Publications
At MedGenome, we are deeply focused on continuous innovation, and publishing our findings for the larger benefit of the genetic testing community. Read through our publications for details of our latest work.
2025
Impact of switching antiplatelet therapy in acute coronary syndrome patients with different CYP2C19 phenotypes: insights from a single-center study
Abstract: Optimizing antiplatelet therapy is crucial in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary interventions (PCIs). This study aimed to assess the prevalence of CYP2C19 loss-of-function (LOF) variants and evaluate the clinical outcome of ticagrelor, clopidogrel, and aspirin in patients with ACS-PCI. Objective: Optimizing antiplatelet therapy is crucial in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary interventions (PCIs).…
Titinopathies: Phenotype – genotype heterogeneity in an Indian cohort
Abstract: Titinopathies are heterogenous group of disorders affecting the skeletal and cardiac muscles variably and caused by Titin (TTN) gene mutations located in Chromosome 2. The manifestations extend from congenital to adult-onset myopathies. Here we describe the phenotype-genotype heterogeneity of patients with myopathy/muscular dystrophy associated with TTN variants in an Indian cohort. Introduction: Titinopathies are heterogenous group of disorders affecting the skeletal and…
2024
Haplotype analysis detects MLH1 founder variant in Indian Lynch syndrome patient cohort
Abstract: Lynch syndrome (LS) is an autosomal dominant hereditary cancer predisposition syndrome whereby the lifetime risk of developing gastrointestinal and genitourinary cancers rises by to over 50%. It is caused by heterozygous variants in the DNA mismatch repair genes- MLH1, MSH2, MSH6 and PMS2, with the majority detected in MLH1 and MSH2. Recurrently observed LS-associated variants in apparently unrelated individuals have…
A Homozygous Nonsense Variant in the BICC1 Gene Associated with Fetal Cystic Kidney Disease and Lower Limb Post-Axial Polydactyly
Abstract:
A rare case of myopathy with fatigability due to PYROXD1 variation
Abstract: Congenital myopathies are a group of heterogenous inherited muscle diseases. With advances in genetics, newer genes with novel features are being described. Pyridine nucleotide-disulfide oxidoreductase domain 1 (PYROXD1) related myopathy is an ultrarare congenital myopathy. Only few cases have been reported worldwide till now. We report the first interesting case of PYROXD1 related myopathy from India. Abstract Introduction: Congenital myopathies are a group…
Child with KBG syndrome
Abstract: We report a male child with developmental delay, microcephaly and facial dysmorphism in the form of a turri-brachycephaly-shaped skull, triangular face, posteriorly rotated lop ears, thick bushy eyebrows, synophrys, long deep philtrum and prominent incisors. The mobile application Face2Gene was used to screen the patient's facial photographs for known syndromes. The application suggested a high likelihood of KBG syndrome. Exome…
Progressive Supranuclear Palsy in India: Past, Present, and Future
Abstract: Progressive supranuclear palsy (PSP) has emerged as a key area of interest among researchers worldwide, including those in India, who have actively studied the disorder over the past several decades. This review meticulously explores the extensive range of Indian research on PSP up to the present and offers insights into both current initiatives and potential future directions for managing PSP…
Our Experiences and Learnings in Diagnosing MODY from Non-Institutional-Based Diabetes Care Clinics
Abstract: Introduction: Maturity-onset diabetes of the young (MODY) is a rare group of disorders characterised by impaired functions or development of pancreatic islets and monogenic diabetes at a young age. Diagnosing MODY can be rewarding for both clinicians and patients as it can change the management from generic to targeted therapy. Methods: This study reports the retrospective analysis of data collected from four…
Activating STAT3 mutations in CD8+ T-cells correlate to serological positivity in rheumatoid arthritis
Abstract: Objectives: Large granular lymphocyte (LGL) leukemia is a rare hematologic malignancy characterized by clonal expansion of cytotoxic T-cells frequent somatic activating STAT3 mutations. Based on the disease overlap between LGL leukemia rheumatoid arthritis (RA)a putative role for CD8+ T-cells in RA we hypothesized that STAT3 mutations may be detected in RA patient CD8+ T-cells correlate with clinical characteristics. Methods: Blood samples, clinical parameters, and demographics were…
Isolated Lateralized Overgrowth – Phenotypic Spectrum and Molecular Alterations
Abstract: Objectives To evaluate the molecular aberrations at 11p15.5 locus in thirty-two patients with isolated lateralized overgrowth (ILO). Methods Among selected 32 cases of ILO, methylation-sensitive multiplex ligation-dependent probe amplification (MS-MLPA) was performed initially followed by short tandem repeats (STR) marker analysis to confirm uniparental disomy (UPD). In those patients with normal MLPA reports, cyclin dependent kinase inhibitor 1C (CDKN1C) gene and…
KBG Syndrome in 16 Indian Individuals
Abstract: We aimed to describe the clinical and genetic characteristics of 16 individuals with KBG syndrome (KBGS) from 13 Indian families. We retrospectively analyzed the clinical details of individuals with KBGS harboring a likely pathogenic/pathogenic variant in ANKRD11. We also analyzed their facial gestalt using Face2Gene and recorded the top three differential disorders suggested by the application. The most frequent clinical features…
High rate of detected variants in male PLCZ1 and ACTL7A genes causing failed fertilization after ICSI
Abstract: Abstract STUDY QUESTION What is the frequency of PLCZ1, ACTL7A, and ACTL9 variants in male patients showing fertilization failure after ICSI, and how effective is assisted oocyte activation (AOA) for them? SUMMARY ANSWER Male patients with fertilization failure after ICSI manifest variants in PLCZ1 (29.09%), ACTL7A (14.81%), and ACTL9 (3.70%), which can be efficiently overcome by AOA treatment with ionomycin. WHAT IS KNOWN ALREADY Genetic variants in PLCZ1, and more recently,…
Results of comprehensive genetic testing in patients presenting to a multidisciplinary inherited heart disease clinic in India
Abstract: Abstract Objectives This study aims to analyze the results of comprehensive genetic testing in patients presenting to a dedicated multidisciplinary inherited heart disease clinic in India. Methods All patients presenting to our clinic from August 2017 to October 2023 with a suspected inherited heart disease and consenting for genetic testing were included. The probands were grouped into familial cardiomyopathies namely hypertrophic cardiomyopathy (HCM), dilated…
Extending HLA allele sequences using next-generation sequencing technology
Abstract: Abstract Extended sequences for 13 HLA alleles were found which had limited coverage previously. CONFLICT OF INTEREST STATEMENT The authors declare no conflicts of interest.
Mosaic embryo transfer after preimplantation genetic testing for structuralrearrangement: a case study
Abstract: Abstract: AbstractBackground: Identifying the cause of recurrent pregnancy loss (RPL) helps in the direct management of future pregnancies. In 3-4% of cases, a chromosomal structural rearrangement is identified in the couple. Pre-implantation genetic testing - structural rearrangements (PGT-SR) is an accepted practice for such couples opting for pregnancy through in-vitro fertilization. However, the result interpretation and clinical outcome for mosaic embryo…
GNE Myopathy: Genotype – Phenotype Correlation and Disease Progression in an Indian Cohort
Abstract: Abstract: Abstract Introduction: GNE myopathy is a rare slowly progressive adult-onset distal myopathy with autosomal recessive inheritance. It has distinctive features of quadriceps sparing with preferential anterior tibial involvement. Most patients eventually become wheelchair bound by 10–20 years after onset. This study analyzes the phenotype-genotype characteristics and disease progression in a large cohort of GNEM patients from India.
Identification of nine novel HLA alleles by next-generation sequencing in individuals from India
Abstract: Abstract Nine novel HLA alleles were identified when HLA typing individuals from the Indian population. Keywords: HLA; IMGT; IPD; India; NGS; novel allele. © 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Movement disorders in Megalencephalic Leukoencephalopathy with subcortical cysts – A case series
Abstract: Background Megalencephalic leukoencephalopathy with subcortical cysts (MLC) has been described in the literature mostly as early-onset leukodystrophy with cerebellar ataxia being the main clinical phenotype. However, other associated movement disorders have also been reported discretely. Cases Here, we present seven cases of MLC. Cerebellar ataxia was common in them, while dystonia was present in six, parkinsonism in one and stereotypy…
Spectrum of Alport syndrome in an Indian cohort
Abstract: Background Next-generation sequencing has enabled non-invasive diagnosis of type IV collagen disease in clinical settings other than the typical presentation of Alport syndrome (AS). Methods We reviewed the clinical and histological records of children diagnosed with Alport syndrome based on next-generation sequencing. Variants on clinical exome sequencing were categorized using ACMG 2015 criteria. Results During 2015–2023, we found 43 patients…
rAbDesFlow: a novel workflow for computational recombinant antibody design for healthcare engineering
Abstract: Recombinant antibodies (rAbs) have emerged as a promising solution to tackle antigen specificity, enhancement of immunogenic potential and versatile functionalization to treat human diseases. The development of single chain variable fragments has helped accelerate treatment in cancers and viral infections, due to their favorable pharmacokinetics and human compatibility. However, designing rAbs is traditionally viewed as a genetic engineering problem, with…
Navigating the clinical landscape: Update on the diagnostic and prognostic biomarkers in multiple myeloma
Abstract: Multiple myeloma, a complex hematologic malignancy, has devastating consequences for patients, including dramatic bone loss, severe bone pain, and pathological fractures that markedly decrease the quality of life and impact the survival of affected patients. This necessitates a refined understanding of biomarkers for accurate diagnosis and prognosis of such severe malignancy. Therefore, this article comprehensively covers current research, elucidating the…
Phenotype-Genotype Correlation of a Cohort of Patients with Congenital Myopathy: A Single Centre Experience from India
Abstract: Abstract Background: Congenital myopathies (CMs) are a diverse group of inherited muscle disorders with broad genotypic and phenotypic heterogeneity. While the literature on CM is available from European countries, comprehensive data from the Indian subcontinent is lacking.
CNS-wide repopulation by hematopoietic-derived microglia-like cells corrects progranulin deficiency in mice
Abstract: Hematopoietic stem cell transplantation can deliver therapeutic proteins to the central nervous system (CNS) through transplant-derived microglia-like cells. However, current conditioning approaches result in low and slow engraftment of transplanted cells in the CNS. Here we optimized a brain conditioning regimen that leads to rapid, robust, and persistent microglia replacement without adverse effects on neurobehavior or hematopoiesis. This regimen combines…
Early detection and diagnosis of cancer with interpretable machine learning to uncover cancer-specific DNA methylation patterns
Abstract: Abstract Cancer, a collection of more than two hundred different diseases, remains a leading cause of morbidity and mortality worldwide. Usually detected at the advanced stages of disease, metastatic cancer accounts for 90% of cancer-associated deaths. Therefore, the early detection of cancer, combined with current therapies, would have a significant impact on survival and treatment of various cancer types. Epigenetic…
Clinical exome sequencing unravels the diverse spectrum of genetic heterogeneity and genotype-phenotype correlations in hypertrophic cardiomyopathy.
