, the precise population-based data regarding incidence of G6PDd among newborns are limited for United States, two large demographic prevalence studies in 2006 and 2018 17 24 estimated that the overall prevalence rate is 2.2%, with the highest prevalence among non-Hispanic Black male adult military recruits (11.2%) and the lowest prevalence in non-Hispanic Caucasian female population (0.3%). Although higher incidence among Black neonates has been recognized and confirmed by more recent prospective cohort studies in newborn population 8 , recent clinical reports 25 26 suggest adverse clinical consequences of neonatal hyperbilirubinemia that are not limited to specific race or ethnicity alone. As a first step to assist the clinicians, we generated estimates of G6PD-deficient neonates classified by maternal race and state of birth that were easily accessed from available relevant epidemiological data.…”

Section: Discussionmentioning

confidence: 95%

Georacial Epidemiological Estimates of Glucose-6-Phosphate Dehydrogenase Deficiency among Newborns in the United States

Vidavalur

Bhutani

2023

Am J Perinatol

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Background: Glucose-6-Phosphate Dehydrogenase deficiency (G6PDd) is the most common inherited enzyme deficiency disorder worldwide and a major risk factor for the development of severe hyperbilirubinemia. The aim of the present study was to predict an empirical estimate of annual prevalence of G6PDd in newborns adjusted for geography (state of birth), racial identity and sex of the infant. Methods: Birth statistics (2019) from National Center for Vital Statistics and CDC-WONDER data; and race-specific prevalence of G6PDd in the USA were evaluated from published sources. We developed Simpsons diversity index (DI) for each State and correlated these to rates of G6PDd in neonates. Descriptive statistics including modelled prevalence and its association with DI were assessed using the Spearman Rho correlation test. We modelled state-specific prevalence using population level allele frequencies and the race, based on Hardy–Weinberg equilibrium. Results: We estimate 78,010 (95% CI: 76,768, 79,252) newborns had G6PDd at birth in 2019 with median prevalence of 17.3 (IQR: 12.4, 23.2) per 1000 live births for USA. A strong association was noted for DI and prevalence of G6PDd (p<.0005). Five states (DC, MS, LA, GA, and MD) have the highest projected G6PDd prevalence, with a range of 35- 48 per 1000 live births. The probability of G6PDd for female heterozygotes, based on male prevalence, ranged from 1.1- 7.5% for each cohort in the select six states. Conclusions: States with diverse populations are likely to have higher rates of G6PDd. These discrepancies are further confounded by known risk of severe neonatal hyperbilirubinemia that results with G6PDd and the life-long risk of hemolysis. Combined universal newborn pre-discharge screening for G6PDd and bilirubin could alert and guide a clinician’s practices for parental education and closer medical surveillance of vulnerable neonatal time period.

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“…The variant spectrum differs among regions and populations (Minucci et al, 2012;Peng et al, 2015;Gómez-Manzo et al, 2016a;Chen et al, 2018;He et al, 2020). Pathogenic G6PD variants disrupt enzyme synthesis, stability, or function, resulting in an enzyme deficiency in the red blood cells and the related clinical presentations (Gómez-Manzo et al, 2014;Gómez-Manzo et al, 2016b;Ramírez-Nava and Ortega-Cuellar, 2017;Hwang and Mruk 2018;Bahr et al, 2020). Among the 200 + pathogenic variants, at least 35 variants have been reported in the Chinese population (Liu et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Newborn Screening for G6PD Deficiency in Xiamen, China: Prevalence, Variant Spectrum, and Genotype-Phenotype Correlations

Wang

Xia

et al. 2021

Front. Genet.

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Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common inherited enzymatic defect. The purpose of this study was to evaluate the profile of G6PD deficiency and investigate the factors associated with the accuracy of newborn screening (NBS) in Xiamen, China.Methods: A total of 99,546 newborns were screened by modified fluorescent spot test at the Women and Children’s Hospital, Xiamen University. High-risk neonates were recalled for diagnosis by either a measurement of G6PD activity or genetic testing for the presence of pathogenic G6PD variants using a quantitative G6PD enzymatic assay or the MeltPro® G6PD assay, respectively.Results: In the first-tier screening, 1,256 newborns were categorized as high risk. Of these, 1,051 were diagnosed with G6PD deficiency, indicating a prevalence of 1.39% in Xiamen, China. Among the 1,013 neonates who underwent genotyping, 851 carried hemizygous, heterozygous, homozygous, or compound heterozygous variants, for a positive predictive value (PPV) of 84.01%. In total, 12 variants and 32 genotypes were identified, and the six most common variants were c.1376G>T, c.1388G>A, c.95A>G, c.1024C>T, c.871G>A, and c.392G>T, which accounted for approximately 94% of the identified alleles. Different variants showed characteristic enzymatic activities, although high phenotypic heterogeneity was observed for each variant. The use of cold-chain transportation significantly improved the PPV of NBS.Conclusions: We determined the profile of G6PD deficiency in Xiamen, including the prevalence, variant spectrum, and genotype-phenotype correlations and confirmed that maintaining a low temperature during sample transport is essential to ensure the high screening accuracy of NBS. Our data provides epidemiological, genotypic, phenotypic, and clinical practice references to standardize future interventions for G6PD deficiency.

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A Novel Variant in <b><i>G6PD</i></b> (c.1375C>G) Identified from a Hispanic Neonate with Extreme Hyperbilirubinemia and Low G6PD Enzymatic Activity

Cited by 6 publications

References 9 publications

Glucose-6-Phosphate Dehydrogenase Deficiency and Neonatal Hyperbilirubinemia: Insights on Pathophysiology, Diagnosis, and Gene Variants in Disease Heterogeneity

Glucose-6-Phosphate Dehydrogenase Deficiency and Neonatal Hyperbilirubinemia: Insights on Pathophysiology, Diagnosis, and Gene Variants in Disease Heterogeneity

Georacial Epidemiological Estimates of Glucose-6-Phosphate Dehydrogenase Deficiency among Newborns in the United States

Newborn Screening for G6PD Deficiency in Xiamen, China: Prevalence, Variant Spectrum, and Genotype-Phenotype Correlations

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