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Inborn errors of immunity (IEIs) consist of numerous rare, inherited defects of the immune system that affect about 500,000 people in the United States. As advancements in diagnosis through genetic testing and treatment with targeted immunotherapy and bone marrow transplant emerge, increasing numbers of patients survive into adulthood posing fresh clinical challenges. A large spectrum of hepatobiliary diseases now present in those with immunodeficiency diseases, leading to morbidity and mortality in this population. Awareness of these hepatobiliary diseases has lagged the improved management of the underlying disorders, leading to missed opportunities to improve clinical outcomes. This review article provides a detailed description of specific liver diseases occurring in various inborn errors of immunity. A generalized approach to diagnosis and management of hepatic complications is provided, and collaboration with hepatologists, immunologists, and pathologists is emphasized as a requirement for optimizing management and outcomes., (© 2022 American Association for the Study of Liver Diseases. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: The prevalence and genetic spectrum of cardiac channelopathies exhibit population-specific differences. We aimed to understand the spectrum of cardiac channelopathy-associated variations in India, which is characterised by a genetically diverse population and is largely understudied in the context of these disorders., Results: We utilised the IndiGenomes dataset comprising 1029 whole genomes from self-declared healthy individuals as a template to filter variants in 36 genes known to cause cardiac channelopathies. Our analysis revealed 186,782 variants, of which we filtered 470 variants that were identified as possibly pathogenic (440 nonsynonymous, 30 high-confidence predicted loss of function ). About 26% (124 out of 470) of these variants were unique to the Indian population as they were not reported in the global population datasets and published literature. Classification of 470 variants by ACMG/AMP guidelines unveiled 13 pathogenic/likely pathogenic (P/LP) variants mapping to 19 out of the 1029 individuals. Further query of 53 probands in an independent cohort of cardiac channelopathy, using exome sequencing, revealed the presence of 3 out of the 13 P/LP variants. The identification of p.G179Sfs*62, p.R823W and c.420 + 2 T > C variants in KCNQ1, KCNH2 and CASQ2 genes, respectively, validate the significance of the P/LP variants in the context of clinical applicability as well as for large-scale population analysis., Conclusion: A compendium of ACMG/AMP classified cardiac channelopathy variants in 1029 self-declared healthy Indian population was created. A conservative genotypic prevalence was estimated to be 0.9-1.8% which poses a huge public health burden for a country with large population size like India. In the majority of cases, these disorders are manageable and the risk of sudden cardiac death can be alleviated by appropriate lifestyle modifications as well as treatment regimens/clinical interventions. Clinical utility of the obtained variants was demonstrated using a cardiac channelopathy patient cohort. Our study emphasises the need for large-scale population screening to identify at-risk individuals and take preventive measures. However, we suggest cautious clinical interpretation to be exercised by taking other cardiac channelopathy risk factors into account., (© 2022. The Author(s).)

Perception and preferences for food and beverages determine dietary behaviour and health outcomes. Inherent differences in chemosensory genes, ethnicity, geo-climatic conditions, and sociocultural practices are other determinants. We aimed to study the variation landscape of chemosensory genes involved in perception of taste, texture, odour, temperature and burning sensations through analysis of 1,029 genomes of the IndiGen project and diverse continental populations. SNPs from 80 chemosensory genes were studied in whole genomes of 1,029 IndiGen samples and 2054 from the 1000 Genomes project. Population genetics approaches were used to infer ancestry of IndiGen individuals, gene divergence and extent of differentiation among studied populations. 137,760 SNPs including common and rare variants were identified in IndiGenomes with 62,950 novel (46%) and 48% shared with the 1,000 Genomes. Genes associated with olfaction harbored most SNPs followed by those associated with differences in perception of salt and pungent tastes. Across species, receptors for bitter taste were the most diverse compared to others. Three predominant ancestry groups within IndiGen were identified based on population structure analysis. We also identified 1,184 variants that exhibit differences in frequency of derived alleles and high population differentiation (F ST ≥0.3) in Indian populations compared to European, East Asian and African populations. Examples include ADCY10 , TRPV1 , RGS6 , OR7D4 , ITPR3 , OPRM1 , TCF7L2 , and RUNX1 . This is a first of its kind of study on baseline variations in genes that could govern cuisine designs, dietary preferences and health outcomes. This would be of enormous utility in dietary recommendations for precision nutrition both at population and individual level., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Prakrithi, Jha, Jaiswal, Sharma, Bhoyar, Jain, Imran, Senthilvel, Divakar, Mishra, Scaria, Sivasubbu and Mukerji.)