Abstract: Background Catalogues of pathogenic genetic mutations in hypertrophic cardiomyopathy (HCM) are disproportionately small when compared to that of the size of the population with South Asian ancestry and their collective increased risk of heart disease. Methods We conducted clinical exome sequencing of 200 HCM patients to identified cardiomyopathy-associated genetic mutations. The clinical and echocardiographic characteristics of genotype-positive and genotype-negative patients…
Epidemiological characteristics and molecular identification of Plasmodium species among cases of imported malaria in Kuwait during the COVID-19 pandemic
Abstract: Cases of imported malaria are reported each year in several malaria non-endemic countries, including Kuwait. PCR testing is the ideal method for identification of the infecting Plasmodium spp. The present study documented the epidemiologic characteristics of molecularly confirmed cases of imported malaria in Kuwait during the first year of COVID-19 pandemic. During the period from February 2020 to February 2021, 100 travelers…
Cystatin F a potential diagnostic biomarker in acute promyelocytic leukemia
Abstract: There are limitations with morphology and a felt need for a diagnostic test with a short turn-around time for rapid diagnosis of acute promyelocytic leukemia (APL). To identify a unique protein biomarker in APL, we did a quantitative proteomic analysis on five acute myeloid leukemia (AML), APL and acute lymphoblastic leukemia (ALL) bone marrow mononuclear cells (MNCs) collected at diagnosis…
Comprehensive germline profiling of patients with breast cancer: initial experience from a Familial Cancer Clinic
Abstract: Breast cancer is the most common cancer among Indian females. There is limited data on germline profiling of breast cancer patients from India. The objective of the current study was to analyse the frequency and spectrum of germline variant profiles and clinicopathological characteristics of breast cancer patients referred to our Familial Cancer Clinic (FCC).
Optimization and Validation of a Harmonized Protocol for Generating Therapeutic-Grade Dendritic Cells in a Randomized Phase II Clinical Trial, Using Two Varied Antigenic Sources
Abstract: Autologous dendritic cell (DC)-based immunotherapy is a cell-based advanced therapy medicinal product (ATMP) that was first introduced more than three decades ago. In the current study, our objective was to establish a harmonized protocol using two varied antigenic sources and a good manufacturing practice (GMP)-compliant, manual method for generating clinical-grade DCs at a limited-resource academic setting. After obtaining ethical committee-approved…
2023
Acute lymphoblastic leukemia with myeloid mutations is a high-risk disease associated with clonal hematopoiesis
Abstract: Myeloid neoplasms arise from pre-existing clonal hematopoiesis (CH), however the role of CH in pathogenesis of ALL is unknown. We found that 18% of adult ALL cases harbored TP53, and 16% had myeloid CH-associated gene mutations. ALL with myeloid mutations (MyM) had distinct genetic and clinical characteristics, associated with inferior survival. By using single cell proteogenomic analysis, we demonstrated that…
Diagnostic exome identifies a novel PRKG2 mutation in a proband with skeletal dysplasia
Abstract: This graphic abstract combines pedigree, dysmorphology features, radiographs, and the PRKG2 protein domain, specifically the CNB-A regulatory domain, which harbors a mutation resulting in premature protein termination.
The Genetic Drivers Of Juvenile, Young, And Early-Onset Parkinson’s Disease In India
Abstract: 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…
Clinical Utility of Proband Only Clinical Exome Sequencing in Neurodevelopmental Disorders
Abstract: 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…
Kindler syndrome with a novel mutation and a rare gynaecological complication
Abstract: Kindler syndrome is a rare genodermatosis characterized by mechanical skin fragility, acral blisters, photosensitivity, poikiloderma, skin atrophy and mucosal inflammation. It is considered a subtype of inherited epidermolysis bullosa. The disease is inherited in an autosomal recessive pattern with the parents of the affected individuals being obligate heterozygotes. We report a case of a patient with Kinder syndrome with a giant…
Identification of a shared, common haplotype segregating with an SGCB c.544 T > G mutation in Indian patients affected with sarcoglycanopathy
Abstract: Sarcoglycanopathy is the most frequent form of autosomal recessive limb-girdle muscular dystrophies caused by mutations in SGCB gene encoding beta-sarcoglycan proteins. In this study, we describe a shared, common haplotype co-segregating in 14 sarcoglycanopathy cases from 13 unrelated families from south Indian region with the likely pathogenic homozygous mutation c.544 T > G (p.Thr182Pro) in SGCB. Haplotype was reconstructed based on 10 polymorphic markers surrounding the…
Detection of 22q11.2 deletion syndrome by single-nucleotide polymorphism based non-invasive prenatal test
Abstract: Non-invasive prenatal test (NIPT) has become a popular screening test worldwide for screening common trisomies. In addition, the test can also sex chromosomal aneuploidies (SCAs) with similar sensitivity. In recent years, the scope of NIPT has extended to screen pregnancies for clinically significant microdeletions (MDs), rare autosomal aneuploidies, and subchromosomal abnormalities. The clinical utility of NIPT screening beyond trisomies 21,18,13…
Novel homozygous leptin receptor mutation in an infant with monogenic obesity
Abstract: Monogenic obesity can be caused by a mutation in one of the single genes involved in hunger and satiety. The most common mutations affect melanocortin 4 (MC4) followed by the leptin gene and its receptor. Leptin receptor (LEPR) gene mutation is an extremely rare endocrine disease characterized by early-onset obesity, hyperphagia in addition to pituitary hormone deficiency, and metabolic abnormalities. We…
South Asian medical cohorts reveal strong founder effects and high rates of homozygosity
Abstract: 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…
Ancient gene linkages support ctenophores as sister to other animals
Abstract: A central question in evolutionary biology is whether sponges or ctenophores (comb jellies) are the sister group to all other animals. These alternative phylogenetic hypotheses imply different scenarios for the evolution of complex neural systems and other animal-specific traits1,2,3,4,5,6. Conventional phylogenetic approaches based on morphological characters and increasingly extensive gene sequence collections have not been able to definitively answer this…
Filaggrin gene polymorphisms in Indian children with atopic dermatitis: A cross-sectional multicentre study
Abstract: Filaggrin (FLG) gene encoding the protein filaggrin plays an important role in barrier function of the skin and its alteration is a predisposing factor for atopic dermatitis. FLG gene variants result in absent or decreased filaggrin protein. Worldwide, the prevalence of FLG variants ranges from 14 to 56%. FLG null variants are distinct in each population. To study the FLG gene polymorphisms…
Large Region of Homozygous (ROH) Identified in Indian Patients with Autosomal Recessive Limb-Girdle Muscular Dystrophy with p.Thr182Pro Variant in SGCB Gene
Abstract: The sarcoglycanopathies are autosomal recessive limb-girdle muscular dystrophies (LGMDs) caused by the mutations in genes encoding the α, β, γ, and δ proteins which stabilizes the sarcolemma of muscle cells. The clinical phenotype is characterized by progressive proximal muscle weakness with childhood onset. Muscle biopsy findings are diagnostic in confirming dystrophic changes and deficiency of one or more sarcoglycan proteins…
Comprehensive laboratory diagnosis of Fanconi anaemia: comparison of cellular and molecular analysis
Abstract: Fanconi anaemia (FA) is a rare inherited bone marrow failure disease caused by germline pathogenic variants in any of the 22 genes involved in the FA-DNA interstrand crosslink (ICL) repair pathway. Accurate laboratory investigations are required for FA diagnosis for the clinical management of the patients. We performed chromosome breakage analysis (CBA), FANCD2 ubiquitination (FANCD2-Ub) analysis and exome sequencing of…
True Fetal Trisomy 22 Detected Using Genome-Wide Noninvasive Prenatal Testing
Abstract: Benn P, Malvestiti F, Grimi B, Maggi F, Simoni G, Grati FR. Rare autosomal trisomies: comparison of detection through cell-free DNA analysis and direct chromosome preparation of chorionic villus samples. Ultrasound Obstet Gynecol. 2019;54(4):458–67. 2. van der Meij K, Sistermans E, Macville M, Stevens S, Bax C, Bekker M, Bilardo C, Boon E, Boter M, Diderich K. Phupong, Vorapong, Suchada…
2022
Genotype-phenotype correlation and natural history study of dysferlinopathy: a single-centre experience from India
Abstract: Dysferlinopathies are a group of limb-girdle muscular dystrophies causing significant disability in the young population. There is a need for studies on large cohorts to describe the clinical, genotypic and natural history in our subcontinent. To describe and correlate the clinical, genetic profile and natural history of genetically confirmed dysferlinopathies. We analysed a retrospective cohort of patients with dysferlinopathy from…
Exome sequencing and microarray identified a novel large exonic deletion in SYT2 gene in an ultra-rare case with recessive CMS type 7
Abstract: Congenital myasthenic syndromes (CMSs) are a diverse group of diseases that have an underlying defect in transmission of signals from nerve cells to muscles that lead to muscular weakness. A 13-year-old male child born of consanguineous parents with profound motor developmental delay and normal cognition was referred to us. The younger male sibling aged 9 months was similarly affected. Electromyography…
Near-chromosomal de novo assembly of Bengal tiger genome reveals genetic hallmarks of apex predation
Abstract: 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…
A novel compound heterozygous BEST1 gene mutation in two siblings causing autosomal recessive bestrophinopathy
Abstract: To describe the clinical features, imaging characteristics, and genetic test results associated with a novel compound heterozygous mutation of the BEST1 gene in two siblings with autosomal recessive bestrophinopathy. Methods Two siblings underwent a complete ophthalmic examination, including dilated fundus examination, fundus photography, fundus autofluorescence imaging, spectral-domain optical coherence tomography, fluorescein angiography, electroretinography, and electrooculography. A clinical diagnosis of autosomal…
