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1.
Brief Bioinform ; 24(4)2023 07 20.
Artículo en Inglés | MEDLINE | ID: mdl-37401370

RESUMEN

The importance of regulatory features in health and disease is increasing, making it crucial to identify the hallmarks of these features. Self-attention networks (SAN) have given rise to numerous models for the prediction of complex phenomena. But the potential of SANs in biological models was limited because of high memory requirement proportional to input token length and lack of interpretability of self-attention scores. To overcome these constraints, we propose a deep learning model named Interpretable Self-Attention Network for REGulatory interactions (ISANREG) that combines both block self-attention and attention-attribution mechanisms. This model predicts transcription factor-bound motif instances and DNA-mediated TF-TF interactions using self-attention attribution scores derived from the network, overcoming the limitations of previous deep learning models. ISANREG will serve as a framework for other biological models in interpreting the contribution of the input with single-nucleotide resolution.


Asunto(s)
Modelos Biológicos , Nucleótidos , Factores de Transcripción
2.
Clin Oral Investig ; 26(2): 1647-1656, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-34436669

RESUMEN

INTRODUCTION: Smoked, and especially smokeless, tobacco are major causes of oral cancer globally. Here, we examine the oral bacteriome of smokers and of smokeless tobacco users, in comparison to healthy controls, using 16S rRNA gene sequencing. METHODS: Oral swab samples were collected from smokers, smokeless tobacco users, and healthy controls (n = 44). Microbial DNA was extracted and the 16S rRNA gene profiled using the Illumina MiSeq platform. Sequencing reads were processed using DADA2, and taxonomical classification was performed using the phylogenetic placement method. Differentially abundant taxa were identified using DESeq2, while functional metagenomes based on KEGG orthology abundance were inferred using LIMMA. RESULTS: A significantly higher microbial diversity was observed in smokeless tobacco users and smokers relative to controls (P < 0.05). Compositional differences in microbial communities were observed in all comparisons with healthy controls (PERMANOVA P < 0.05) but not between smokers and smokeless tobacco users. Levels of Fusobacterium spp., Saccharibacterium spp., and members of Shuttleworthia were elevated in smokers when compared to controls (BH adj P < 0.01). In addition, the relative abundance of three bacterial taxa belonging to genera Fusobacterium spp., Catonella, and Fretibacterium spp. was significantly increased in smokeless tobacco users relative to controls (BH adj P < 0.01). Major functional pathways significantly increased in smokeless tobacco users relative to both controls, and smokers were similar and involved amino acid metabolism including glutamate and aspartate biosynthesis and degradation (log FC > 1.5; BH adj P < 0.01). CONCLUSIONS: A distinct taxonomic and functional profile of oral microbiome in smokers and smokeless tobacco users as compared to healthy controls implicates a significant role of microbes and their metabolites in diseases associated with tobacco use including oral cancer. CLINICAL RELEVANCE: Future efforts in preventive, diagnostic, curative, and prognostic strategies for diseases associated with tobacco use in smokers and smokeless tobacco users could incorporate the oral microbiome.


Asunto(s)
Microbiota , Mucosa Bucal/microbiología , Tabaco sin Humo , Bacterias/clasificación , Humanos , Filogenia , ARN Ribosómico 16S/genética , Fumadores , Uso de Tabaco
3.
FASEB J ; 34(7): 8787-8795, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32525600

RESUMEN

The dynamics, such as transmission, spatial epidemiology, and clinical course of Coronavirus Disease-2019 (COVID-19) have emerged as the most intriguing features and remain incompletely understood. The genetic landscape of an individual in particular, and a population in general seems to play a pivotal role in shaping the above COVID-19 dynamics. Considering the implications of host genes in the entry and replication of SARS-CoV-2 and in mounting the host immune response, it appears that multiple genes might be crucially involved in the above processes. Herein, we propose three potentially important genetic gateways to COVID-19 infection; these could explain at least in part the discrepancies of its spread, severity, and mortality. The variations within Angiotensin-converting enzyme 2 (ACE2) gene might constitute the first genetic gateway, influencing the spatial transmission dynamics of COVID-19. The Human Leukocyte Antigen locus, a master regulator of immunity against infection seems to be crucial in influencing susceptibility and severity of COVID-19 and can be the second genetic gateway. The genes regulating Toll-like receptor and complement pathways and subsequently cytokine storm induced exaggerated inflammatory pathways seem to underlie the severity of COVID-19, and such genes might represent the third genetic gateway. Host-pathogen interaction is a complex event and some additional genes might also contribute to the dynamics of COVID-19. Overall, these three genetic gateways proposed here might be the critical host determinants governing the risk, severity, and outcome of COVID-19. Genetic variations within these gateways could be key in influencing geographical discrepancies of COVID-19.