India confines more than 17% of the world's population and has a diverse genetic makeup with several clinically relevant rare mutations belonging to many sub-group which are undervalued in global sequencing datasets like the 1000 Genome data (1KG) containing limited samples for Indian ethnicity. Such databases are critical for the pharmaceutical and drug development industry where diversity plays a crucial role in identifying genetic disposition towards adverse drug reactions. A qualitative and comparative sequence and structural study utilizing variant information present in the recently published, largest curated Indian genome database (IndiGen) and the 1000 Genome data was performed for variants belonging to the kinase coding genes, the second most targeted group of drug targets. The sequence-level analysis identified similarities and differences among different populations based on the nsSNVs and amino acid exchange frequencies whereas a comparative structural analysis of IndiGen variants was performed with pathogenic variants reported in UniProtKB Humsavar data. The influence of these variations on structural features of the protein, such as structural stability, solvent accessibility, hydrophobicity, and the hydrogen-bond network was investigated. In-silico screening of the known drugs to these Indian variation-containing proteins reveals critical differences imparted in the strength of binding due to the variations present in the Indian population. In conclusion, this study constitutes a comprehensive investigation into the understanding of common variations present in the second largest population in the world and investigating its implications in the sequence, structural and pharmacogenomic landscape. The preliminary investigation reported in this paper, supporting the screening and detection of ADRs specific to the Indian population could aid in the development of techniques for pre-clinical and post-market screening of drug-related adverse events in the Indian population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Panda, Mishra, Sharma, Kutum, Bhoyar, Jain, Imran, Senthilvel, Divakar, Mishra, Garg, Banerjee, Sivasubbu, Scaria and Ray.)

Atherosclerotic plaques consist mostly of smooth muscle cells (SMC), and genes that influence SMC phenotype can modulate coronary artery disease (CAD) risk. Allelic variation at 15q22.33 has been identified by genome-wide association studies to modify the risk of CAD and is associated with the expression of SMAD3 in SMC. However, the mechanism by which this gene modifies CAD risk remains poorly understood. Here we show that SMC-specific deletion of Smad3 in a murine atherosclerosis model resulted in greater plaque burden, more outward remodelling and increased vascular calcification. Single-cell transcriptomic analyses revealed that loss of Smad3 altered SMC transition cell state toward two fates: a SMC phenotype that governs both vascular remodelling and recruitment of inflammatory cells, as well as a chondromyocyte fate. Together, the findings reveal that Smad3 expression in SMC inhibits the emergence of specific SMC phenotypic transition cells that mediate adverse plaque features, including outward remodelling, monocyte recruitment, and vascular calcification., Competing Interests: Competing interests The authors have no competing interests to declare.

Background: Smooth muscle cells (SMCs) transition into a number of different phenotypes during atherosclerosis, including those that resemble fibroblasts and chondrocytes, and make up the majority of cells in the atherosclerotic plaque. To better understand the epigenetic and transcriptional mechanisms that mediate these cell state changes, and how they relate to risk for coronary artery disease (CAD), we have investigated the causality and function of transcription factors at genome-wide associated loci., Methods: We used CRISPR-Cas 9 genome and epigenome editing to identify the causal gene and cells for a complex CAD genome-wide association study signal at 2q22.3. Single-cell epigenetic and transcriptomic profiling in murine models and human coronary artery smooth muscle cells were used to understand the cellular and molecular mechanism by which this CAD risk gene exerts its function., Results: CRISPR-Cas 9 genome and epigenome editing showed that the complex CAD genetic signals within a genomic region at 2q22.3 lie within smooth muscle long-distance enhancers for ZEB2 , a transcription factor extensively studied in the context of epithelial mesenchymal transition in development of cancer. Zeb2 regulates SMC phenotypic transition through chromatin remodeling that obviates accessibility and disrupts both Notch and transforming growth factor β signaling, thus altering the epigenetic trajectory of SMC transitions. SMC-specific loss of Zeb2 resulted in an inability of transitioning SMCs to turn off contractile programing and take on a fibroblast-like phenotype, but accelerated the formation of chondromyocytes, mirroring features of high-risk atherosclerotic plaques in human coronary arteries., Conclusions: These studies identify ZEB2 as a new CAD genome-wide association study gene that affects features of plaque vulnerability through direct effects on the epigenome, providing a new therapeutic approach to target vascular disease.

