Chromosome 22q11.2 microdeletion in monozygotic twins with discordant phenotype and deletion size

We report on a pair of male monozygotic twins with 22q11.2 microdeletion, discordant phenotype and discordant deletion size. The second twin had findings suggestive of DiGeorge syndrome, while the first twin had milder anomalies without any cardiac malformation. The second twin had presented with intractable convulsion, cyanosis and cardiovascular failure in the fourth week of life and expired on the sixth week of life, whereas the first twin had some characteristic facial appearance with developmental delay but no other signs of the 22q11.2 microdeletion syndrome including cardiovascular malformation. The fluorescence in situ hybridization (FISH) analysis had shown a microdeletion on the chromosome 22q11.2 in both twins. The interphase FISH did not find any evidence for the mosaicism. The genomic DNA microarray analysis, using HumanCytoSNP-12 BeadChip (Illumina), was identical between the twins except different size of deletion of 22q11.2. The zygosity using HumanCytoSNP-12 BeadChip (Illumina) microarray analysis suggested monozygosity. This observation indicates that altered size of the deletion may be the underlying etiology for the discordance in phenotype in monozygotic twins. We think early post zygotic events (mitotic non-allelic homologous recombination) could have been played a role in the alteration of 22q11.2 deletion size and, thus phenotypic variability in the monozygotic twins

Polymorphisms in renin-angiotensin-aldosterone system and vascular endothelial growth factor may cross talk in preeclampsia: a pilot study of maternal and fetal dyads in Indian population

Background: Preeclampsia (PE) is a multi-system disorder complicating 5-7% pregnancies and one of the leading causes of fetal/maternal morbidity and mortality worldwide.Methods: We have analyzed the association of common genetic polymorphisms of renin-angiotensin-aldosterone system (RAAS) and angiogenesis pathway in preeclamptic/eclamptic mother-fetal dyad samples, as we have hypothesized that there is a cross-talk between the maternal and fetal genotypes. Maternal venous and fetal umbilical vein blood of 50 primigravidae with preeclampsia /eclampsia and 100 matched normotensive controls of north Indian origin were collected.Results: A significant association was observed in the prevalence of VEGFA (vascular endothelial growth factor) polymorphism (rs25648 T>C) with PE. Moreover, difference in the prevalence of the AGT (rs7079 A>C) polymorphism was observed between mild vs. severe PE. Fetal genotypes showed a strong association with respect to RENIN (rs11240688 A>G) and AGT (rs11122576 G>A) to preeclampsia.Conclusions: Preeclamptic mothers and their fetuses have shown association with genes that are interacting partners in the regulation of angiogenesis and it would be interesting to expand the study to include more genes and connected pathways for the better understanding of the interplay of the biological process that goes dysregulated in this multi-systemic disorder.  

A cross-sectional study on the nasopharyngeal microbiota of individuals with SARS-CoV-2 infection across three COVID-19 waves in India

BackgroundMultiple variants of the SARS-CoV-2 virus have plagued the world through successive waves of infection over the past three years. Independent research groups across geographies have shown that the microbiome composition in COVID-19 positive patients (CP) differs from that of COVID-19 negative individuals (CN). However, these observations were based on limited-sized sample-sets collected primarily from the early days of the pandemic. Here, we study the nasopharyngeal microbiota in COVID-19 patients, wherein the samples have been collected across the three COVID-19 waves witnessed in India, which were driven by different variants of concern.MethodsThe nasopharyngeal swabs were collected from 589 subjects providing samples for diagnostics purposes at the Centre for Cellular and Molecular Biology (CSIR-CCMB), Hyderabad, India and subjected to 16s rRNA gene amplicon - based sequencing.FindingsWe found variations in the microbiota of symptomatic vs. asymptomatic COVID-19 patients. CP showed a marked shift in the microbial diversity and composition compared to CN, in a wave-dependent manner. Rickettsiaceae was the only family that was noted to be consistently depleted in CP samples across the waves. The genera Staphylococcus, Anhydrobacter, Thermus, and Aerococcus were observed to be highly abundant in the symptomatic CP patients when compared to the asymptomatic group. In general, we observed a decrease in the burden of opportunistic pathogens in the host microbiota during the later waves of infection.InterpretationTo our knowledge, this is the first analytical cross-sectional study of this scale, which was designed to understand the relation between the evolving nature of the virus and the changes in the human nasopharyngeal microbiota. Although no clear signatures were observed, this study shall pave the way for a better understanding of the disease pathophysiology and help gather preliminary evidence on whether interventions to the host microbiota can help in better protection or faster recovery