Asunto(s)
Betacoronavirus/fisiología , Activación de Complemento/genética , Infecciones por Coronavirus/genética , Antígenos HLA/genética , Interacciones Huésped-Patógeno/genética , Pandemias , Peptidil-Dipeptidasa A/genética , Neumonía Viral/genética , Receptores Virales/genética , Receptores Toll-Like/genética , Enzima Convertidora de Angiotensina 2 , COVID-19 , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/transmisión , Síndrome de Liberación de Citoquinas/etiología , Síndrome de Liberación de Citoquinas/genética , Resistencia a la Enfermedad/inmunología , Predisposición Genética a la Enfermedad , Variación Genética , Antígenos HLA/inmunología , Interacciones Huésped-Patógeno/inmunología , Humanos , Inflamación , Metagenómica , Mutación Missense , Peptidil-Dipeptidasa A/fisiología , Neumonía Viral/complicaciones , Neumonía Viral/inmunología , Neumonía Viral/transmisión , Pronóstico , Sitios de Carácter Cuantitativo , Grupos Raciales/genética , Receptores Virales/fisiología , Riesgo , SARS-CoV-2 , Receptores Toll-Like/inmunología , Resultado del Tratamiento
4.
Mol Biol Rep ; 47(11): 8669-8677, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-33074413

RESUMEN

Rheumatoid arthritis (RA) is a crucial inflammatory joint disease characterized by loss of self-tolerance and severe cartilage loss, autoimmune, and subchondral bone erosions. Cytokines are the key regulators of inflammatory responses. Homeostatic imbalances in pro- and anti-inflammatory cytokine activities can result in pathogenic inflammatory reactions. These imbalances could be initiated by environmental factors but the ability to define the threshold of environmental impact relies on the genetic background of the pro- and anti-inflammatory cytokines. To address this a case-control association study was carried out in 429 individuals from Malayalam speaking ethnic population from South India. Functionally relevant SNPs from IL-10, IL-6, IL-1ß and IL-1RN were genotyped using PCR -RFLP and sequencing. Meta-analysis was performed for the associated variants of IL-10, IL-1ß. Significant association with RA was observed with IL-1ß rs1143634, rs1143627, IL-10 rs1800896, IL-6 rs1800796, rs1800797. The associated SNPs are likely to impact transcriptional activity of a gene. Meta-analysis with global populations also provide evidence that IL-10 and IL-1ß could be a global marker for RA. The functional significance of associated risk variants of IL-1ß and IL-6 indicate increased production of the pro-inflammatory cytokines while IL-10 risk allele suggest reduced production of anti- inflammatory cytokines. The study concludes that increased production of pro-inflammatory cytokines and reduced production of anti- inflammatory cytokines may influence the Th1/Th2 equilibrium resulting in a triggering of Th1 mediated inflammatory responses in development of RA.


Asunto(s)
Artritis Reumatoide , Citocinas , Predisposición Genética a la Enfermedad , Polimorfismo Genético , Balance Th1 - Th2 , Adulto , Artritis Reumatoide/genética , Artritis Reumatoide/inmunología , Estudios de Casos y Controles , Citocinas/genética , Citocinas/inmunología , Femenino , Humanos , India , Inflamación/inmunología , Masculino , Persona de Mediana Edad
5.
IUBMB Life ; 71(7): 901-907, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30786140

RESUMEN

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with impairments in social communication, restricted, repetitive and stereotyped behaviors. Both genetic and environmental factors are known to contribute toward pathophysiology of Autism. Environmental influences on gene expression can be mediated by methylation patterns which are established and maintained by DNA methyltransferases. Several studies in the past have investigated the role of global methylations in Autism. The present study is aimed to investigate the role of genetic variations in the DNA methyltransferase which might be critical in defining the threshold for environmental factors toward susceptibility to autism. Polymorphisms in DNA methyltransferases, DNMT1, DNMT3A, DNMT3B, and DNMT3L were screened for association with ASD in 180 autistic patients and 260 healthy controls from a south Indian population. DNMT1 rs10418707 and rs10423341, and DNMT3A rs2289195 were found to be significantly associated at genotypic and allelic level with ASD. Functional prediction indicates that these SNPs have a role in transcriptional regulation and increased expression, indicating that hypermethylation might be induced by its genotype status. The study might reflect the role of genetics variants in DNMTs in defining the threshold of environmental impact in influencing the disease or phenotype variations in ASD. © 2019 IUBMB Life, 2019.