Background: Autoinflammatory disorders are the group of inherited inflammatory disorders caused due to the genetic defect in the genes that regulates innate immune systems. These have been clinically characterized based on the duration and occurrence of unprovoked fever, skin rash, and patient's ancestry. There are several autoinflammatory disorders that are found to be prevalent in a specific population and whose disease genetic epidemiology within the population has been well understood. However, India has a limited number of genetic studies reported for autoinflammatory disorders till date. The whole genome sequencing and analysis of 1029 Indian individuals performed under the IndiGen project persuaded us to perform the genetic epidemiology of the autoinflammatory disorders in India., Results: We have systematically annotated the genetic variants of 56 genes implicated in autoinflammatory disorder. These genetic variants were reclassified into five categories (i.e., pathogenic, likely pathogenic, benign, likely benign, and variant of uncertain significance (VUS)) according to the American College of Medical Genetics and Association of Molecular pathology (ACMG-AMP) guidelines. Our analysis revealed 20 pathogenic and likely pathogenic variants with significant differences in the allele frequency compared with the global population. We also found six causal founder variants in the IndiGen dataset belonging to different ancestry. We have performed haplotype prediction analysis for founder mutations haplotype that reveals the admixture of the South Asian population with other populations. The cumulative carrier frequency of the autoinflammatory disorder in India was found to be 3.5% which is much higher than reported., Conclusion: With such frequency in the Indian population, there is a great need for awareness among clinicians as well as the general public regarding the autoinflammatory disorder. To the best of our knowledge, this is the first and most comprehensive population scale genetic epidemiological study being reported from India., (© 2021. The Author(s).)

With the advent of next-generation sequencing, large-scale initiatives for mining whole genomes and exomes have been employed to better understand global or population-level genetic architecture. India encompasses more than 17% of the world population with extensive genetic diversity, but is under-represented in the global sequencing datasets. This gave us the impetus to perform and analyze the whole genome sequencing of 1029 healthy Indian individuals under the pilot phase of the 'IndiGen' program. We generated a compendium of 55,898,122 single allelic genetic variants from geographically distinct Indian genomes and calculated the allele frequency, allele count, allele number, along with the number of heterozygous or homozygous individuals. In the present study, these variants were systematically annotated using publicly available population databases and can be accessed through a browsable online database named as 'IndiGenomes' http://clingen.igib.res.in/indigen/. The IndiGenomes database will help clinicians and researchers in exploring the genetic component underlying medical conditions. Till date, this is the most comprehensive genetic variant resource for the Indian population and is made freely available for academic utility. The resource has also been accessed extensively by the worldwide community since it's launch., (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Human migration and community specific cultural practices have contributed to founder events and enrichment of the variants associated with genetic diseases. While many founder events in isolated populations have remained uncharacterized, the application of genomics in clinical settings as well as for population scale studies in the recent years have provided an unprecedented push towards identification of founder variants associated with human health and disease. The discovery and characterization of founder variants could have far reaching implications not only in understanding the history or genealogy of the disease, but also in implementing evidence based policies and genetic testing frameworks. This further enables precise diagnosis and prevention in an attempt towards precision medicine. This review provides an overview of founder variants along with methods and resources cataloging them. We have also discussed the public health implications and examples of prevalent disease associated founder variants in specific populations., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Competing Interests: There are no conflicts of interest.

