Genotype-Phenotype Correlation of G6PD Mutations among Central Thai Children with G6PD Deficiency

Anemia ◽

10.1155/2021/6680925 ◽

2021 ◽

Vol 2021 ◽

pp. 1-7

Author(s):

Boonchai Boonyawat ◽

Tim Phetthong ◽

Nithipun Suksumek ◽

Chanchai Traivaree

Keyword(s):

Dna Sequencing ◽

Hemolytic Anemia ◽

G6pd Deficiency ◽

Neonatal Hyperbilirubinemia ◽

Molecular Heterogeneity ◽

Phenotype Correlation ◽

Direct Dna Sequencing ◽

Female Patients ◽

Genotype Phenotype Correlation ◽

G6pd Gene

Background. Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common X-linked inherited erythroenzymopathy in Thailand. The clinical and hematological manifestations of G6PD deficiency are variable. Objective. This study aimed to characterize the genotype-phenotype correlation of G6PD mutations in Thai pediatric patients who were followed-up in Phramongkutklao Hospital, a tertiary center in central Thailand. Material and Method. A total of 102 children including 73 males (71.6%) and 29 females (28.4%) were included in our study. Mutation analysis was performed by direct DNA sequencing of all coding exons of the G6PD gene. Ninety-one patients (89.2%) were presented with neonatal hyperbilirubinemia and 11 patients (10.8%) were presented with acute hemolytic anemia beyond the neonatal period. Results. Molecular analysis of the G6PD gene in 102 G6PD-deficient Thai children identified 12 different mutations. G6PD Viangchan (871G > A) and G6PD Canton (1376G > T) were the first (46.2%) and the second (15.4%) most common identified mutations among both male and female G6PD-deficient individuals, respectively. All affected males were hemizygous for G6PD mutations and had an average G6PD level of 16.7 ± 11.5 (3–76) IU/ml.RBC. Majority of female patients (27 in 29, 93.1%) were heterozygous for G6PD mutations and had an average G6PD level of 133.6 ± 43.4 (9–195) IU/ml.RBC. Two female patients (6.9%) were either homozygous or compound heterozygous for the mutations and had G6PD level in the affected male range (35 and 10 IU/ml.RBC). Only 1 in 27 heterozygous females (3.7%) had G6PD level in the affected male range (9 IU/ml.RBC) which is possibly explained by nonrandom X-chromosome inactivation. The correlation of genotypes, G6PD levels, and clinical phenotypes was not demonstrated in our study in which all of the included G6PD-deficient patients were presented with neonatal hyperbilirubinemia and acute hemolytic anemia, since the genotype-phenotype correlation is normally demonstrated in chronic nonspherocytic hemolytic anemia (CNSHA) G6PD-deficient individuals. Conclusion. This study characterizes the molecular heterogeneity of G6PD variants causing G6PD deficiency in Thai children. Our study demonstrated the efficiency of direct DNA sequencing which can identify 12 missense mutations in Thai children.

Download Full-text

Mechanism and Genotype-Phenotype Correlation of Two Proximal 6q Deletions Characterized Using mBAND, FISH, Array CGH, and DNA Sequencing

Cytogenetic and Genome Research ◽

10.1159/000334709 ◽

2012 ◽

Vol 136 (1) ◽

pp. 15-20 ◽

Cited By ~ 5

Author(s):

M. Vlckova ◽

M. Trkova ◽

Z. Zemanova ◽

M. Hancarova ◽

D. Novotna ◽

...

Keyword(s):

Dna Sequencing ◽

Array Cgh ◽

Phenotype Correlation ◽

Genotype Phenotype Correlation

Download Full-text

A Somatic Mutation in the G6PD Gene in Hematopoietic Cells Causes a Chronic Haemolytic Anemia.

Blood ◽

10.1182/blood.v114.22.4033.4033 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4033-4033 ◽

Cited By ~ 1

Author(s):

Loïc Garçon ◽

Gérard Tertian ◽

Audrey Boutron ◽

Françoise Driss ◽

Stéphane Giraudier ◽

...