Asunto(s)
Trastorno del Espectro Autista/genética , ADN (Citosina-5-)-Metiltransferasa 1/genética , ADN (Citosina-5-)-Metiltransferasas/genética , Metilación de ADN , Regulación de la Expresión Génica , Polimorfismo de Nucleótido Simple/genética , Trastorno del Espectro Autista/patología , Estudios de Casos y Controles , ADN Metiltransferasa 3A , Epigénesis Genética , Femenino , Genotipo , Humanos , Masculino
6.
Mov Disord ; 34(4): 496-505, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30485545

RESUMEN

BACKGROUND: Genetic variability in LRRK2 has been unequivocally established as a major risk factor for familial and sporadic forms of PD in ethnically diverse populations. OBJECTIVES: To resolve the role of LRRK2 in the Indian population. METHODS: We performed targeted resequencing of the LRRK2 locus in 288 cases and 298 controls and resolved the haplotypic structure of LRRK2 in a combined cohort of 800 cases and 402 controls in the Indian population. We assessed the frequency of novel missense variants in the white and East Asian population by leveraging exome sequencing and densely genotype data, respectively. We did computational modeling and biochemical approach to infer the potential role of novel variants impacting the LRRK2 protein function. Finally, we assessed the phosphorylation activity of identified novel coding variants in the LRRK2 gene. RESULTS: We identified four novel missense variants with frequency ranging from 0.0008% to 0.002% specific for the Indian population, encompassing armadillo and kinase domains of the LRRK2 protein. A common genetic variability within LRRK2 may contribute to increased risk, but it was nonsignificant after correcting for multiple testing, because of small cohort size. The computational modeling showed destabilizing effect on the LRRK2 function. In comparison to the wild-type, the kinase domain variant showed 4-fold increase in the kinase activity. CONCLUSIONS: Our study, for the first time, identified novel missense variants for LRRK2, specific for the Indian population, and showed that a novel missense variant in the kinase domain modifies kinase activity in vitro. © 2018 International Parkinson and Movement Disorder Society.


Asunto(s)
Predisposición Genética a la Enfermedad , Variación Genética , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Enfermedad de Parkinson/genética , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Femenino , Frecuencia de los Genes , Genotipo , Haplotipos , Humanos , India , Masculino , Persona de Mediana Edad , Mutación Missense , Adulto Joven
7.
J Neuroinflammation ; 13(1): 105, 2016 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-27177030

RESUMEN

BACKGROUND: In schizophrenia, genetic background may provide a substrate for intrinsic maldevelopment of the brain through environmental influences, by recruiting neurotrophic factors and cytokines, to trigger the changes that lead to impaired neuronal functions. Cytokines being the key regulators of immune/inflammatory reactions are also known to influence the dopaminergic, noradrenergic, and serotonergic neurotransmission. Therefore, functional polymorphisms in cytokine genes may result in imbalances in the pro- and anti-inflammatory cytokine production. METHODS: We screened polymorphisms in pro- and anti-inflammatory cytokine genes using a case-control association study in a South Indian population. The role of allele, genotype, haplotype, and diplotypes of these cytokine genes and their epistatic interactions were assessed in contributing to the risk of developing schizophrenia. Meta-analysis for the reported associations was also monitored for global significance. RESULTS: The pro-inflammatory cytokine gene polymorphisms in IL1Ars1800587, IL6rs1800796, TNFArs361525, and IFNGrs2069718 were associated with schizophrenia. The study also provides significant evidence for strong epistatic interactions among pro-inflammatory cytokine genes IL6 and IFNG in the development of schizophrenia. In silico analysis suggested that associated risk variants were indicative of altered transcriptional activity with higher production of IL1α, IL-6, TNF-α, and IFN-ɤ cytokines. Meta-analysis indicated heterogeneity among study population while IL1Ars1800587 was found to be globally significant. CONCLUSIONS: It is important to identify the nature of inflammatory response that can be amplified by the environment, to influence either Th1 response or Th2 response. The associated functional variants in the study are involved with increased expression resulting in higher production of the pro-inflammatory cytokines IL-1α, IL-6, TNF-α, and IFN-γ. The interaction of immunological stressors with these high producer alleles of pro-inflammatory cytokines may suggest that even a lower threshold may be sufficient to induce a resultant chronic effect on the psycho-social and environmental stressors that may result in the development and pathogenesis of schizophrenia. Understanding environmental factors that influence the expression of these pro-inflammatory cytokine genes or their interaction can possibly help in dissecting the phenotypic variation and therapeutic response to antipsychotics in schizophrenia.