Prenatal Diagnosis for Primary Immunodeficiency Disorders – An Overview of the Indian Scenario
Abstract: Prenatal Diagnosis (PND) forms an important part of primary preventive management for families having a child affected with primary immunodeficiency. Although individually sparse, collectively this group of genetic disorders represents a significant burden of disease. This paper discusses the prenatal services available for affected families at various centers across the country and the challenges and ethical considerations associated with genetic…
Clinico-epidemiological and genomic profile of first Zika Virus outbreak in India at Jaipur city of Rajasthan state
Abstract: First Zika virus (ZIKV) positive case from North India was detected on routine surveillance of Dengue-Like Illness in an 85-year old female. Objective of the study was to conduct an investigation for epidemiological, clinical and genomic analysis of first ZIKV outbreak in Rajasthan, North India and enhance routine ZIKV surveillance. Method Outbreak investigation was performed in 3 Km radius of…
Think of SCA45 in Late-Onset Familial Ataxias: The First Report from the Indian Subcontinent with a Novel Variant
Abstract: An 82-year-old male patient presented with insidious onset and slowly progressive imbalance during walking over a period of the last 20 years. He also suffered from recurrent bouts of bullous pemphigoid for the last 30 years and developed hearing difficulty for the last 3 years. He had a strong family history of late onset gait imbalance involving his mother, four of his elder…
Multiomic analysis of papillary thyroid cancers identifies BAIAP2L1-BRAF fusion and requirement of TRIM25, PDE5A and PKCδ for tumorigenesis
Abstract: Papillary thyroid carcinoma (PTC) is one of the most common forms of thyroid cancer with a cure rate of over 90% after surgery. However, aggressive forms may still occur, and personalized therapeutic strategies are increasingly required. Methods We performed integrated genomic and proteomic analysis of PTC tumor samples from patients who did not harbor BRAF or RAS mutations. We validate…
Molecular epidemiology of SARS-CoV-2 in healthcare workers and identification of viral genomic correlates of transmissibility and vaccine break through infection: A retrospective observational study from a cancer hospital in eastern India
Abstract: Despite COVID vaccination with ChAdOx1 ncov-19 (COVISHIELD®) (ChAdOx1 ncov-19) a large number of healthcare workers (HCWs) were getting infected in wave-2 of the pandemic in a cancer hospital of India. It was important therefore to determine the genotypes responsible for vaccine breakthrough infections. Methods & Objectives Retrospective observational study of HCWs. Whole genome sequencing of SARS CoV-2 using Illumina NovaSeq…
Bioplatforms in liquid biopsy: advances in the techniques for isolation, characterization and clinical applications
Abstract: Tissue biopsy analysis has conventionally been the gold standard for cancer prognosis, diagnosis and prediction of responses/resistances to treatments. The existing biopsy procedures used in clinical practice are, however, invasive, painful and often associated with pitfalls like poor recovery of tumor cells and infeasibility for repetition in single patients. To circumvent these limitations, alternative non-invasive, rapid and economical, yet sturdy,…
Genomic Variations in ATP7B Gene in Indian Patients with Wilson Disease
Abstract: To report genotype data of the patients with Wilson disease (WD) hailing from across several parts of India to add to the available spectrum of causative variants in ATP7B gene (ATPase copper transporting beta polypeptide gene) and associated phenotypes in the Indian population. Methods The entire ATP7B gene was sequenced in 58 patients with WD and additional testing was also…
Retinoblastoma genetics screening and clinical management
PMID: 34294096
Abstract: India accounts for 20% of the global retinoblastoma (RB) burden. However, the existing data on RB1 gene germline mutations and its influence on clinical decisions is minimally explored. Methods: Fifty children with RB underwent complete clinical examination and appropriate multidisciplinary management.
Metabolic and Genetic Evaluation in Children with Nephrolithiasis
PMID: 35819704
Abstract: To evaluate metabolic and genetic abnormalities in children with nephrolithiasis attending a referral center in North India. Methods The patients aged 1–18 y old with nephrolithiasis underwent biochemical evaluation and whole-exome sequencing. The authors evaluated for monogenic variants in 56 genes and compared allele frequency of 39 reported polymorphisms between patients and 1739 controls from the GenomeAsia 100 K database…
Genome-Wide Polygenic Score Predicts Large Number of High Risk Individuals in Monogenic Undiagnosed Young Onset Parkinson’s Disease Patients from India
PMID: 35810474
Abstract: Parkinson's disease (PD) is a genetically heterogeneous neurodegenerative disease with poorly defined environmental influences. Genomic studies of PD patients have identified disease-relevant monogenic genes, rare variants of significance, and polygenic risk-associated variants. In this study, whole genome sequencing data from 90 young onset Parkinson's disease (YOPD) individuals are analyzed for both monogenic and polygenic risk. The genetic variant analysis identifies…
Chorea-acanthocytosis: 3 New Families with Novel Genetic and Metabolic Findings
PMID: 34447025
Abstract: Parkinson’s disease (PD) is the second most common neurodegenerative disorder in the world and is characterized by loss of dopaminergic neurons in the substantia nigra leading to bradykinesia, rigidity, tremors, and a large number of motor and non‑motor symptoms. It is a complex disorder with pathology showing Lewy body deposition in the brain. The main treatment option consists of dopaminergic…
Wilms tumor with Mulibrey Nanism: A case report and review of literature
Abstract: Mulibrey-Nanism (Muscle-liver-brain-eye Nanism = dwarfism; MUL) is a rare genetic syndrome. The underlying TRIM37 mutation predisposes these children to develop tumors frequently. In the largest published series of MUL, 8% patients were reported to develop Wilms tumor (WT). The published literature lacks data regarding the best treatment protocol and outcome of this cohort of children with WT and MUL. Case…
Clinical, radiological and molecular studies in 24 individuals with Dyggve-Melchior-Clausen dysplasia and Smith-McCort dysplasia from India
PMID: 35477554
Abstract: Dyggve-Melchior-Clausen dysplasia (DMC) and Smith-McCort dysplasia (SMC types 1 and 2) are rare spondyloepimetaphyseal dysplasias with identical radiological findings. The presence of intellectual disability in DMC and normal intellect in SMC differentiates the two. DMC and SMC1 are allelic and caused by homozygous or compound heterozygous variants in DYM. SMC2 is caused by variations in RAB33B. Both DYM and RAB33B are important in intravesicular transport…
Clinical, genetic profile and disease progression of sarcoglycanopathies in a large cohort from India: high prevalence of SGCB c.544A > C
PMID: 35416532
Abstract: The clinico-genetic architecture of sarcoglycanopathies in Indian patients is reported only as short series. In the present study, we aimed to investigate the clinical picture, genetic basis, and disease progression of patients genetically confirmed to have sarcoglycanopathy. Next-generation sequencing was performed in 68 probands with suspected sarcoglycanopathy. A total of 35 different variants were detected in the sarcoglycan genes in…
A New Variant of an Old Itch: Novel Missense Variant in ABCB4 Presenting with Intractable Pruritus
Abstract: Progressive familial intrahepatic cholestasis (PFIC) refers to a group of autosomal recessive disorders characterized by impaired bile transport due to a defect in bile acid transport or tight junction structure of hepatocyte, resulting in intrahepatic cholestasis.1 PFIC results in early-onset cholestasis and intractable pruritus. Progressive familial intrahepatic cholestasis (PFIC) refers to a group of autosomal recessive disorders characterized by impaired…
Evaluation of cytogenetic and molecular markers with MTX-mediated toxicity in pediatric acute lymphoblastic leukemia patients
Abstract: Pediatric acute lymphoblastic leukemia (pALL) patients have better overall survival and methotrexate (MTX) is an effective drug used in their treatment. However, the treatment-related adverse effects (TRAEs) have a bigger impact on the therapy. In this study, we have evaluated the association of polymorphisms in genes encoding proteins engaged in MTX metabolism, and the cytogenetic aberrations with TRAEs. Methods A…
Growth and neurodevelopmental disorder with arthrogryposis, microcephaly and structural brain anomalies caused by Bi-allelic partial deletion of SMPD4 gene
Abstract: Neutral sphingomyelinases have an important role in generation of ceramide and phosphorylcholine from sphingomyelins which then act as secondary messengers in various signaling pathways of the cellular machinery. They function ubiquitously with a predominant role in the central nervous system. Neutral sphingomyelinase type 3, encoded by SMPD4 gene has recently been reported to cause a severe autosomal recessive neurodevelopmental disorder…
Oculogyric Crisis Phenotype of Levodopa-Induced Ocular Dyskinesia
Abstract: Ocular dyskinesia (OD) is an uncommon form of the levodopa induced dyskinesia (LIOD) characterized by short-lasting horizontal or upward conjugate gaze deviation. More sustained deviations resembling oculogyric crises (OGC) are distinctly uncommon. A 62-yr-old man with a 10-yr history of Parkinson's disease (PD) presented florid ocular dyskinesia mimicking OGC. Levodopa introduction caused increased blinking, up rolling of the eyeballs and…
Factor XIII Deficiency with a Novel Nonsense Mutation
Abstract: Factor XIII deficiency is a rare inherited autosomal recessive disorder and occurs at a frequency of approximately 1 in 1–5 million people. During the last 4 decades, over 200 cases of congenital factor XIII (FXIII) deficiency have been reported in the literature. FXIII circulates as a tetramer of two FXIIIA and two FXIIIB subunits. The active catalytic FXIIIA subunit covalently cross-links…
True Fetal Trisomy 22 Detected Using Genome‑Wide Noninvasive Prenatal Testing
Abstract: Autosomal aneuploidies occurring in chromosomes other than 13, 18, and 21 and sex chromosomal aneuploidies are referred to as 'Rare autosomal aneuploidies' (RAAs).A prenatal incidence of 0.41% is noted for RAAs on chorionic villus sampling (CVS) procedures.
