The Genetic Drivers of Juvenile, Young, and Early-Onset Parkinson's Disease in India.

BACKGROUND: Recent studies have advanced our understanding of the genetic drivers of Parkinson's disease (PD). Rare variants in more than 20 genes are considered causal for PD, and the latest PD genome-wide association study (GWAS) identified 90 independent risk loci. However, there remains a gap in our understanding of PD genetics outside of the European populations in which the vast majority of these studies were focused. OBJECTIVE: The aim was to identify genetic risk factors for PD in a South Asian population. METHODS: A total of 674 PD subjects predominantly with age of onset (AoO) ≤50 years (encompassing juvenile, young, or early-onset PD) were recruited from 10 specialty movement disorder centers across India over a 2-year period; 1376 control subjects were selected from the reference population GenomeAsia, Phase 2. We performed various case-only and case-control genetic analyses for PD diagnosis and AoO. RESULTS: A genome-wide significant signal for PD diagnosis was identified in the SNCA region, strongly colocalizing with SNCA region signal from European PD GWAS. PD cases with pathogenic mutations in PD genes exhibited, on average, lower PD polygenic risk scores than PD cases lacking any PD gene mutations. Gene burden studies of rare, predicted deleterious variants identified BSN, encoding the presynaptic protein Bassoon that has been previously associated with neurodegenerative disease. CONCLUSIONS: This study constitutes the largest genetic investigation of PD in a South Asian population to date. Future work should seek to expand sample numbers in this population to enable improved statistical power to detect PD genes in this understudied group. © 2023 Denali Therapeutics and The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Clinical Utility of Proband Only Clinical Exome Sequencing in Neurodevelopmental Disorders.

Chromosomal microarray is recommended as the first line of investigation in neurodevelopmental disorders (NDDs). However, advances in next-generation sequencing have unraveled more than 900 genes associated with NDDs, thus improving the genetic diagnosis. Therefore, this study was conducted to explore the utility of clinical exome sequencing (CES) in NDDs from a tertiary care centre in India. A retrospective observational analysis of 78 children with NDDs for whom CES was performed between 2017 and 2021 was conducted. The American College of Medical Genetics and Genomics (ACMG) criteria were used to classify the variants. The mean age was 5.8 ± 3.6 y, and 42 (53%) were male. Pathogenic, likely pathogenic, and variants of uncertain significance (VUS) were observed in 22 (28.2%), 10 (12.8%), and 26 (33.3%) patients, respectively, which included five copy number variants. The diagnostic yield for pathogenic and likely pathogenic variants in NDDs by CES was 41%, which was reasonably high.

South Asian medical cohorts reveal strong founder effects and high rates of homozygosity.

The benefits of large-scale genetic studies for healthcare of the populations studied are well documented, but these genetic studies have traditionally ignored people from some parts of the world, such as South Asia. Here we describe whole genome sequence (WGS) data from 4806 individuals recruited from the healthcare delivery systems of Pakistan, India and Bangladesh, combined with WGS from 927 individuals from isolated South Asian populations. We characterize population structure in South Asia and describe a genotyping array (SARGAM) and imputation reference panel that are optimized for South Asian genomes. We find evidence for high rates of reproductive isolation, endogamy and consanguinity that vary across the subcontinent and that lead to levels of rare homozygotes that reach 100 times that seen in outbred populations. Founder effects increase the power to associate functional variants with disease processes and make South Asia a uniquely powerful place for population-scale genetic studies.

HNF4α, SP1 and c-myc are master regulators of CNS autoimmunity.

Hepatocyte nuclear factor 4 α (HNF4α), a transcription factor (TF) essential for embryonic development, has been recently shown to regulate the expression of inflammatory genes. To characterize HNF4a function in immunity, we measured the effect of HNF4α antagonists on immune cell responses in vitro and in vivo. HNF4α blockade reduced immune activation in vitro and disease severity in the experimental model of multiple sclerosis (MS). Network biology studies of human immune transcriptomes unraveled HNF4α together with SP1 and c-myc as master TF regulating differential expression at all MS stages. TF expression was boosted by immune cell activation, regulated by environmental MS risk factors and higher in MS immune cells compared to controls. Administration of compounds targeting TF expression or function demonstrated non-synergic, interdependent transcriptional control of CNS autoimmunity in vitro and in vivo. Collectively, we identified a coregulatory transcriptional network sustaining neuroinflammation and representing an attractive therapeutic target for MS and other inflammatory disorders.

