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.
2024
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.
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.
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…
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…
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…
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…
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…
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…
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…
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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