Clinical Study of 668 Indian Subjects with Juvenile, Young, and Early Onset Parkinson’s Disease
PMID: 33685545
Abstract: To determine the demographic pattern of juvenile-onset parkinsonism (JP, <20 years), young-onset (YOPD, 20-40 years), and early onset (EOPD, 40-50 years) Parkinson's disease (PD) in India. Materials and methods: We conducted a 2-year, pan-India, multicenter collaborative study to analyze clinical patterns of JP, YOPD, and EOPD. All patients under follow-up of movement disorders specialists and meeting United Kingdom (UK) Brain…
Whole-exome sequencing and variant spectrum in children with suspected inherited renal tubular disorder: the East India Tubulopathy Gene Study
PMID: 35006361
Abstract: Inherited tubulopathies are a heterogeneous group of genetic disorders making whole-exome sequencing (WES) the preferred diagnostic methodology. Methods This was a multicenter descriptive study wherein children (< 18 years) with clinically suspected tubular disorders were recruited for molecular testing through WES. Multiplex ligation-dependent probe amplification (MLPA) and Sanger sequencing were done when required. Variants were classified as per American College…
2021
Maternal opioid use disorder: Placental transcriptome analysis for neonatal opioid withdrawal syndrome
Abstract: Excessive prenatal opioid exposure may lead to the development of Neonatal Opioid Withdrawal Syndrome (NOWS). RNA-seq was done on 64 formalin-fixed paraffin-embedded placental tissue samples from 32 mothers with opioid use disorder, with newborns with NOWS that required treatment, and 32 prenatally unexposed controls. We identified 93 differentially expressed genes in the placentas of infants with NOWS compared to unexposed…
Novel Consensus Splice Site Pathogenic Variation in THOC2 Gene Leads to Recurrent Arthrogryposis Multiplex Congenita Phenotype: A Case Report
Abstract: The THOC2 gene encodes THO complex subunit 2, a subunit of the Transcription-Export (TREX) complex which binds specifically to splice messenger ribonucleic acid (mRNAs) to facilitate mRNA export. Mutations in the THOC2 gene have been described to lead to X-linked mental retardation syndrome type 12/35 (XLMR-12/35) (MIM#300957). Here, we describe for the first time a recurrent arthrogryposis multiplex congenita phenotype (AMC) in two male fetuses…
Drug-resistant ‘Non-Lesional’ Visual Sensitive Epilepsies of Childhood – Electroclinical Phenotype-Genotype Associations
Abstract: Awake brain mapping is an important tool in cranial surgeries involving the eloquent regions of the cerebral cortex. It provides real‑time feedback about the functionality of the cerebral cortex and the subcortical white matter. It involves the application of direct cortical and subcortical stimulation of the gyrus of interest to identify the related functions. It helps decide the margins of…
Profile of Pathogenic Mutations and Evaluation of Germline Genetic Testing Criteria in Consecutive Breast Cancer Patients Treated at a North Indian Tertiary Care Center
Abstract: The burden of hereditary breast cancer in India is not well defined. Moreover, genetic testing criteria (National Comprehensive Cancer Network [NCCN] and Mainstreaming Cancer Genetics [MCG] Plus) have never been validated in the Indian population. Methods All new female patients with invasive breast cancer attending our OPD from 1st March 2019 to 28th Feb 2020 were screened. Those without previous…
Myoneuropathic presentation of limb girdle muscular dystrophy R8 with a novel TRIM32 mutation
Abstract: TRIM 32-related Limb Girdle Muscular Dystrophy (LGMD R8/2H) is a rare genetic muscle disease reported in fewer than 100 patients worldwide. Here, we report a male patient with progressive proximo-distal lower limb weakness with onset in the third decade who had mixed myopathic and neurogenic pattern in electrophysiology and muscle biopsy. Clinical exome sequencing revealed a homozygous pathogenic single base…
Initial experience and results of a cardiogenetic clinic in a tertiary cardiac care center in India
Abstract: Cardiogenetic clinics have gained importance over the past two decades due to their ability to integrate genetic medicine with clinical cardiology and thereby provide comprehensive care to affected patients and their families.[12] A multidisciplinary team approach comprising the cardiologist, electrophysiologist, and clinical geneticist has resulted in significant changes in the management of children with inherited cardiac disorders. However, the concept…
HopA1 Effector from Pseudomonas syringae pv syringae Strain 61 Affects NMD Processes and Elicits Effector-Triggered Immunity
Abstract: Pseudomonas syringae-secreted HopA1 effectors are important determinants in host range expansion and increased pathogenicity. Their recent acquisitions via horizontal gene transfer in several non-pathogenic Pseudomonas strains worldwide have caused alarming increase in their virulence capabilities. In Arabidopsis thaliana, RESISTANCE TO PSEUDOMONAS SYRINGAE 6 (RPS6) gene confers effector-triggered immunity (ETI) against HopA1pss derived from P. syringae pv. syringae strain 61. Surprisingly, a closely related HopA1pst from the tomato pathovar evades…
Retinoblastoma Genetics Screening And Clinical Management
Abstract: India accounts for 20% of the global retinoblastoma (RB) burden. However, the existing data on RB1 gene germline mutations and its infuence on clinical decisions is minimally explored. Methods: Fifty children with RB underwent complete clinical examination and appropriate multidisciplinary management. Screening of germline RB1 gene mutations was performed through next-generation sequencing and Multiplex Ligation-dependent Probe Amplifcation (MLPA) analysis. The…
BCR-ABL1 kinase domain mutation analysis by next generation sequencing detected additional mutations in chronic myeloid leukemia patients with suboptimal response to imatinib
Abstract: Mutations in the BCR-ABL1 kinase domain (BCR-ABL1 KD) is one of the most common determinants of tyrosine kinase inhibitor (TKI) resistance in patients with chronic myelogenous leukemia (CML) . The emergence of BCR-ABL1 kinase domain (KD) mutations contributes to 40-50% of all TKI resistant cases. The current gold standard method for BCR-ABL1 KD mutation detection is Sanger sequencing (SS), which has an analytical sensitivity limit of 10-20%…
Immunodominant T‐cell epitopes from the SARS‐CoV‐2 spike antigen reveal robust pre‐existing T‐cell immunity in unexposed individuals
Abstract: The COVID-19 pandemic has revealed a range of disease phenotypes in infected patients with asymptomatic, mild, or severe clinical outcomes, but the mechanisms that determine such variable outcomes remain unresolved. In this study, we identified immunodominant CD8 T-cell epitopes in the spike antigen using a novel TCR-binding algorithm. The predicted epitopes induced robust T-cell activation in unexposed donors demonstrating pre-existing…
Matrilineal Analysis Of Mutations In The DMD Gene In A Multigenerational South Indian Cohort Using DMD Gene Panel Sequencing
Abstract: Duchenne muscular dystrophy (DMD) is an X‐linked recessive neuromuscular disorder characterised by progressive irreversible muscle weakness, primarily of the skeletal and the cardiac muscles. DMD is characterised by mutations in the dystrophin gene, resulting in the absence or sparse quantities of dystrophin protein. A precise and timely molecular detection of DMD mutations encourages interventions such as carrier genetic counselling and…
Nemaline Rod/Cap Myopathy Due to Novel Homozygous MYPN Mutations: The First Report from South Asia and Comprehensive Literature Review
Abstract: Pathogenic variants in the myopalladin gene (MYPN) are known to cause mildly progressive nemaline/cap myopathy. Only nine cases have been reported in the English literature. Methods A detailed evaluation was conducted of the clinical, muscle magnetic resonance imaging (MRI), and genetic findings of two unrelated adults with MYPN-related cap myopathy. Genetic analysis was performed using whole-exome sequencing. MRI was performed on…
Pharmacogenetic evaluation of 6-mercaptopurine-mediated toxicity in pediatric acute lymphoblastic leukemia patients from a South Indian population
Abstract: To evaluate the variants in the genes coding for the proteins involved in thiopurine and folate metabolism with treatment related adverse effects (TRAEs). Materials & methods: Eleven variants in seven candidate genes were genotyped in 127 pediatric acute lymphoblastic leukemia patients under 6-mercaptopurine (6-MP) treatment to infer the association of selected genotypes with TRAEs. Results: Among the genotypes inspected, NUDT15 (c.415C>T) and SLC19A1 (c.80G>A) showed…
Insulin Infusion Is Linked to Increased NPPC Expression in Muscle and Plasma C-type Natriuretic Peptide in Male Dogs
Abstract: The purpose of this study was to assess insulin-stimulated gene expression in canine skeletal muscle with a particular focus on NPPC, the gene that encodes C-type natriuretic peptide, a key hormonal regulator of cardiometabolic function. Four conscious canines underwent hyperinsulinemic, euglycemic clamp studies. Skeletal muscle biopsy and arterial plasma samples were collected under basal and insulin-stimulated conditions. Bulk RNA sequencing of…
Phenotypic variability in distal acidification defects associated with WDR72 mutations
PMID: 33033857
Abstract: Distal renal tubular acidosis (RTA) is typically caused by defects in ATP6V0A4, ATP6V1B1, and SLC4A1, accounting for 60-80% of patients. Genes recently implicated include FOXI1, ATP6V1C2, and WDR72, of which WDR72 is associated with dental enamel defects. Methods: We describe 4 patients, from three unrelated consanguineous families, with RTA and amelogenesis imperfecta. Distal tubular acidification was evaluated by furosemide-fludrocortisone test,…
Genetic Testing in Neonatal Intensive Care: Experience from a Tertiary Care Unit
Abstract: Institute of Medicine (US) Committee on Improving Birth Outcomes; Bale JR, Stoll BJ, Lucas AO, editors. Reducing Birth Defects: Meeting the Challenge in the Developing World. Washington (DC): National Academies Press (US). 2003. Available at: https://www.ncbi.nlm.nih.gov/books/NBK222082/. 2. Willig L, Petrikin J, Smith L, et al. Whole-genome sequencing for identification of Mendelian disorders in critically ill infants: a retrospective analysis of…
Whole-exome sequencing identifies two novel ALMS1 mutations in Indian patients with Leber congenital amaurosis
Abstract: Leber congenital amaurosis (LCA) is a severe autosomal recessive retinal degenerative disease. The current study describes exome sequencing results for two unrelated Indian LCA patients carrying novel nonsense p.(Glu636*) and frameshift p.(Pro2281Leufs*63) mutations in the ALMS1 gene. Although ALMS1 gene mutations are associated with Alstrom syndrome (AS), the current patients did not exhibit typical syndromic features of AS. These data suggest that ALMS1 should be included…
Recent Evolutionary History of Tigers Highlights Contrasting Roles of Genetic Drift and Selection
Abstract: Species conservation can be improved by knowledge of evolutionary and genetic history. Tigers are among the most charismatic of endangered species and garner significant conservation attention. However, their evolutionary history and genomic variation remain poorly known, especially for Indian tigers. With 70% of the world's wild tigers living in India, such knowledge is critical. We re-sequenced 65 individual tiger genomes…
Clinical And Whole Genome Characterization Of SARS-CoV-2 In India
Abstract: We report clinical profile of hundred and nine patients with SARS CoV-2 infection, and whole genome sequences (WGS) of seven virus isolates from the first reported cases in India, with various international travel histories. Comorbidities such as diabetes, hypertension, and cardiovascular disease were frequently associated with severity of the disease. WBC and neutrophil counts showed an increase, while lymphocyte counts…
Novel CTSF Indel in a patient with Kufs disease and resistant schizophrenia: A case report
Abstract: UMM receives an honorarium from Elsevier for serving as Associate Editor of Schizophrenia Research. Drs. GK, SD, GA, SG, SRC and LSM report no biomedical financial interests or potential conflicts of interest. Acknowledgments UMM was supported by the Wellcome Trust/DBT India Alliance Early Career Fellowship, Grant/Award Number: IA/E/12/1/500755. We also thank our patient and her family for providing consent to…
NGS-Based Expanded Carrier Screening For Genetic Disorders In North Indian Population Reveals Unexpected Results – A Pilot Study