Transcriptome analysis of human macrophages upon chikungunya virus (CHIKV) infection reveals regulation of distinct signaling and metabolic pathways during the early and late stages of infection

Macrophages are efficient reservoirs for viruses that enable the viruses to survive over a longer period of infection. Alphaviruses such as chikungunya virus (CHIKV) are known to persist in macrophages even after the acute febrile phase. The viral particles replicate in macrophages at a very low level over extended period of time and are localized in tissues that are often less accessible by treatment. Comprehensive experimental studies are thus needed to characterize the CHIKV-induced modulation of host genes in these myeloid lineage cells and in one such pursuit, we obtained global transcriptomes of a human macrophage cell line infected with CHIKV, over its early and late timepoints of infection. We analyzed the pathways, especially immune related, perturbed over these timepoints and observed several host factors to be differentially expressed in infected macrophages in a time-dependent manner. We postulate that these pathways may play crucial roles in the persistence of CHIKV in macrophages

Polymorphisms in renin-angiotensin-aldosterone system and vascular endothelial growth factor may cross talk in preeclampsia: a pilot study of maternal and fetal dyads in Indian population

Background: Preeclampsia (PE) is a multi-system disorder complicating 5-7% pregnancies and one of the leading causes of fetal/maternal morbidity and mortality worldwide. Methods: We have analyzed the association of common genetic polymorphisms of renin-angiotensin-aldosterone system (RAAS) and angiogenesis pathway in preeclamptic/eclamptic mother-fetal dyad samples, as we have hypothesized that there is a cross-talk between the maternal and fetal genotypes. Maternal venous and fetal umbilical vein blood of 50 primigravidae with preeclampsia /eclampsia and 100 matched normotensive controls of north Indian origin were collected. Results: A significant association was observed in the prevalence of VEGFA (vascular endothelial growth factor) polymorphism (rs25648 T>C) with PE. Moreover, difference in the prevalence of the AGT (rs7079 A>C) polymorphism was observed between mild vs. severe PE. Fetal genotypes showed a strong association with respect to RENIN (rs11240688 A>G) and AGT (rs11122576 G>A) to preeclampsia. Conclusions: Preeclamptic mothers and their fetuses have shown association with genes that are interacting partners in the regulation of angiogenesis and it would be interesting to expand the study to include more genes and connected pathways for the better understanding of the interplay of the biological process that goes dysregulated in this multi-systemic disorder. [Int J Res Med Sci 2016; 4(5.000): 1666-1672

Spectrum of large copy number variations in 26 diverse Indian populations: potential involvement in phenotypic diversity