Near-chromosomal de novo assembly of Bengal tiger genome reveals genetic hallmarks of apex predation.

The tiger, a poster child for conservation, remains an endangered apex predator. Continued survival and recovery will require a comprehensive understanding of genetic diversity and the use of such information for population management. A high-quality tiger genome assembly will be an important tool for conservation genetics, especially for the Indian tiger, the most abundant subspecies in the wild. Here, we present high-quality near-chromosomal genome assemblies of a female and a male wild Indian tiger (Panthera tigris tigris). Our assemblies had a scaffold N50 of >140 Mb, with 19 scaffolds corresponding to the 19 numbered chromosomes, containing 95% of the genome. Our assemblies also enabled detection of longer stretches of runs of homozygosity compared to previous assemblies, which will help improve estimates of genomic inbreeding. Comprehensive genome annotation identified 26,068 protein-coding genes, including several gene families involved in key morphological features such as the teeth, claws, vision, olfaction, taste, and body stripes. We also identified 301 microRNAs, 365 small nucleolar RNAs, 632 transfer RNAs, and other noncoding RNA elements, several of which are predicted to regulate key biological pathways that likely contribute to the tiger's apex predatory traits. We identify signatures of positive selection in the tiger genome that are consistent with the Panthera lineage. Our high-quality genome will enable use of noninvasive samples for comprehensive assessment of genetic diversity, thus supporting effective conservation and management of wild tiger populations.

Phenotypic expression and clinical outcomes in a South Asian PRKAG2 cardiomyopathy cohort.

The PRKAG2 syndrome is a rare autosomal dominant phenocopy of sarcomeric hypertrophic cardiomyopathy (HCM), characterized by ventricular pre-excitation, progressive conduction system disease and left ventricular hypertrophy. This study describes the phenotype, genotype and clinical outcomes of a South-Asian PRKAG2 cardiomyopathy cohort over a 7-year period. Clinical, electrocardiographic, echocardiographic, and cardiac MRI data from 22 individuals with PRKAG2 variants (68% men; mean age 39.5 ± 18.1 years), identified at our HCM centre were studied prospectively. At initial evaluation, all of the patients were in NYHA functional class I or II. The maximum left ventricular wall thickness was 22.9 ± 8.7 mm and left ventricular ejection fraction was 53.4 ± 6.6%. Left ventricular hypertrophy was present in 19 individuals (86%) at baseline. 17 patients had an WPW pattern (77%). After a mean follow-up period of 7 years, 2 patients had undergone accessory pathway ablation, 8 patients (36%) underwent permanent pacemaker implantation (atrio-ventricular blocks-5; sinus node disease-2), 3 patients developed atrial fibrillation, 11 patients (50%) developed progressive worsening in NYHA functional class, and 6 patients (27%) experienced sudden cardiac death or equivalent. PRKAG2 cardiomyopathy must be considered in patients with HCM and progressive conduction system disease.

Inferring Multiple Sclerosis Stages from the Blood Transcriptome via Machine Learning.

Peripheral blood mononuclear cells (PBMCs) bear specific dysregulations in genes and pathways at distinct stages of multiple sclerosis (MS) that may help with classifying MS and non-MS subjects, specifying the early stage of disease, or discriminating among MS courses. Here we describe an unbiased machine learning workflow to build MS stage-specific classifiers based on PBMC transcriptomics profiles from more than 300 individuals, including healthy subjects and patients with clinically isolated syndromes, relapsing-remitting MS, primary or secondary progressive MS, or other neurological disorders. The pipeline, designed to optimize and compare the performance of distinct machine learning algorithms in the training cohort, generates predictive models not influenced by demographic features, such as age and gender, and displays high accuracy in the independent validation cohort. Proper application of machine learning to transcriptional profiles of circulating blood cells may allow identification of disease state and stage in MS.

Coronavirus disease 2019 in children: Clinical & epidemiological implications.

Despite the global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, there are limited data emerging in children. This review provides an update on clinical features, diagnosis, epidemiology, management and prevention of coronavirus disease 2019 (COVID-19) in children. Specific characteristics noted in children and their implications in disease management as well as transmission control are highlighted. Besides respiratory symptoms, gastrointestinal and atypical features such as chilblains, neurological symptoms and multisystem inflammation are also reported. Younger infants and those with comorbidity were found to be at risk of severe illness. Infected pregnant women and neonates were reported to have good prognosis. It is possible to manage the children with mild disease at home, with strict infection prevention control measures; severely affected require respiratory support and intensive care management. There are anecdotal reports of using antiviral and immunomodulatory drugs, benefit of which needs to be confirmed in clinical trials. A significant percentage of asymptomatic infection in children has epidemiological implication as these may act as links in transmission chain in the community. There is a need for systematic data on extra-pulmonary manifestations and atypical features, risk factors of severity, role of imaging and biomarkers, testing and management strategies and trials with antivirals and immunomodulatory drugs in children. The psychosocial effects of quarantine, closure of schools, lack of play activities and impact of lockdown need to be addressed. Understanding the biological basis for the profound age-dependent differential outcome of COVID-19 infection is important. Elucidating the protective mechanisms in children may aid in developing novel treatment strategies.