Keyword(s):

Bone Marrow ◽

Hemolytic Anemia ◽

Somatic Mutation ◽

G6pd Deficiency ◽

Hematopoietic Cells ◽

Red Cells ◽

G6pd Activity ◽

Red Cell ◽

G6pd Gene ◽

Exon 10

Abstract Abstract 4033 Poster Board III-969 G6PD deficiency is the more common human enzyme defect, leading typically to an acute intravascular hemolysis occurring when red cells are exposed to an oxidative stress. However, in rare patients, very low enzymatic level induces the class I G6PD deficiency according to the WHO classification, i.e. a chronic non-spherocytic hemolytic anemia. These cases are all sporadic, occur worldwide, and almost all arise from de novo independent mutations. These mutations are found at the genomic level in both hematopoietic and non hematopoietic cells and occur recurrently in “hot spots”: most of them are located in the exon 10 of the G6PD gene, implicated in the dimer formation and the stability of the active enzyme. No null or frameshift mutations have been reported yet, probably because such mutations would be lethal; indeed, a minimal residual G6PD activity is essential during embryogenesis. We report here the case of 65 years-old Caucasian man referred in 1993 for hemolytic anemia. No personal or familial history of anemia was noted. Nine and five years before, the hemoglobin (Hb) level and the mean corpuscular volume (MCV) were normal. At diagnosis, the anemia was moderate (Hb: 11.9 g/dL), macrocytic (MCV: 104 fL) and regenerative (reticulocyte count: 550G/L) with hemolytic features. Platelets and leucocytes counts were normal. No clinical or ultrasound spleen enlargement was noted. The screening tests ruled out all the classical causes of acquired hemolytic anemia. Red cells half life after Cr51 labelling was shortened with autologous (5 days) but not with allogenous red cells confirming the corpuscular mechanism of the hemolysis. Dosage of erythocyte G6PD activity revealed a very low level (from 0.6 to 1.5 UI/g of Hb, normal range 5.3-7.9). Pyruvate kinase, pyrimidine 5'-nucleotidase and hexokinase enzymatic activities were increased in agreement with the reticulocytosis. With a follow-up of 16 years, evolution was marked by a progressive worsening of the anemia, requiring 8 to 16 packed red cell transfusions per year in parallel with an iron chelation and folic acid therapy. Concomittantly, the macrocytosis increased up to 144 fL. At the molecular level, sequencing of the genomic DNA of the G6PD gene revealed presence of a single nucleotide mutation that altered the IVS 10 nucleotide 1 G>A from donor consensus sequence, leading to an impaired splicing between exon 10 and exon 11. The missplicing creates a premature termination codon giving theorically a truncated protein (464 versus 514 amino-acid). This severe genotype was discordant with the normal hemoglobin level five years before the diagnosis. Moreover, such a mutation at the germinal level would be expected to be lethal; therefore, we hypothesized that it arised at the somatic level in an hematopoietic stem cell; we measured the G6PD activity in hematopoietic and non hematopoietic cells and observed that it was decreased in red cells, polymorphonuclear cells and lymphocytes from blood, but was normal in skin fibroblasts; molecular analysis confirmed that the mutation was present in blood mononuclear cells but was absent in the fibroblasts. Bone marrow CD34+ cells were then sorted and plated at one cell per dish in the presence of a cocktail of cytokines including EPO and the different clones were harvested at day 10 for genomic analysis of the G6PD gene. Out of the 44 tested clones, we found that most of them carried the mutation (61%), but we were still able to detect a few unmutated clones (7%), reflecting the persistence of a minor polyclonal unmutated hematopoiesis. Surprisingly, we detect in the rest of the clones both the normal and mutated genotypes; at this time, we have no clear explanation to this finding. Acquired modifications of structure or expression of genes implicated in red cell physiology have been long recognized, occurring principally in myeloid malignancies such as myelodysplastic syndromes (MDS). This includes genes implicated in the red cell membrane skeleton or in haemoglobin synthesis or structure. However, our patient presented no MDS features on repeated bone marrow examination and on cytogenetic analysis. Regardless to all our data, we concluded that our patient present the first case ever reported of chronic non spherocytic anemia related to an acquired somatic mutation of the G6PD gene at the level of a hematopoietic pluripotent cell. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Genotype‐phenotype correlation and molecular heterogeneity in pyruvate kinase deficiency