8.
J Neuroinflammation ; 12: 135, 2015 Jul 22.
Artículo en Inglés | MEDLINE | ID: mdl-26198819

RESUMEN

BACKGROUND: Intracranial aneurysm (IA) is often asymptomatic until the time of rupture resulting in subarachnoid hemorrhage (SAH).There is no precise biochemical or phenotype marker for diagnosis of aneurysm. Environmental risk factors that associate with IA can result in modifying the effect of inherited genetic factors and thereby increase the susceptibility to SAH. In addition subsequent to aneurismal rupture, the nature and quantum of inflammatory response might be critical for repair. Therefore, genetic liability to inflammatory response caused by polymorphisms in cytokine genes might be the common denominator for gene and environment in the development of aneurysm and complications associated with rupture. METHODS: Functionally relevant polymorphisms in the pro- and anti-inflammatory cytokine genes IL-1 complex (IL1A, IL1B, and IL1RN), TNFA, IFNG, IL3, IL6, IL12B, IL1RN, TGFB1, IL4, and IL10] were screened in radiologically confirmed 220 IA patients and 250 controls from genetically stratified Malayalam-speaking Dravidian ethnic population of south India. Subgroup analyses with genetic and environmental variables were also carried out. RESULTS: Pro-inflammatory cytokines TNFA rs361525, IFNG rs2069718, and anti-inflammatory cytokine IL10 rs1800871 and rs1800872 were found to be significantly associated with IA, independent of epidemiological factors. TGFB1 rs1800469 polymorphism was observed to be associated with IA through co-modifying factors such as hypertension and gender. Functional prediction of all the associated SNPs of TNFA, IL10, and TGFB1 indicates their potential role in transcriptional regulation. Meta-analysis further reiterates that IL1 gene cluster and IL6 were not associated with IA. CONCLUSIONS: The study suggests that chronic exposure to inflammatory response mediated by genetic variants in pro-inflammatory cytokines TNFA and IFNG could be a primary event, while stochastic regulation of IL10 and TGFB1 response mediated by comorbid factors such as hypertension may augment the pathogenesis of IA through vascular matrix degradation. The implication and interaction of these genetic variants under a specific environmental background will help us identify the resultant phenotypic variation in the pathogenesis of intracranial aneurysm. Identifying genetic risk factors for inflammation might also help in understanding and addressing the posttraumatic complications following the aneurismal rupture.


Asunto(s)
Interferón gamma/genética , Interleucina-10/genética , Aneurisma Intracraneal/genética , Procesos Estocásticos , Factor de Crecimiento Transformador beta1/genética , Factor de Necrosis Tumoral alfa/genética , Adulto , Estudios de Casos y Controles , Comorbilidad , Femenino , Predisposición Genética a la Enfermedad/genética , Humanos , Hipertensión/genética , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Factores Sexuales , Fumar , Hemorragia Subaracnoidea/genética
9.
Mol Biol Rep ; 41(6): 3597-602, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24510388

RESUMEN

Homocysteine (Hcy) is known to be a prognostic marker for neurological, cardiovascular and cerebrovascular diseases and several other pathophysiological conditions. A sudden surge in Hcy can increase cardiovascular events. Hemodynamic modulations are known to be associated with individual's chronotype. Therefore, precise monitoring of Hcy is crucial for evaluating its impact on risk. The aim of the present study was to investigate the rhythmicity of Hcy under controlled dietary conditions and whether this rhythmicity is under the genetic control of circadian rhythm. Five subjects were selected from 200 Malayalam speaking healthy ethnic individuals who were screened for functionally critical variants of MTHFR and hCLOCK genes. MTHFR is the rate-limiting enzyme in the methionine cycle and critical for regulating Hcy levels while hCLOCK is a critical gene responsible in regulating the day and night cycles. Rhythmicity in Hcy levels were observed in all the subjects with a consensus on a morning nadir and an evening peak. Gender specific stratification of Hcy levels were observed among similar genotypes of MTHFR and hCLOCK genes. Variations from the conventional rhythmicity of Hcy were observed among similar genotypes of MTHFR and dissimilar hCLOCK genotypes. A reduced plasma Hcy in hCLOCK rs1801260 CC genotype individuals were observed in contrast to CT genotype individuals. The study tends to suggest that Hcy and body time are genetically interdependent and throws light on some of the previously unexplained reasons for variability in Hcy levels. A population specific variation of MTHFR and hCLOCK genes also highlights ethnicity specific risk management.


Asunto(s)
Proteínas CLOCK/metabolismo , Ritmo Circadiano/genética , Homocisteína/metabolismo , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Adulto , Proteínas CLOCK/genética , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/patología , Ritmo Circadiano/fisiología , Etnicidad/genética , Femenino , Genotipo , Homocisteína/genética , