IndiGenomes: a comprehensive resource of genetic variants from over 1000 Indian genomes.

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.

Autosomal dominant cortical tremor, myoclonus, and epilepsy (ADCME) in a unique south Indian community.

Autosomal dominant cortical tremor, myoclonus, and epilepsy (ADCME)/familial adult onset myoclonic epilepsy (FAME) is a nonprogressive disorder characterized by (1) distal tremors that are usually precipitated by posture and action; (2) stimulus-sensitive myoclonus that is predominantly seen in the upper limb and is precipitated by photic stimuli, fatigue, emotional stress, and sleep deprivation; (3) seizures that were predominantly of the generalized tonic-clonic type that showed significant response to antiepileptic drugs (AEDs). ADCME has been reported worldwide with different genetic loci in Japanese families (8q23.3-q24.1), Italian families (2p11.1-q12.2), a French family (5p15.3.1-p15.1), and a Thai family (3q26.32-q28). ADCME has not been reported in South India and is still not recognized as an independent entity under the International League Against Epilepsy (ILAE). We report 241 patients with ADCME identified belonging to 48 families. The 48 families are domiciled in two southern districts of Tamilnadu in India, belonging to a community called "Nadar" whose nativity is confined to these southern districts, with reported unique genetic characteristics. This study is reported for the presentation of this rare disease in a unique ethnic group, and is the largest single report on ADCME worldwide.

Stroke incidence, mortality, subtypes in rural and urban populations in five geographic areas of India (2018-2019): results from the National Stroke Registry Programme.

Background: Increasing stroke burden in India demands a long-term stroke surveillance framework. Earlier studies in India were urban-based, short term and provided limited data on stroke incidence and its outcomes. This gap is addressed by the establishment of five population-based stroke registries (PBSRs) of the National Stroke Registry Programme, India. This paper describes stroke incidence, mortality and age, sex, and subtypes distribution in the five PBSRs with urban and rural populations. Methods: First-ever incident stroke patients in age group ≥18 years, resident for at least one year in the defined geographic area, identified from health facilities were registered. Death records with stroke as the cause of death from the Civil Registration System (CRS) were included. Transient ischemic attack (TIA) was excluded. Three PBSRs (Cuttack, Tirunelveli, Cachar) included urban and rural populations. PBSRs in Kota and Varanasi were urban areas. The crude and age-standardized incidence rate (ASR) by age, sex, and residence (urban and rural), rate ratios of ASR, case fatality proportions and rates at day 28 after onset of stroke were calculated for years 2018-2019. Findings: A total of 13,820 registered first-ever stroke cases that included 985 death certificate-only cases (DCOs) were analysed. The pooled crude incidence rate was 138.1 per 100,000 population with an age-standardized incidence rate (ASR) of 103.4 (both sexes), 125.7 (males) and 80.8 (females). The risk of stroke among rural residents was one in seven (Cuttack), one in nine (Tirunelveli), and one in 15 (Cachar). Ischemic stroke was the most common type in all PBSRs. Age-standardized case fatality rates (ASCFR) per 100,000 population for pooled PBSRs was 30.0 (males) and 18.8 (females), and the rate ratio (M/F) ranged from 1.2 (Cuttack) to 2.0 (Cachar). Interpretation: Population-based registries have provided a comprehensive stroke surveillance platform to measure stroke burden and outcomes by age, sex, residence and subtype across India. The rural-urban pattern of stroke incidence and mortality shall guide health policy and programme planning to strengthen stroke prevention and treatment measures in India. Funding: The National Stroke Registry Programme is funded through the intramural funding of the Indian Council of Medical Research, Department of Health Research, Ministry of Health and Family Welfare, India.

Methodology for the early identification of neurodevelopmental disorders in the primary and preschool children in rural India by applying intervention module developed for teachers.

Objective: Neurodevelopmental disorders NDD are neurologic processing problems that interfere with learning in children. Primary and preschool teachers who are essential links in public health reach out to such children do not receive any formal training to identify these disorders. Hence, a primary and preschool level intervention addressing the issue is proposed. Materials and Methods: Primary and preschool teachers of government and government-aided schools and Anganwadi/preschools in the Model Rural Health Research Unit Tirunelveli field practice area will be assigned into two groups. The training module will be developed and validated using neurodevelopmental screening tool (NDST). Before identifying the students using the NDST, the teachers in Group A will get training using the module. Group B is the control group, in which untrained teachers administer the NDST to the children and then will be trained. Neurologists will assess the same children over 1 year. Results: The effectiveness of teacher training for the early detection of children with NDD will be assessed. Thus, the validity of the screening for NDD by the teachers will be estimated. Conclusion: If successful, the module can be incorporated into the Rashtriya Bal Swasthya Karyakram program of India for the early identification of children with NDD.

Genomic analysis of patients in a South Indian Community with autosomal dominant cortical tremor, myoclonus and epilepsy suggests a founder repeat expansion mutation in the SAMD12 gene.

Autosomal Dominant Cortical Tremor, Myoclonus and Epilepsy is a non-progressive disorder characterized by distal tremors. Autosomal Dominant Cortical Tremor, Myoclonus and Epilepsy has been reported globally with different genetic predispositions of autosomal dominant inheritance with a high degree of penetrance. In south India, Autosomal Dominant Cortical Tremor, Myoclonus and Epilepsy has been reported in a large cohort of 48 families, in which the genetic defect was not identified. This report pertains to the whole-genome analysis of four individuals followed by repeat-primed PCR for 102 patients from a familial cohort of 325 individuals. All the patients underwent extensive clinical evaluation including neuropsychological examinations. The whole-genome sequencing was done for two affected and two unaffected individuals, belonging to two different families. The whole-genome sequencing analysis revealed the repeat expansion of TTTTA and TTTCA in intron 4 of the SAMD12 gene located on chromosome 8 in the patients affected with Autosomal Dominant Cortical Tremor, Myoclonus and Epilepsy, whereas the unaffected family members were negative for the similar expansion. Further, the repeat-primed PCR analysis of 102 patients showed the expansion of the TTTCA repeats in the intron 4 of SAMD12 gene. All patients registered for this study belong to a single community called "Nadar" whose nativity is confined to the southern districts of India, with reported unique genetic characteristics. This is the largest and most comprehensive single report on clinically and genetically characterized Autosomal Dominant Cortical Tremor, Myoclonus and Epilepsy patients belonging to a unique ethnic group worldwide.

Pharmacogenomic landscape of COVID-19 therapies from Indian population genomes.

Aim: Numerous drugs are being widely prescribed for COVID-19 treatment without any direct evidence for the drug safety/efficacy in patients across diverse ethnic populations. Materials & methods: We analyzed whole genomes of 1029 Indian individuals (IndiGen) to understand the extent of drug-gene (pharmacogenetic), drug-drug and drug-drug-gene interactions associated with COVID-19 therapy in the Indian population. Results: We identified 30 clinically significant pharmacogenetic variants and 73 predicted deleterious pharmacogenetic variants. COVID-19-associated pharmacogenes were substantially overlapped with those of metabolic disorder therapeutics. CYP3A4, ABCB1 and ALB are the most shared pharmacogenes. Fifteen COVID-19 therapeutics were predicted as likely drug-drug interaction candidates when used with four CYP inhibitor drugs. Conclusion: Our findings provide actionable insights for future validation studies and improved clinical decisions for COVID-19 therapy in Indians.

Genetic epidemiology of autoinflammatory disease variants in Indian population from 1029 whole genomes.

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.