Copy number variations (CNVs) have provided a dynamic aspect to the apparently static human genome. We have analyzed CNVs larger than 100 kb in 477 healthy individuals from 26 diverse Indian populations of different linguistic, ethnic and geographic backgrounds. These CNVRs were identified using the Affymetrix 50K Xba 240 Array. We observed 1,425 and 1,337 CNVRs in the deletion and amplification sets, respectively, after pooling data from all the populations. More than 50% of the genes encompassed entirely in CNVs had both deletions and amplifications. There was wide variability across populations not only with respect to CNV extent (ranging from 0.04–1.14% of genome under deletion and 0.11–0.86% under amplification) but also in terms of functional enrichments of processes like keratinization, serine proteases and their inhibitors, cadherins, homeobox, olfactory receptors etc. These did not correlate with linguistic, ethnic, geographic backgrounds and size of populations. Certain processes were near exclusive to deletion (serine proteases, keratinization, olfactory receptors, GPCRs) or duplication (homeobox, serine protease inhibitors, embryonic limb morphogenesis) datasets. Populations having same enriched processes were observed to contain genes from different genomic loci. Comparison of polymorphic CNVRs (5% or more) with those cataloged in Database of Genomic Variants revealed that 78% (2473) of the genes in CNVRs in Indian populations are novel. Validation of CNVs using Sequenom MassARRAY revealed extensive heterogeneity in CNV boundaries. Exploration of CNV profiles in such diverse populations would provide a widely valuable resource for understanding diversity in phenotypes and disease

Genetic profile of patients with epilepsy on first-line antiepileptic drugs and potential directions for personalized treatment

Background: The first-line antiepileptic drugs, although affordable and effective in the control of seizures, are associated with adverse drug effects, and there is large interindividual variability in the appropriate dose at which patients respond favorably. This variability may partly be explained by functional consequences of genetic polymorphisms in the drug-metabolizing enzymes, such as the CYP450 family, microsomal epoxide hydrolase and UDP-glucuronosyltransferases, drug transporters, mainly ATP-binding cassette transporters, and drug targets, including sodium channels. The purpose of this study was to determine the allele and genotype frequencies of such genetic variants in patients with epilepsy from North India administered first-line antiepileptic drugs, such as phenobarbitone, phenytoin, carbamazepine and valproic acid, and compare them with worldwide epilepsy populations. Materials & methods: SNP screening of 19 functional variants from 12 genes in 392 patients with epilepsy was carried out, and the patients were classified with respect to the metabolizing rate of their drug-metabolizing enzymes, efflux rate of drug transporters and sensitivity of drug targets. Results: A total of 16 SNPs were found to be polymorphic, and the allelic frequencies for these SNPs were in conformance with Hardy–Weinberg equilibrium. Among all the polymorphisms studied, functional variants from genes encoding CYP2C19, EPHX1, ABCB1 and SCN1A were highly polymorphic in North Indian epilepsy patients, and might account for differential drug response to first-line antiepileptic drugs. Conclusion: Interethnic differences were elucidated for several polymorphisms that might be responsible for differential serum drug levels and optimal dose requirement for efficacious treatment

Common variants of FTO and the risk of obesity and type 2 diabetes in Indians

Common variants of fat mass and obesity-associated gene (FTO, fat mass- and obesity-associated gene) have been shown to be associated with obesity and type 2 diabetes in population of European and non-European ethnicity. However, studies in Indian population have provided inconsistent results. Here, we examined association of eight FTO variants (rs1421085, rs8050136, rs9939609, rs9930506, rs1861867, rs9926180, rs2540769 and rs708277) with obesity and type 2 diabetes in 5364 North Indians (2474 type 2 diabetes patients and 2890 non-diabetic controls) in two stages. None of the variants including previously reported intron 1 variants (rs1421085, rs8050136, rs9939609 and rs9930506) showed Body Mass Index (BMI)-dependent/independent association with type 2 diabetes. However, rs1421085, rs8050136 and rs9939609 were associated with obesity status and measures of obesity (BMI, waist circumference and waist-to-hip ratio) in stage 2 and combined study population. Meta-analysis of the two study population results also revealed that rs1421085, rs8050136 and rs9939609 were significantly associated with BMI both under the random- and fixed-effect models (P (random/fixed)=0.02/0.0001, 0.004/0.0006 and 0.01/0.01, respectively). In conclusion, common variants of FTO were associated with obesity, but not with type 2 diabetes in North Indian population