Introduction: WHO endorsed Xpert MTB/RIF assay has proven to be rapid with results obtained within 2h. The evidence base regarding the use of Xpert MTB/RIF in pulmonary TB is strong. Relatively few performance data have been published to date on detection of Mycobacterium tuberculosis in aspirated pus specimens from abscesses., Objectives: The aim of the study was to determine the sensitivity and specificity of Xpert MTB/RIF assay for the detection of M. tuberculosis and rifampicin resistance in aspirated pus specimens using culture on Lowenstein Jensen (LJ) medium and economic variant of proportion method (PM) for drug susceptibility testing (DST) as the reference standard., Results: Xpert MTB/RIF assay in comparison to conventional reference method showed sensitivity and specificity of 76.19% and 68.75% for detection of M. tuberculosis and 71.4% and 100% for detection of rifampicin resistance respectively., Conclusion: The simplicity, sensitivity, speed and automation makes this assay a very promising diagnostic test for detection of M. tuberculosis and rifampicin resistance in aspirated pus specimens., (Copyright © 2018 Tuberculosis Association of India. Published by Elsevier B.V. All rights reserved.)

Mitochondria are organelles involved in a variety of biological functions in the cell, apart from their principal role in generation of ATP, the cellular currency of energy. The mitochondria, in spite of being compact organelles, are capable of performing complex biological functions largely because of the ability to exchange proteins, RNA, chemical metabolites and other biomolecules between cellular compartments. A close network of biomolecular interactions are known to modulate the crosstalk between the mitochondria and the nuclear genome. Apart from the small repertoire of genes encoded by the mitochondrial genome, it is now known that the functionality of the organelle is highly reliant on a number of proteins encoded by the nuclear genome, which localize to the mitochondria. With exceptions to a few anecdotal examples, the transcripts that have the potential to localize to the mitochondria have been poorly studied. We used a deep sequencing approach to identify transcripts encoded by the nuclear genome which localize to the mitoplast in a zebrafish model. We prioritized 292 candidate transcripts of nuclear origin that are potentially localized to the mitochondrial matrix. We experimentally demonstrated that the transcript encoding the nuclear encoded ribosomal protein 11 (Rpl11) localizes to the mitochondria. This study represents a comprehensive analysis of the mitochondrial localization of nuclear encoded transcripts. Our analysis has provided insights into a new layer of biomolecular pathways modulating mitochondrial-nuclear cross-talk. This provides a starting point towards understanding the role of nuclear encoded transcripts that localize to mitochondria and their influence on mitochondrial function., (Copyright © 2018 Elsevier B.V. and Mitochondria Research Society. All rights reserved.)

Circular RNAs are an emerging class of transcript isoforms created by unique back splicing of exons to form a closed covalent circular structure. While initially considered as product of aberrant splicing, recent evidence suggests unique functions and conservation across evolution. While circular RNAs could be largely attributed to have little or no potential to encode for proteins, recent evidence points to at least a small subset of circular RNAs which encode for peptides. Circular RNAs are also increasingly shown to be biomarkers for a number of diseases including neurological disorders and cancer. The advent of deep sequencing has enabled large-scale identification of circular RNAs in human and other genomes. A number of computational approaches have come up in recent years to query circular RNAs on a genome-wide scale from RNA-seq data. In this chapter, we describe the application and methodology of identifying circular RNAs using three popular computational tools: FindCirc, Segemehl, and CIRI along with approaches for experimental validation of the unique splice junctions.

Introduction: The WHO endorsed Xpert Mycobacterium tuberculosis/rifampicin (MTB/RIF) assay, has been evaluated for pulmonary TB in a number of studies but very few have investigated it for extrapulmonary specimens. The present study evaluates the performance of Xpert MTB/RIF assay in the diagnosis of extrapulmonary TB (EPTB)., Aim and Objectives: The aim of the study is to determine sensitivity and specificity of Xpert MTB/RIF assay for diagnosis of EPTB and RIF resistance in comparison to culture on Lowenstein-Jensen (LJ) medium and proportion method (PM), respectively., Materials and Methods: A total of 738 specimens from clinically suspected cases of EPTB were subjected to Ziehl-Neelsen staining, Xpert MTB/RIF assay and culture on LJ medium. PM was done on MTB isolates., Results: The sensitivity, specificity of Xpert MTB/RIF assay for diagnosis of EPTB were 84.91% (95% confidence interval [CI] 72.41%-93.25%) and 86.72% (95% CI 83.94%-89.17%) and for RIF resistance detection were 60.00% (95% CI 32.29%-83.66%) and 94.74% (95% CI 73.97%-99.87%), respectively. Among culture-positive cases, the sensitivity of Xpert MTB/RIF assay was 94.12% in smear positive and 80.56% in smear-negative cases. Xpert MTB/RIF showed maximum sensitivity of MTB detection from lymph node specimens (100% [95% CI 54.07%-100.00%]) and other body fluids (100% [95% CI 15.81%-100.00%])., Conclusion: The present study establishes Xpert MTB/RIF assay as a promising tool in the rapid diagnosis of EPTB and detection of RIF resistance., Competing Interests: There are no conflicts of interest

