Beta-thalassemia and the advent of new interventions beyond transfusion and iron chelation.

Beta-thalassaemia, including sickle cell anaemia and thalassaemia E, is most common in developing countries in tropical and subtropic regions. Because carriers have migrated there owing to demographic migration, ß-thalassaemia can now be detected in areas other than malaria-endemic areas. Every year, an estimated 300 000-500 000 infants, the vast majority of whom are from developing countries, are born with a severe haemoglobin anomaly. Currently, some basic techniques, which include iron chelation therapy, hydroxyurea, blood transfusion, splenectomy and haematopoietic stem cell transplantation, are being used to manage thalassaemia patients. Despite being the backbone of treatment, traditional techniques have several drawbacks and limitations. Ineffective erythropoiesis, correction of globin chain imbalance and adjustment of iron metabolism are some of the innovative treatment methods that have been developed in the care of thalassaemia patients in recent years. Moreover, regulating the expression of B-cell lymphoma/leukaemia 11A and sex-determining region Y-box through the enhanced expression of micro RNAs can also be considered putative targets for managing haemoglobinopathies. This review focuses on the biological basis of ß-globin gene production, the pathophysiology of ß-thalassaemia and the treatment options that have recently been introduced.

The coefficients of inbreeding revealed by ROH study among inbred individuals belonging to each type of the first cousin marriage: A preliminary report from North India.

BACKGROUND: Genome-wide runs of homozygosity (ROH) are appropriate to estimate genomic inbreeding, determine population history, unravel the genetic architecture of complex traits and disorders. OBJECTIVE: The study sought to investigate and compare the actual proportion of homozygosity or autozygosity in the genomes of progeny of four subtypes of first cousin mating in humans, using both pedigree and genomic measures for autosomes and sex chromosomes. METHODS: For this purpose, Illumina Global Screening Array-24 v1.0 BeadChip followed by cyto-ROH analysis through Illumina Genome Studio was used to characterise the homozygosity in five participants from North Indian state (Uttar Pradesh). PLINK v.1.9 software was used to estimate the genomic inbreeding coefficients viz. ROH-based inbreeding estimate (FROH) and homozygous loci-based inbreeding estimate (FHOM). RESULTS: A total of 133 ROH segments were detected with maximum number and genomic coverage in Matrilateral Parallel (MP) type and minimum in outbred individual. ROH pattern revealed that MP type has a higher degree of homozygosity than other subtypes. The comparison of FROH, FHOM, and pedigree-based inbreeding estimate (FPED) showed some difference in theoretical and realised proportion of homozygosity for sex-chromosomal loci but not for autosome for each type of consanguinity. CONCLUSIONS: This is the very first study to compare and estimate the pattern of homozygosity among the kindreds of first cousin unions. However, a greater number of individuals from each type of marriage is required for statistical inference of no difference between theoretical and realized homozygosity among different degrees of inbreeding prevalent in humans worldwide.

Association of BDNF gene missense polymorphism rs6265 (Val66Met) with three quantitative traits, namely, intelligence quotient, body mass index, and blood pressure: A genetic association analysis from North India.

Background: Brain-derived neurotrophic factor (BDNF), a neurotransmitter modulator, plays a significant role in neuronal survival and growth and participates in neuronal plasticity, thus being essential for learning, memory, and the development of cognition. Additionally, it is crucial for appetite, weight, and metabolic control and plays a pivotal role in the cardiovascular system. The Val66Met polymorphism (rs6265) of the BDNF gene causes a decrease in BDNF secretion and plays a role in impairments in cognition, energy homeostasis, and cardiovascular events. The present study aimed to evaluate the association of polymorphism (rs6265) of the BDNF gene with three quantitative traits simultaneously, namely, intelligence quotient (IQ), body mass index (BMI), and blood pressure (BP). Methods: Psychometric, morphometric, and physiometric data of the total participants (N = 246) were collected. WASI-IIINDIA was used to measure cognitive ability. Genotyping was carried out using allele-specific PCR for the rs6265 polymorphism (C196T), and genotypes were determined. Statistical analyses were performed at p < 0.05 significance level using MS-Excel and SigmaPlot. The odds ratio models with a 95% confidence interval were used to test the associations. The used models are co-dominant, recessive, dominant, over-dominant, and additive. Results: The allelic frequencies of alleles C and T were 72 and 28%, respectively. Under the dominant genetic model, a significant susceptible association of minor allele T was observed with a lower average verbal comprehensive index (OR = 2.216, p = 0.003, CI (95%) =1.33-3.69), a lower average performance reasoning index (OR = 2.634, p < 0.001, CI (95%) = 1.573-4.41), and a lower average full-scale IQ-4 (OR = 3.159, p < 0.001, CI (95%) = 1.873-5.328). Carriers of Met-alleles were found to have an increased body mass index (OR = 2.538, p < 0.001, CI (95%) = 1.507-4.275), decreased systolic blood pressure (OR = 2.051, p = 0.012, CI (95%) = 1.202-3.502), and decreased diastolic blood pressure (OR = 2.162, p = 0.006, CI (95%) = 1.278-3.657). Under the recessive genetic model, several folds decrease in IQ and BP and an increase in BMI with the presence of the T allele was also detected. Conclusion: This novel study may improve our understanding of genetic alterations to the traits and hence be helpful for clinicians and researchers to investigate the diagnostic and prognostic value of this neurotrophic factor.

Direct sequencing of ß-globin gene reveals a rare combination of two exonic and two intronic variants in a ß-thalassemia major patient: a case report.

BACKGROUND: Due to indels in the ß-globin gene, patients with ß-thalassemia major exhibit a range of severity, with genotype ß0ß0 > ß0ß+ > ß+ß+, according to the production level of the ß-globin chain. More than 300 mutations have been identified in the ß-globin gene. CASE PRESENTATION: In this case study, we report a compound heterozygous condition with a rare concoction of four different variants (CD 3(T > C), CD41/42 (-CTTT), IVS II-16 (G > C), and IVS II-666 (C > T) in a single ß-globin gene. A regular transfusion-dependent 4-year-old male patient from India was included in the study. Augmented direct sequencing of the ß-globin gene helped reveal the presence of an unusual combination of different variants in a single gene. This patient clinically presented as ß-thalassemia major and was genotypically considered as ß0ß+, although CD41/42(-CTTT) was the only causative/pathogenic mutation in the disease severity. CONCLUSION: Although CD41/42-(CTTT) is the only pathogenic variant among the four variants, the clinical complications of such a combination of variants (pathogenic and benign) is not well understood. Intronic mutations may have the ability to modify clinical characteristics. The variants must therefore be reclassified using additional mRNA splicing and expression-based studies. Additionally, these types of combinations may have significance in studying population migration around the world.