Validation of a Genome-Wide Polygenic Score for Coronary Artery Disease in South Asians.

BACKGROUND: Genome-wide polygenic scores (GPS) integrate information from many common DNA variants into a single number. Because rates of coronary artery disease (CAD) are substantially higher among South Asians, a GPS to identify high-risk individuals may be particularly useful in this population. OBJECTIVES: This analysis used summary statistics from a prior genome-wide association study to derive a new GPSCAD for South Asians. METHODS: This GPSCAD was validated in 7,244 South Asian UK Biobank participants and tested in 491 individuals from a case-control study in Bangladesh. Next, a static ancestry and GPSCAD reference distribution was built using whole-genome sequencing from 1,522 Indian individuals, and a framework was tested for projecting individuals onto this static ancestry and GPSCAD reference distribution using 1,800 CAD cases and 1,163 control subjects newly recruited in India. RESULTS: The GPSCAD, containing 6,630,150 common DNA variants, had an odds ratio (OR) per SD of 1.58 in South Asian UK Biobank participants and 1.60 in the Bangladeshi study (p < 0.001 for each). Next, individuals of the Indian case-control study were projected onto static reference distributions, observing an OR/SD of 1.66 (p < 0.001). Compared with the middle quintile, risk for CAD was most pronounced for those in the top 5% of the GPSCAD distribution-ORs of 4.16, 2.46, and 3.22 in the South Asian UK Biobank, Bangladeshi, and Indian studies, respectively (p < 0.05 for each). CONCLUSIONS: The new GPSCAD has been developed and tested using 3 distinct South Asian studies, and provides a generalizable framework for ancestry-specific GPS assessment.

Convergence between Microglia and Peripheral Macrophages Phenotype during Development and Neuroinflammation.

Differently from other myeloid cells, microglia derive exclusively from precursors originating within the yolk sac and migrate to the CNS under development, without any contribution from fetal liver or postnatal hematopoiesis. Consistent with their unique ontology, microglia may express specific physiological markers, which have been partly described in recent years. Here we wondered whether profiles distinguishing microglia from peripheral macrophages vary with age and under pathology. To this goal, we profiled transcriptomes of microglia throughout the lifespan and included a parallel comparison with peripheral macrophages under physiological and neuroinflammatory settings using age- and sex-matched wild-type and bone marrow chimera mouse models. This comprehensive approach demonstrated that the phenotypic differentiation between microglia and peripheral macrophages is age-dependent and that peripheral macrophages do express some of the most commonly described microglia-specific markers early during development, such as Fcrls, P2ry12, Tmem119, and Trem2. Further, during chronic neuroinflammation CNS-infiltrating macrophages and not peripheral myeloid cells acquire microglial markers, indicating that the CNS niche may instruct peripheral myeloid cells to gain the phenotype and, presumably, the function of the microglia cell. In conclusion, our data provide further evidence about the plasticity of the myeloid cell and suggest caution in the strict definition and application of microglia-specific markers.SIGNIFICANCE STATEMENT Understanding the respective role of microglia and infiltrating monocytes in neuroinflammatory conditions has recently seemed possible by the identification of a specific microglia signature. Here instead we provide evidence that peripheral macrophages may express some of the most commonly described microglia markers at some developmental stages or pathological conditions, in particular during chronic neuroinflammation. Further, our data support the hypothesis about phenotypic plasticity and convergence among distinct myeloid cells so that they may act as a functional unit rather than as different entities, boosting their mutual functions in different phases of disease. This holds relevant implications in the view of the growing use of myeloid cell therapies to treat brain disease in humans.

Author Correction: Transcriptional dysregulation of Interferome in experimental and human Multiple Sclerosis.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Neural precursor cell-secreted TGF-ß2 redirects inflammatory monocyte-derived cells in CNS autoimmunity.