Abstract: To determine the carrier frequency and pathogenic variants of common genetic disorders in the north Indian population by using next generation sequencing (NGS). Methods After pre-test counselling, 200 unrelated individuals (including 88 couples) were screened for pathogenic variants in 88 genes by NGS technology. The variants were classified as per American College of Medical Genetics criteria. Pathogenic and likely pathogenic…
2020
Galectin antagonist use in mild cases of SARS-CoV-2; pilot feasibility randomised, open label, controlled trial
Abstract: Importance Novel SARS-CoV-2 virus has infected nearly half a billion people across the world and is highly contagious. There is a need for a novel mechanism to block viral entry and stop its replication. Background Spike protein N terminal domain (NTD) of the novel SARS-CoV-2 is essential for viral entry and replication in human cell. Thus the S1 NTD of…
Phenotypic expression and clinical outcomes in a South Asian PRKAG2 cardiomyopathy cohort
Abstract: 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;…
Ophthatome™: an integrated knowledgebase of ophthalmic diseases for translating vision research into the clinic
Abstract: Medical big data analytics has revolutionized the human healthcare system by introducing processes that facilitate rationale clinical decision making, predictive or prognostic modelling of the disease progression and management, disease surveillance, overall impact on public health and research. Although, the electronic medical records (EMR) system is the digital storehouse of rich medical data of a large patient cohort collected over…
NGS-Based Expanded Carrier Screening For Genetic Disorders In North Indian Population Reveals Unexpected Results – A Pilot Study
Abstract: To determine the carrier frequency and pathogenic variants of common genetic disorders in the north Indian population by using next generation sequencing (NGS). Methods After pre-test counselling, 200 unrelated individuals (including 88 couples) were screened for pathogenic variants in 88 genes by NGS technology. The variants were classified as per American College of Medical Genetics criteria. Pathogenic and likely pathogenic…
Infantile spasms: Etiology, lead time and treatment response in a resource limited setting
Abstract: This study explores the etiology and lead time to treatment for infantile spasm (IS) patients and their effect on treatment responsiveness, in a limited resource setting. Patients with IS onset age ≤12 months', seen over 3 years were recruited retrospectively. Clinical information, neuroimaging and genetic results retrieved. Patients categorized into three primary etiological groups: Structural (including Structural Genetic), Genetic, and…
Seven novel genetic variants in a North Indian cohort with classical homocystinuria
Abstract: Classical homocystinuria is the most common cause of isolated homocystinuria. The variants of the CBS gene remain unidentified in Indian children with this disorder. Based on the hallmark clinical features, family history, and/or biochemical clues for classical homocystinuria, 16 children below the age of 18 years were evaluated by Sanger sequencing of the coding exons of CBS gene with flanking intronic regions. The common C677T variant of…
Integrated genomic analysis reveals mutated ELF3 as a potential gallbladder cancer vaccine candidate
Abstract: Gallbladder cancer (GBC) is an aggressive gastrointestinal malignancy with no approved targeted therapy. Here, we analyze exomes (n = 160), transcriptomes (n = 115), and low pass whole genomes (n = 146) from 167 gallbladder cancers (GBCs) from patients in Korea, India and Chile. In addition, we also sequence samples from 39 GBC high-risk patients and detect evidence of early cancer-related genomic lesions. Among the several…
A Case of Autosomal Dominant Ataxia with Vocal Cord Palsy Attributed to a Mutation in the PRNP Gene
Abstract: Cerebellar ataxias, are a group progressively expanding spectrum of heterogeneous disorders. The clinical features and life expectancies are varied based on genetic and phenotypic presentations. We present a familial case with an autosomal dominant inheritance of rapidly progressive ataxia with vocal cord palsy, due to D178N mutation in the PRNP gene. Case Report A 54-year-old man (III-8; Fig. 1.1) presented with a…
Validation of a Genome-Wide Polygenic Score for Coronary Artery Disease in South Asians
Abstract: 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…
A Rare Neurological Presentation of Familial Hemophagocytic Lymphohistiocytosis
Abstract: In this case report, we described a 15-year-old boy who presented with intermittent episodes of ataxia and diplopia since 6.5 years of age. Extensive workup done over several years was negative. Brain biopsy showed a neuroinflammatory disorder, and hence, differential diagnosis of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids, central nervous system (CNS) lymphoma, and small vessel…
Non-coding and Coding Transcriptional Profiles Are Significantly Altered in Pediatric Retinoblastoma Tumors
Abstract: Retinoblastoma is a rare pediatric tumor of the retina, caused by the homozygous loss of the Retinoblastoma 1 (RB1) tumor suppressor gene. Previous microarray studies have identified changes in the expression profiles of coding genes; however, our understanding of how non-coding genes change in this tumor is absent. This is an important area of research, as in many adult malignancies,…
Late-onset KMT2B-related dystonia in an Indian patient with normal cognition, dystonic opisthotonus and lack of oromandibular and laryngeal involvement
Abstract: KMT2B-related dystonia is characterized by childhood-onset and progressive disease course with prominent lower-limb, cervical, cranial, and laryngeal involvement [ [1] ]. Developmental delay and intellectual disability are commonly reported [ [1] , [2] ]. Here we are reporting an Indian patient with KMT2B-related dystonia who had a disease onset at the age of 19 years. Other interesting features in our…
Human ACE2 receptor polymorphisms predict SARS-CoV-2 susceptibility
Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of coronavirus disease (COVID-19) that has resulted in a global pandemic. It is a highly contagious positive strand RNA virus and its clinical presentation includes severe to critical respiratory disease that appears to be fatal in ~3-5% of the cases. The viral spike (S) coat protein engages the human angiotensin-converting…
First report of THOC6 related intellectual disability (Beaulieu Boycott Innes syndrome) in two siblings from India
Abstract: THOC6 is a newly described causal gene for an autosomal recessive intellectual disability (ID) - Beaulieu Boycott Innes syndrome (BBIS) (OMIM # 613680). It is characterized by ID with dysmorphic facies, genitourinary, cardiac anomalies, and dentition problems. Here, we report the first two siblings of BBIS from the Indian subcontinent with previously unreported skeletal anomalies such as Sprengel shoulder, calcaneo…
Robinow Syndrome and Brachydactyly: An Interplay of High-Throughput Sequencing and Deep Phenotyping in a Kindred
Abstract: We report a family with a spectrum of short stature, craniofacial dysmorphism, and digital anomalies in a father and 2 daughters, with the youngest (proband) displaying a severe phenotype. Clinically, autosomal dominant Robinow syndrome (ADRS) was diagnosed. Whole-exome sequencing identified a heterozygous pathogenic BMP2 variant in the father and his daughters. The phenotype of short stature, facial dysmorphism, and skeletal anomalies with…
Whole genome enrichment approach for rapid detection of Mycobacterium tuberculosis and drug resistance-associated mutations from direct sputum sequencing
Abstract: Tuberculosis is the leading cause of death among infectious diseases worldwide. Detection of Mycobacterium tuberculosis (Mtb), using routine culture-based methods is time consuming resulting in delayed diagnosis and poor treatment outcomes. Currently available molecular tests provide faster diagnosis but are able to screen only limited hot-spot mutations. Whole genome sequencing from direct sputum offers a potential solution, however, due to the presence of other microbes and host DNA…
Horizontal Gaze Palsy And Progressive Scoliosis—A Tale Of Two Siblings With ROBO3 Mutation
Abstract: Dr. Poornima Narayanan Nambiar: study design, acquisition of data, and drafting of manuscript. Dr. Santha Kumar S: acquisition of data and drafting of manuscript. Dr. Ramshekhar Menon: study design and critical revision of the manuscript. Dr. Sruthi. and S. Nair: critical revision of manuscript. Dr. Soumya Sundaram: study concept, design, and critical revision of manuscript. Dr. GK Madhavilatha: acquisition of…
Heterogeneity of Satellite Cells Implicates DELTA1/NOTCH2 Signaling in Self-Renewal
Abstract: How satellite cells and their progenitors balance differentiation and self-renewal to achieve sustainable tissue regeneration is not well understood. A major roadblock to understanding satellite cell fate decisions has been the difficulty of studying this process in vivo. By visualizing expression dynamics of myogenic transcription factors during early regeneration in vivo, we identify the time point at which cells undergo…
Natural Killer cell transcriptome during primary EBV infection and EBV associated Hodgkin Lymphoma in children—A preliminary observation
Abstract: Epstein Barr Viral infection is a common childhood infection in India and is also nearly 100 % etiologically associated with pediatric Hodgkin Lymphoma (HL). The main question in EBV immunobiology has been, why only a small subset of infected individuals develop EBV associated malignancies, while the vast majority carry this virus asymptomatically for life. Natural Killer (NK) cells, with a…
A newly recognized multiple malformation syndrome with caudal regression associated with a biallelic c.402G>A variant in TBX4
Abstract: The T-box4 (TBX4) gene (OMIM *601719) belongs to the T-box family of transcription regulators that share a conserved homology domain and are expressed at specific sites during various stages of embryonic development. Tbx4 has been found to be a crucial transcriptional regulator in embryonic hindlimb development in animal models. Monoallelic variants in the TBX4 gene are reported to be associated with skeletal…
Successful renal transplantation in a family with a novel mutation in COL4A3 gene and autosomal recessive Alport syndrome
Abstract: Alport syndrome (AS) is an inherited disorder of basement membranes caused by mutations affecting specific proteins of the type IV collagen family, presenting with nephropathy and extrarenal manifestations such as sensorineural deafness and ocular anomalies. Ten percentage to 15% of the patients with AS have autosomal recessive (ARAS) due to mutation in either COL4A3 or COL4A4 gene. We report a novel mutation in the COL4A3 gene…
Genetic analysis of familial hypercholesterolemia in Asian Indians: A single-center study
Abstract: Highlights There is paucity of data on genetic studies of FH in Asian Indians. 100 unrelated cases with clinical suspicion of FH classified using modified DLCN. Sanger sequencing of LDLR, PCSK9, 2 fragments of ApoB, and targeted lipid panel by NGS. 38 different disease-causing mutations (10 novel) identified in 47 unrelated cases. Mutations identified in the study not reported before…
The Indian cobra reference genome and transcriptome enables comprehensive identification of venom toxins
Abstract: Snakebite envenoming is a serious and neglected tropical disease that kills ~100,000 people annually. High-quality, genome-enabled comprehensive characterization of toxin genes will facilitate development of effective humanized recombinant antivenom. We report a de novo near-chromosomal genome assembly of Naja naja, the Indian cobra, a highly venomous, medically important snake. Our assembly has a scaffold N50 of 223.35 Mb, with 19…
2019
Genetic analysis of familial hypercholesterolemia in Asian Indians: a single center study
Abstract: Familial Hypercholesterolemia (FH), an autosomal co-dominant disorder characterized by very high LDL cholesterol, is strongly associated with premature coronary artery disease. Molecular landscape of FH in Asian Indians is not well studied, although this ethnic group comprises a large proportion of the world population. Knowledge of mutations in these groups is useful for identifying persons affected with FH, saving their…
S100a4 upregulation in Pik3caH1047R;Trp53R270H;MMTV-Cre-driven mammary tumors promotes metastasis
Abstract: PIK3CA mutations are frequent in human breast cancer. Pik3caH1047R mutant expression in mouse mammary gland promotes tumorigenesis. TP53 mutations co-occur with PIK3CA mutations in human breast cancers. We previously generated a conditionally activatable Pik3caH1047R;MMTV-Cre mouse model and found a few malignant sarcomatoid (spindle cell) carcinomas that had acquired spontaneous dominant-negative Trp53 mutations.