Zoonotic infections are increasingly becoming public health menaces and are usually transmitted to humans due to unsuitable environmental conditions. One of them is hepatic capillariasis, caused by the parasite Capillaria hepatica, primarily a disease of rodents, with hepatic manifestations in humans. Although its prevalence is very low, it can cause significant morbidity and mortality, with cases reported from all over the world. The main infective form for humans is the embryonated egg of the parasite, which hatches in the intestine and ultimately colonize the liver. The larvae mature and reproduce, and eventually form embryonated eggs, which cause chronic focal inflammation and septal hepatic fibrosis. Clinical presentation mainly consists of fever, abdominal pain, hepatomegaly and eosinophilia. Spurious infection with unembryonated eggs cause gastrointestinal symptoms. Diagnostic modalities include liver biopsy, ultrasonography, CT scan, immunological tests like ELISA and IIFT. The infection can be treated mainly with a combination of benzimidazoles like thiabendazole, mebendazole and albendazole; with corticosteroids. The study emphasizes the need for hepatic capillariasis to be considered as a differential diagnosis in cases of suspected hepatitis, leptospirosis, abdominal lymphadenopathy or other hepatic or parasitic infections prevalent in the region concerned; and meticulously assess the cases to facilitate early diagnosis and prompt treatment, thus reducing the distress faced by patients., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

In view of the escalating need for autologous cell-based therapy for treatment of liver diseases, a novel candidate has been explored in the present study. The monocytes isolated from hepatitis B surface antigen (HBsAg) nucleic acid test (NAT)-positive (HNP) blood were differentiated to hepatocyte-like cells (NeoHep) in vitro by a two-step culture procedure. The excess neutrophils present in HNP blood were removed before setting up the culture. In the first step of culture, apoptotic cells were depleted and genes involved in hypoxia were induced, which was followed by the upregulation of genes involved in the c-MET signaling pathway in the second step. The NeoHep were void of hepatitis B virus and showed expression of albumin, connexin 32, hepatocyte nuclear factor 4-α, and functions such as albumin secretion and cytochrome P450 enzyme-mediated detoxification of xenobiotics. The engraftment of NeoHep derived from HBsAg-NAT-positive blood monocytes in partially hepatectomized NOD.CB17-Prkdc scid /J mice liver and the subsequent secretion of human albumin and clotting factor VII activity in serum make NeoHep a promising candidate for cell-based therapy. Stem Cells Translational Medicine 2017;6:174-186., (© 2016 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

In this study, we analysed spatial and temporal patterns of Suspended Particulate Matter (SPM) concentrations across India. We have also assessed MODIS-derived aerosol optical depth (AOD) variations to characterize the air quality and relate it to SPM, NO2 and SO2 in different areas. In addition, the pollutant concentrations have been mapped using geospatial techniques. The results indicated significant differences in air pollutant levels across rural and urban areas. In general, districts of central and northern India had relatively higher SPM concentrations compared to southern India. Out of the top ten SPM polluted districts in India, nine were located in the state of Uttar Pradesh (UP). We observed significant correlations between the SPM and AOD at different sites. Although spatial and temporal patterns of NO2 and SO2 matched AOD patterns, the correlation strength (r2) varied based on location. The causes and implications of these findings are presented., (Copyright © 2014 Elsevier Ltd. All rights reserved.)