In multiple sclerosis, the pathological interaction between autoreactive Th cells and mononuclear phagocytes in the CNS drives initiation and maintenance of chronic neuroinflammation. Here, we found that intrathecal transplantation of neural stem/precursor cells (NPCs) in mice with experimental autoimmune encephalomyelitis (EAE) impairs the accumulation of inflammatory monocyte-derived cells (MCs) in the CNS, leading to improved clinical outcome. Secretion of IL-23, IL-1, and TNF-α, the cytokines required for terminal differentiation of Th cells, decreased in the CNS of NPC-treated mice, consequently inhibiting the induction of GM-CSF-producing pathogenic Th cells. In vivo and in vitro transcriptome analyses showed that NPC-secreted factors inhibit MC differentiation and activation, favoring the switch toward an antiinflammatory phenotype. Tgfb2-/- NPCs transplanted into EAE mice were ineffective in impairing MC accumulation within the CNS and failed to drive clinical improvement. Moreover, intrathecal delivery of TGF-ß2 during the effector phase of EAE ameliorated disease severity. Taken together, these observations identify TGF-ß2 as the crucial mediator of NPC immunomodulation. This study provides evidence that intrathecally transplanted NPCs interfere with the CNS-restricted inflammation of EAE by reprogramming infiltrating MCs into antiinflammatory myeloid cells via secretion of TGF-ß2.

Transcriptional dysregulation of Interferome in experimental and human Multiple Sclerosis.

Recent evidence indicates that single multiple sclerosis (MS) susceptibility genes involved in interferon (IFN) signaling display altered transcript levels in peripheral blood of untreated MS subjects, suggesting that responsiveness to endogenous IFN is dysregulated during neuroinflammation. To prove this hypothesis we exploited the systematic collection of IFN regulated genes (IRG) provided by the Interferome database and mapped Interferome changes in experimental and human MS. Indeed, central nervous system tissue and encephalitogenic CD4 T cells during experimental autoimmune encephalomyelitis were characterized by massive changes in Interferome transcription. Further, the analysis of almost 500 human blood transcriptomes showed that (i) several IRG changed expression at distinct MS stages with a core of 21 transcripts concordantly dysregulated in all MS forms compared with healthy subjects; (ii) 100 differentially expressed IRG were validated in independent case-control cohorts; and (iii) 53 out of 100 dysregulated IRG were targeted by IFN-beta treatment in vivo. Finally, ex vivo and in vitro experiments established that IFN-beta administration modulated expression of two IRG, ARRB1 and CHP1, in immune cells. Our study confirms the impairment of Interferome in experimental and human MS, and describes IRG signatures at distinct disease stages which can represent novel therapeutic targets in MS.

Modified blalock-taussig shunt and levosimendan for left ventricular preparation in a child with transposition of great arteries and regressed ventricle undergoing rapid 2 stage arterial switch operation.

Rapid two-stage arterial switch operation (ASO) is very relevant as many patients of transposition of great arteries (TGA) present late to the hospital when primary switch either is not possible or carries a high risk of morbidity and mortality. Hence, other means apart from the traditional methods of left ventricle preparedness should be tried to help this category of patients, who are to undergo rapid two-stage ASO. We successfully used levosimendan and continuous positive airway pressure after 1st stage operation in a patient with dTGA and regressed ventricle, which helped in left ventricular preparedness, and the child underwent rapid two-stage ASO uneventfully.

Dysregulation of MS risk genes and pathways at distinct stages of disease.

OBJECTIVE: To perform systematic transcriptomic analysis of multiple sclerosis (MS) risk genes in peripheral blood mononuclear cells (PBMCs) of subjects with distinct MS stages and describe the pathways characterized by dysregulated gene expressions. METHODS: We monitored gene expression levels in PBMCs from 3 independent cohorts for a total of 297 cases (including clinically isolated syndromes (CIS), relapsing-remitting MS, primary and secondary progressive MS) and 96 healthy controls by distinct microarray platforms and quantitative PCR. Differential expression and pathway analyses for distinct MS stages were defined and validated by literature mining. RESULTS: Genes located in the vicinity of MS risk variants displayed altered expression in peripheral blood at distinct stages of MS compared with the healthy population. The frequency of dysregulation was significantly higher than expected in CIS and progressive forms of MS. Pathway analysis for each MS stage-specific gene list showed that dysregulated genes contributed to pathogenic processes with scientific evidence in MS. CONCLUSIONS: Systematic gene expression analysis in PBMCs highlighted selective dysregulation of MS susceptibility genes playing a role in novel and well-known pathogenic pathways.