MAP2K1 is a potential therapeutic target in erlotinib resistant head and neck squamous cell carcinoma
Abstract: Epidermal growth factor receptor (EGFR) targeted therapies have shown limited efficacy in head and neck squamous cell carcinoma (HNSCC) patients despite its overexpression. Identifying molecular mechanisms associated with acquired resistance to EGFR-TKIs such as erlotinib remains an unmet need and a therapeutic challenge. In this study, we employed an integrated multi-omics approach to delineate mechanisms associated with acquired resistance to…
Association of HLA-A, -B, DRB, and DQB Alleles with Persistent HPV-16 Infection in Women from Tamil Nadu, India
Abstract: Women with persistent human papillomavirus (HPV) infections have a high risk of developing cervical cancer (CaCx). HPV-16 alone accounts for more than 60% of CaCx worldwide. Most of the HPV infections are transient and only a subset of women develop persistent HPV-16 infection. Many studies have shown associations of different human leukocyte antigen (HLA) alleles with HPV-mediated CaCx, but there…
Prevalence of mutations in inherited retinal diseases: A comparison between the United States and India
Abstract: Studies evaluating next‐generation sequencing (NGS) for retinal disorders may not reflect clinical practice. We report results of retrospective analysis of patients referred for clinical testing at two institutions (US and India). Methods This retrospective study of 131 patients who underwent clinically validated targeted NGS or exome sequencing for a wide variety of clinical phenotypes categorized results into a definitive, indeterminate,…
Identification of African-Specific Admixture between Modern and Archaic Humans
Abstract: Recent work has demonstrated that two archaic human groups (Neanderthals and Denisovans) interbred with modern humans and contributed to the contemporary human gene pool. These findings relied on the availability of high-coverage genomes from both Neanderthals and Denisovans. Here we search for evidence of archaic admixture from a worldwide panel of 1,667 individuals using an approach that does not require…
The GenomeAsia 100K Project Enables Genetic Discoveries Across Asia
Abstract: The underrepresentation of non-Europeans in human genetic studies so far has limited the diversity of individuals in genomic datasets and led to reduced medical relevance for a large proportion of the world’s population. Population-specific reference genome datasets as well as genome-wide association studies in diverse populations are needed to address this issue. Here we describe the pilot phase of the…
Detection of clinically relevant epidermal growth factor receptor pathway mutations in circulating cell-free tumor DNA using next generation sequencing in squamous cell carcinoma lung
Abstract: Limited repertoires of targets are available in the management of squamous cell carcinoma lung. In this study, we analyzed epidermal growth factor receptor (EGFR), RAS, BRAF mutations in lung cancer patients of squamous cell histology using next-generation sequencing (NGS) on the circulating cell-free DNA (cf-DNA). In this prospective observational study, patients with squamous cell carcinoma lung, either newly diagnosed or…
Vitamin K1 prevents diabetic cataract by inhibiting lens aldose reductase 2 (ALR2) activity
Abstract: his study investigated the potential of vitamin K1 as a novel lens aldose reductase inhibitor in a streptozotocin-induced diabetic cataract model. A single, intraperitoneal injection of streptozotocin (STZ) (35 mg/kg) resulted in hyperglycemia, activation of lens aldose reductase 2 (ALR2) and accumulation of sorbitol in eye lens which could have contributed to diabetic cataract formation. However, when diabetic rats were…
Role of VEGF165b/VEGFTOTAL ratio in gestational diabetes mellitus
Abstract: Proper vascular function is important for well-being of mother and growing fetus. VEGFTOTAL, and VEGF165b levels and its vascular endothelial complications in gestational diabetes mellitus (GDM) together with the association of inflammation and advanced glycation end products (AGEs) are less studied. VEGF165b/VEGFTOTAL (VEGF RATIO) in GDM pregnant women was investigated in this study. Plasma VEGFTOTAL was lower in GDM (17.68 ± 1.30 pg/mL)…
Chronic Exposure to Chewing Tobacco Induces Metabolic Reprogramming and Cancer Stem Cell-Like Properties in Esophageal Epithelial Cells
Abstract: Tobacco in its smoke and smokeless form are major risk factors for esophageal squamous cell carcinoma (ESCC). However, molecular alterations associated with smokeless tobacco exposure are poorly understood. In the Indian subcontinent, tobacco is predominantly consumed in chewing form. An understanding of molecular alterations associated with chewing tobacco exposure is vital for identifying molecular markers and potential targets. We developed…
Resequencing CYP2D6 gene in Indian population: CYP2D6*41 identified as the major reduced function allele
Abstract: The CYP2D6 gene is highly polymorphic and harbors population specific alleles that define its predominant metabolizer phenotype. This study aimed to identify polymorphisms in Indian population owing to scarcity of CYP2D6 data in this population. Materials & methods: The CYP2D6 gene was resequenced in 105 south Indians using next generation sequencing technology and haplotypes were reconstructed. Results & conclusion: Four novel missense variants have been designated as CYP2D6*110, *111, *112 and *113. The…
Is shed hair the most effective non-invasive resource for estimating wild pedigrees?
Abstract: Wild pedigrees are critical for better understanding mating systems and inbreeding scenarios to inform conservation strategies for endangered species. To delineate pedigrees in wild populations, many identified individuals will have to be genotyped at thousands of loci, mostly from non-invasive samples. This requires us to quantify (a) the most common non-invasive sample available from identified individuals (b) the ability to…
Immunodeficiency, Motor Delay, and Hypouricemia Caused by a Novel Mutation of Purine Nucleoside Phosphorylase Gene in an Indian Infant
Abstract: We describe an 11-month-old boy who presented with recurrent respiratory infections from 6 months of age. His elder sister died at 10 months with severe septicemia and meningitis. The boy had a mild motor delay. Investigations revealed T cell deficiency and very low serum uric acid suggestive of purine nucleoside phosphorylase (PNP) deficiency – a rare variant of severe combined…
Emerging biomarkers and clinical significance of HPV genotyping in prevention and management of cervical cancer
Abstract: Cervical cancer is a growing and serious problem world-wide in women, but more acute in developing countries especially in Indian subcontinent. The main causative agent for the disease is Human Papilloma Virus (HPV). The history of the cervical cancer goes back to eighteenth century as the HPV infection is reported since 1800s. Presently, the genetic structure of HPV is well…
Somatic Mutations Profile of a Young Patient With Metastatic Urothelial Carcinoma Reveals Mutations in Genes Involved in Ion Channels
Abstract: Urothelial carcinoma is the most common malignancy of the bladder and is primarily considered as a disease of the elderly. Studies that address bladder tumor occurrence in young age groups are rare. Case Presentation: A 19-year-old male presented with a gross total painless hematuria. A histology after biopsy revealed a high-grade transitional cell carcinoma with lymph node metastasis. The patient…
Methylglyoxal – An emerging biomarker for diabetes mellitus diagnosis and its detection methods
Abstract: Diabetes Mellitus (DM) is one among the supreme metabolic issues observed in history since 3000 BCE and has gained much interest recently due to the increasing number of diabetic cases every year. Glucose is considered as the most iconic biomarker for diabetes detection, and fluctuations in its levels are related to different stages of DM. However, methylglyoxal (MG) is evolving as a…
Whole Genome Sequencing and Comparative Genomic Analysis Reveal Allelic Variations Unique to a Purple Colored Rice Landrace (Oryza sativa ssp. indica cv. Purpleputtu)
Abstract: Purpleputtu (Oryza sativa ssp. indica cv. Purpleputtu) is a unique rice landrace from southern India that exhibits predominantly purple color. This study reports the underlying genetic complexity of the trait, associated domestication and de-domestication processes during its coevolution with present day cultivars. Along-with genome level allelic variations in the entire gene repertoire associated with the purple, red coloration of grain and other plant…
Simultaneous diagnosis of unilateral retinoblastoma and contralateral optic pathway glioma in a child with neurofibromatosis type 1
Abstract: Neurofibromtosis-1 (NF-1) is the commonest oculo-neuro-cutaneous syndrome with multiple ocular manifestations. Reporting three children who presented with unilateral glaucoma (buphthalmos), ipsilateral facial hemihypertrophy, and eyelid plexiform neurofibroma: completing the triad of François syndrome, a rare NF1 variant. Two presented with leukocoria and were referred to as retinoblastoma suspects. Histopathology showed ganglioneuroma, a benign choroidal tumor, associated with NF-1, which does…
First International Conference on RASopathies and Neurofibromatoses in Asia: Identification and advances of new therapeutics
Abstract: The neurofibromatoses, which include neurofibromatosis type I (NF1), neurofibromatosis type II (NF2), and schwannomatosis, are a group of syndromes characterized by tumor growth in the nervous system. The RASopathies are a group of syndromes caused by germline mutations in genes that encode components of the RAS/mitogen-activated protein kinase (MAPK) pathway. The RASopathies include NF1, Noonan syndrome, Noonan syndrome with multiple…
Novel GNAL mutation in an Indian patient with generalized dystonia and response to deep brain stimulation
Abstract: Mutations in GNAL have been associated with cranio-cervical dystonia (DYT-GNAL) [ 1 ]. The dystonia most often progresses to involve other regions, particularly the face and laryngeal muscles and less commonly the trunk, arm and lower limbs. The clinical phenotype in GNAL-related dystonia appears to be similar to that caused by mutations in THAP1.