American Journal of Hematology ◽

10.1002/ajh.25753 ◽

2020 ◽

Vol 95 (5) ◽

pp. 472-482 ◽

Cited By ~ 6

Author(s):

Paola Bianchi ◽

Elisa Fermo ◽

Kimberly Lezon‐Geyda ◽

Eduard J. Beers ◽

Holmes D. Morton ◽

...

Keyword(s):

Pyruvate Kinase ◽

Molecular Heterogeneity ◽

Phenotype Correlation ◽

Pyruvate Kinase Deficiency ◽

Genotype Phenotype Correlation

Download Full-text

Molecular heterogeneity of myophosphorylase deficiency (Mcardle's disease): A genotype-phenotype correlation study

Annals of Neurology ◽

10.1002/ana.1225 ◽

2001 ◽

Vol 50 (5) ◽

pp. 574-581 ◽

Cited By ~ 54

Author(s):

Miguel A. Martín ◽

Juan C. Rubio ◽

Jenny Buchbinder ◽

Roberto Fernández-Hojas ◽

Pilar Del Hoyo ◽

...

Keyword(s):

Correlation Study ◽

Molecular Heterogeneity ◽

Phenotype Correlation ◽

Mcardle's Disease ◽

Genotype Phenotype Correlation ◽

Mcardle’S Disease

Download Full-text

Clinical and molecular spectrum of P/Q type calcium channel Cav2.1 in epileptic patients

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-021-02101-y ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Elham Alehabib ◽

Zahra Esmaeilizadeh ◽

Sakineh Ranji-Burachaloo ◽

Abbas Tafakhori ◽

Hossein Darvish ◽

...

Keyword(s):

Brain Imaging ◽

Neurodevelopmental Disorders ◽

Age At Onset ◽

Incomplete Penetrance ◽

Molecular Heterogeneity ◽

Phenotype Correlation ◽

Pathogenic Variants ◽

Genotype Phenotype Correlation ◽

Wide Range ◽

Epileptic Patients

Abstract Background Epilepsy is a neurological disorder characterized by the potential to induce seizure and accompanied by cognitive, psychological, and social consequences. CACNA1A gene is a voltage-gated P/Q-type Cav2.1 channel that is broadly expressed in the central nervous system, and the pathogenic variants within this gene may be associated with the epileptic phenotype. In the present study, we collected clinical and molecular data related to epileptic patients with CACNA1A pathogenic variants and investigated possible meaningful relationship between age at onset, neurodevelopmental disorders, type of seizures, brain imaging abnormalities, genotype, and protein domains. Results In our retrospective literature studies, from among 890 articles reviewed, a total of 90 individuals were related to epilepsy phenotype. Our findings showed that about 90 percent of patients have shown the first symptoms in childhood and teenage years and different types of neurodevelopmental disorders, such as intellectual disability, developmental arrest, and behavioral disorders, have been common findings for these patients. Further, a wide range of abnormalities have been observed in their brain imaging, and generalized seizures have been the most type of seizures in these patients. However, our data showed no specific genotype–phenotype correlation in epileptic patients with CACNA1A pathogenic alterations. Conclusions Our study focused on epileptic phenotype in patients with CACNA1A pathogenic variants and showed a wide range of clinical and molecular heterogeneity with no specific genotype–phenotype correlation. It seems that incomplete penetrance, de-novo variants, and modifier genes are obstacles in predicting the clinical outcome.

Download Full-text