Adult-Onset Myoclonus-Dystonia Syndrome preceding Characteristic Facial Myoclonus in Indian ADCY5-related Dyskinesia
Abstract: A 21-year-old man presented to us with involuntary jerking movements of his hands and head that started at the age of 13. In the early years, the movements would come in intermittent spells, and sometimes his whole body would tremble when anxious, concentrating on an activity, or riding his scooter. Initially mild, the movements had progressed to moderate severity over…
A Synthetic DNA, Multi-Neoantigen Vaccine Drives Predominately MHC Class I CD8+ T-cell Responses, Impacting Tumor Challenge
Abstract: T-cell recognition of cancer neoantigens is important for effective immune-checkpoint blockade therapy, and an increasing interest exists in developing personalized tumor neoantigen vaccines. Previous studies utilizing RNA and long-peptide neoantigen vaccines in preclinical and early-phase clinical studies have shown immune responses predominantly driven by MHC class II CD4+ T cells. Here, we report on a preclinical study utilizing a DNA vaccine…
Differential methylation of the type 2 diabetes susceptibility locus KCNQ1 is associated with insulin sensitivity and is predicted by CpG site specific genetic variation
Abstract: Epigenetic mechanisms regulate gene expression and may influence the pathogenesis of type 2 diabetes through the loss of insulin sensitivity. The aims of this study were to measure variation in DNA methylation at the type 2 diabetes locus KCNQ1 and assess its relationship with metabolic measures and with genotype. Methods DNA methylation from whole blood DNA was quantified using pyrosequencing…
2018
A Computational Approach Identifies Immunogenic Features of Prognosis in Human Cancers
Abstract: A large number of tumor intrinsic and extrinsic factors determine long-term survival in human cancers. In this study, we stratified 9120 tumors from 33 cancers with respect to their immune cell content and identified immunogenomic features associated with long-term survival. Our analysis demonstrates that tumors infiltrated by CD8+ T cells expressing higher levels of activation marker (PD1hi) along with TCR signaling…
Metabolite systems profiling identifies exploitable weaknesses in retinoblastoma
Abstract: Retinoblastoma (RB) is a childhood eye cancer. Currently, chemotherapy, local therapy, and enucleation are the main ways in which these tumors are managed. The present work is the first study that uses constraint-based reconstruction and analysis approaches to identify and explain RB-specific survival strategies, which are RB tumor specific. Importantly, our model-specific secretion profile is also found in RB1-depleted human…
Actionable Activating Oncogenic ERBB2/HER2 Transmembrane and Juxtamembrane Domain Mutations
Abstract: Deregulated HER2 is a target of many approved cancer drugs. We analyzed 111,176 patient tumors and identified recurrent mutations in HER2 transmembrane domain (TMD) and juxtamembrane domain (JMD) that include G660D, R678Q, E693K, and Q709L. Using a saturation mutagenesis screen and testing of patient-derived mutations we found several activating TMD and JMD mutations. Structural modeling and analysis showed that the…
Is there a Chance to Promote Arteriogenesis by DPP4 Inhibitors Even in Type 2 Diabetes? A Critical Review
Abstract: Cardiovascular diseases (CVD) are still the prevailing cause of death not only in industrialized countries, but even worldwide. Type 2 diabetes mellitus (type 2 DM) and hyperlipidemia, a metabolic disorder that is often associated with diabetes, are major risk factors for developing CVD. Recently, clinical trials proved the safety of gliptins in treating patients with type 2 DM. Gliptins are…
A neoepitope derived from a novel human germline APC gene mutation in familial adenomatous polyposis shows selective immunogenicity
Abstract: Familial adenomatous polyposis (FAP) is an inherited condition arising from genetic defects in the Adenomatous polyposis coli (APC) gene. Carriers with mutations in the APC gene develop polyps in the colon and rectum which if not managed, transition into colon cancer. In this study, we identified a novel germline mutation in the APC gene in members of an FAP-affected (Familial…
Progressive nonparoxysmal chorea and dystonia due to myofibrillogenesis regulator-1 gene mutation
Abstract: Mutations in the myofibrillogenesis regulator gene (MR-1) causes paroxysmal non -kinesigenic dyskinesia (PNKD) characterized by episodic (paroxysmal) attacks of any combination of chorea, dystonia and athetosis (MR-1/PNKD) [ [1] ]. This gene is transcribed into three alternatively spliced isoforms: long (MR-1L), medium (MR-1M) and small (MR-1S) [ [2] , [3] ]. Three mutations namely, A7V, A9V and A33P have been…
A cancer vaccine approach for personalized treatment of Lynch Syndrome
Abstract: Lynch syndrome (LS) is a cancer predisposition disorder wherein patients have a 70–80% lifetime risk of developing colorectal cancers (CRC). Finding germline mutations in predisposing genes allows for risk assessment of CRC development. Here we report a germline heterozygous frame-shift mutation in the mismatch repair MLH1 gene which was identified in members of two unrelated LS families. Since defects in DNA mismatch…
Identification of deletion-duplication in HEXA gene in five children with Tay-Sachs disease from India
Abstract: Background Tay-Sachs disease (TSD) is a sphingolipid storage disorder caused by mutations in the HEXA gene. To date, nearly 170 mutations of HEXA have been described, including only one 7.6 kb large deletion. Methods Multiplex Ligation-dependent Probe Amplification (MLPA) study was carried out in 5 unrelated patients for copy number changes where heterozygous and/or homozygous disease causing mutation/s could not…
Complete mitogenome reveals genetic divergence and phylogenetic relationships among Indian cattle (Bos indicus) breeds
Abstract: Indigenous cattle of India belong to the species, Bos indicus and they possess various adaptability and production traits. However, little is known about the genetic diversity and origin of these breeds. To investigate the status, we sequenced and analyzed the whole mitochondrial DNA (mtDNA) of seven Indian cattle breeds. In total, 49 single-nucleotide variants (SNVs) were identified among the seven breeds analyzed.…
Noninvasive prenatal testing (NIPT) detects variant of Turner syndrome not detectable by fluorescent in situ hybridization
Abstract: Noninvasive prenatal testing (NIPT) is a reliable screening method for fetal aneuploidy detection of trisomy 18, 13, 21 along with few sex chromosome abnormalities monosomy X, XXX, XXY (Klinefelter), XYY (Jacob) syndromes and certain microdeletions which include cri-du-chat, DiGeorge, 1p36, Angelman, and Prader-Willi syndromes in comparison to the available screening methods. Prenatal screening of Turners syndrome is possible by ultrasound…
Molecular alterations associated with chronic exposure to cigarette smoke and chewing tobacco in normal oral keratinocytes
Abstract: Tobacco usage is a known risk factor associated with development of oral cancer. It is mainly consumed in two different forms (smoking and chewing) that vary in their composition and methods of intake. Despite being the leading cause of oral cancer, molecular alterations induced by tobacco are poorly understood. We therefore sought to investigate the adverse effects of cigarette smoke/chewing…
A non-enzymatic two step catalytic reduction of methylglyoxal by nanostructured V2O5 modified electrode
Abstract: Methylglyoxal (MG) is a predominant precursor for advanced glycation end products (AGEs) due to its protein glycation reactions, which are the major causes of diabetic complications. MG is explored as a significant biomarker towards the prediction of diabetic complications. With this background, a non-enzymatic electrochemical biosensor has been developed to detect MG in human blood plasma samples. Microwave synthesized V2O5 nanoplates…
Tumor Microenvironment is a powerful companion diagnostic for cancer immunotherapy applications
Abstract: Currently approved checkpoint inhibitors are antibodies that block the function of three key proteins expressed on the surface of T cells: CTLA-4, PD-1 and PD-L1. Under normal conditions, these proteins function as brakes to prevent immune-related toxicity from arising because of persistent T cell activity. Cancer hijacks this essential function of immune homeostasis to protect itself from immune-mediated elimination [1,…
Clinical, Immunological, and Molecular Findings in Five Patients with Major Histocompatibility Complex Class II Deficiency from India
Abstract: Major histocompatibility complex (MHC) class II deficiency is a rare autosomal recessive form of primary immunodeficiency disorder (PID) characterized by the deficiency of MHC class II molecules. This deficiency affects the cellular and humoral immune response by impairing the development of CD4+ T helper (Th) cells and Th cell-dependent antibody production by B cells. Affected children typically present with severe respiratory…
Comprehensive genomic analysis identifies pathogenic variants in maturity-onset diabetes of the young (MODY) patients in South India
Abstract: Background Maturity-onset diabetes of the young (MODY) is an early-onset, autosomal dominant form of non-insulin dependent diabetes. Genetic diagnosis of MODY can transform patient management. Earlier data on the genetic predisposition to MODY have come primarily from familial studies in populations of European origin. Methods In this study, we carried out a comprehensive genomic analysis of 289 individuals from India…
The complete mitochondrial genome of Indian cattle (Bos indicus)
Abstract: India has 40 distinct zebuine cattle breeds with different adaptability and production traits. In the present study, we report the complete mitochondrial genome sequence of Indian cattle for the first time. The mitogenome contains 13 protein-coding genes, 22 transfer RNA genes, two ribosomal RNA genes and a control region (D-loop region). The phylogenetic analysis showed close genetic relationship among the…
Single Nucleotide Polymorphism-Based Noninvasive Prenatal Testing: Experience in India
Abstract: Noninvasive prenatal testing (NIPT) has revolutionized prenatal screening for chromosomal aneuploidies in some countries. Its implementation has been sporadic in developing countries. Given the genetic variation of the people in different countries, we evaluated the performance of the SNP-based NIPT in India. Materials and Methods The Panorama™ NIPT was performed in 516 pregnancies, which had tested intermediate-to-high risk on conventional…
Ancient human migrations to and through Jammu Kashmir- India were not of males exclusively
Abstract: Jammu and Kashmir (J&K), the Northern most State of India, has been under-represented or altogether absent in most of the phylogenetic studies carried out in literature, despite its strategic location in the Himalayan region. Nonetheless, this region may have acted as a corridor to various migrations to and from mainland India, Eurasia or northeast Asia. The belief goes that most…
Validation of liquid biopsy: plasma cell-free DNA testing in clinical management of advanced non-small cell lung cancer
Abstract: Plasma cell-free tumor DNA, or circulating tumor DNA (ctDNA), from liquid biopsy is a potential source of tumor genetic material, in the absence of tissue biopsy, for EGFR testing. Our validation study reiterates the clinical utility of ctDNA next generation sequencing (NGS) for EGFR mutation testing in non-small cell lung cancer (NSCLC). A total of 163 NSCLC cases were included in the…
2017
A novel splice variant in EMC1 is associated with cerebellar atrophy, visual impairment, psychomotor retardation with epilepsy
Abstract: Background Several genes have been implicated in a highly variable presentation of developmental delay with psychomotor retardation. Mutations in EMC1 gene have recently been reported. Herein, we describe a proband born of a consanguineous marriage, who presented with early infantile onset epilepsy, scaphocephaly, developmental delay, central hypotonia, muscle wasting, and severe cerebellar and brainstem atrophy. Methods Genetic testing in the…
Serum starvation of ARPE-19 changes the cellular distribution of cholesterol and Fibulin3 in patterns reminiscent of age-related macular degeneration
Abstract: Retinal pigment epithelium (RPE) has been implicated as key source of cholesterol-rich deposits at Bruch's membrane (BrM) and in drusen in aging human eye. We have shown that serum-deprivation of confluent RPE cells is associated with upregulation of cholesterol synthesis and accumulation of unesterified cholesterol (UC). Here we investigate the cellular processes involved in this response. We compared the distribution and localization…
Asparagine Synthetase deficiency-report of a novel mutation and review of literature
Abstract: Asparagine synthetase deficiency is a rare inborn error of metabolism caused by a defect in ASNS, a gene encoding asparagine synthetase. It manifests with a severe neurological phenotype manifesting as severe developmental delay, congenital microcephaly, spasticity and refractory seizures. To date, nineteen patients from twelve unrelated families have been identified. Majority of the mutations are missense and nonsense mutations in homozygous…
Autosomal Recessive Spastic Ataxia of Charlevoix‐Saguenay (ARSACS)–First Report of Clinical and Imaging Features from India, and a Novel SACS Gene Duplication
Abstract: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) was described by Bouchard and colleagues in 1978 from Quebec, Canada, as a rare cause of autosomal recessive cerebellar ataxia. 1.2 Subsequent reports confirmed the presence of this condition in other parts of the world, including Europe and, in Asia, Japan.3 Although mutations in the sacsin molecular chaperone gene (SACS) were also identified during a recent…
Next-Generation Sequencing Reveals Novel Mutations in X-linked Intellectual Disability
Abstract: Robust diagnostics for many human genetic disorders are much needed in the pursuit of global personalized medicine. Next-generation sequencing now offers new promise for biomarker and diagnostic discovery, in developed as well as resource-limited countries. In this broader global health context, X-linked intellectual disability (XLID) is an inherited genetic disorder that is associated with a range of phenotypes impacting societies…
Mycobacterium Tuberculosis In Wild Asian Elephants, Southern India
Abstract: We tested 3 ild Asian elephants (Elephas maximus) in southern India and confirmed infection in 3 animals with Mycobacterium tuberculosis, an obligate human pathogen, by PCR and genetic sequencing. Our results indicate that tuberculosis may be spilling over from humans (reverse zoonosis) and emerging in wild elephants. Infection with Mycobacterium tuberculosis in domestic and wild animals of various species living in close…
The Utility And Futility Of Targeted Next-Generation Sequencing For Carrier Detection In ‘At Risk’ Couples
Abstract: Next generation sequencing has changed the approach to genetic diagnosis and testing in recent times. The days have arrived when a molecular genetic diagnosis can be attempted even without the availability of the proband or affected person. However this requires additional strong evidence of diagnosis in the proband, such as biochemical or radiological hallmarks. Needless to say, this attempt should…
2016
Predicting Response to Immunosuppressive Therapy in Patients with Acquired Aplastic Anemia using EGFR and TWIST1 Expression Levels
Abstract: EGFR (epidermal growth factor receptor) is important for the proliferation of stem cells across the body including the hematopoietic niche. However, the role of EGFR in aplastic anemia and subsequent responses to standard-of-care therapy is unknown.TWIST is a basic helix-loop-helix transcription factor recently found to regulate the hematopoietic stem cell (HSC) niche. The HSC niche is important for treatment of…
Manitoba Oculotrichoanal Syndrome: First Case Report From India
Abstract: Manitoba-oculo-tricho-anal (MOTA) syndrome is very rare syndrome characterized by aberrant hairline, eye anomalies (ocular hypertelorism, cryptophthalmos, and upper eyelid colobomas), bifid nose, omphalocele and anorectal anomalies. MOTA syndrome was first reported in 1992 in Oji-cree community from the Island Lake region of Manitoba, Canada. Till date very few cases of MOTA have been reported and none from India. We report…
A Splice Site Mutation In HERC1 Leads To Syndromic Intellectual Disability With Macrocephaly And Facial Dysmorphism: Further Delineation Of The Phenotypic Spectrum
Abstract: We report on a sib pair of Indian origin presenting with intellectual disability, dysmorphism, and macrocephaly. Exome sequencing revealed a homozygous splice site HERC1 mutation in both probands. Functional analysis revealed use of an alternate splice site resulting in formation of a downstream stop codon and nonsense mediated decay. In the light of recent reports of HERC1 mutations in two…
The expression dynamics of mechanosensitive genes in extra-embryonic vasculature after heart starts to beat in chick embryo
Abstract: Fluid flow plays an important role in vascular development. However, the detailed mechanisms, particularly the link between flow and modulation of gene expression during vascular development, remain unexplored. In chick embryo, the key events of vascular development from initiation of heart beat to establishment of effective blood flow occur between the stages HH10 and HH13. Therefore, we propose a novel…
Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations
Abstract: We analyzed transcriptomes (n = 211), whole exomes (n = 99) and targeted exomes (n = 103) from 216 malignant pleural mesothelioma (MPM) tumors. Using RNA-seq data, we identified four distinct molecular subtypes: sarcomatoid, epithelioid, biphasic-epithelioid (biphasic-E) and biphasic-sarcomatoid (biphasic-S). Through exome analysis, we found BAP1, NF2, TP53, SETD2, DDX3X, ULK2, RYR2, CFAP45, SETDB1 and DDX51 to be significantly mutated…
A novel H395R mutation in MKKS/BBS6 causes retinitis pigmentosa and polydactyly without other findings of Bardet-Biedl or McKusick-Kaufman syndrome
Abstract: To identify the causative mutation in two siblings from a consanguineous family in India with retinitis pigmentosa (RP) and polydactyly without other findings of Bardet-Biedl syndrome (BBS). We also performed functional characterization of the mutant protein to explore its role in this limited form of BBS. Methods The siblings underwent a thorough ophthalmological examination, including retinal optical coherence tomography (OCT)…
2015
First Report of Kufor‐Rakeb Syndrome (PARK 9) from India, and a Novel Nonsense Mutation in ATP13A2 Gene
Abstract: Kufor-Rakeb syndrome (KRS; PARK 9) is a rare autosomal-recessive form of juvenile-onset Parkinson's disease (PD) caused by ATP13A2 gene mutations. The classical description of KRS is that of rapidly progressive symptoms in the form of parkinsonism, spasticity, supranuclear upgaze paresis, facial-faucial-finger minimyoclonus, visual hallucinations, oculogyric dystonic spasms, and dementia, usually noted between 12 and 16 years of age, resulting in early severe motor…
Identification of Novel Mutations in ABCA4 Gene: Clinical and Genetic Analysis of Indian Patients with Stargardt Disease
Abstract: Stargardt disease (STGD) is the leading cause of juvenile macular degeneration associated with progressive central vision loss, photophobia, and colour vision abnormalities. In this study, we have described the clinical and genetic features of Stargardt patients from an Indian cohort. The next generation sequencing was carried out in five clinically confirmed unrelated patients and their family members using a gene…
Evolution of targeted therapies in cancer: opportunities and challenges in the clinic
Abstract: Targeted therapies have changed the course of cancer treatment in recent years. By reducing toxicity and improving outcome, these new generations of precision medicines have extended patient lives beyond what could be achieved by the use of nontargeted therapies. In the last 2 years, several new molecular entities targeting signaling proteins and immune pathways have gone through successful clinical development…
2014
Cost-efficient HIV-1 drug resistance surveillance using multiplexed high-throughput amplicon sequencing: implications for use in low- and middle-income countries
Abstract: Increased trends of primary drug resistance mutations (DRMs) among treatment-naive HIV-1-infected patients in low- and middle-income countries (LMICs) and the non-availability of pre-antiretroviral therapy (ART) genotypic resistance testing (GRT) may severely affect future therapeutic outcomes. The main objective of this study was therefore to develop a simplified, cost- and labour-efficient but high-throughput GRT protocol to be applied in the large-scale…
Regulation of Macrophage Polarization by RON Receptor Tyrosine Kinase Signaling
Abstract: The M1 and M2 states of macrophage polarization are the two extremes of a physiologic/phenotypic continuum that is dynamically influenced by environmental signals. The M1/M2 paradigm is an excellent framework to understand and appreciate some of the diverse functions that macrophages perform. Molecular analysis of mouse and human macrophages indicated that they gain M1 and M2-related functions after encountering specific…
Prevalence of genetic variants associated with cardiovascular disease risk and drug response in the Southern Indian population of Kerala
Abstract: This study reports the prevalence of five clinically significant variants associated with increased risk of cardiovascular disorders, and variable responses of individuals to commonly prescribed cardiovascular drugs in a South Indian population from the state of Kerala. Materials and methods: Genomic DNA isolated from 100 out-patient samples from Kerala were sequenced to examine the frequency of clinically relevant polymorphisms in…
2013
Recessive mutations in SLC38A8 cause Foveal Hypoplasia and Optic Nerve Misrouting without Albinism
Abstract: Foveal hypoplasia and optic nerve misrouting are developmental defects of the visual pathway and only co-occur in connection with albinism; to date, they have only been associated with defects in the melanin-biosynthesis pathway. Here, we report that these defects can occur independently of albinism in people with recessive mutations in the putative glutamine transporter gene SLC38A8. Nine different mutations were identified in…
2012
Sequencing and analysis of a South Asian-Indian personal genome
Abstract: With over 1.3 billion people, India is estimated to contain three times more genetic diversity than does Europe. Next-generation sequencing technologies have facilitated the understanding of diversity by enabling whole genome sequencing at greater speed and lower cost. While genomes from people of European and Asian descent have been sequenced, only recently has a single male genome from the Indian…
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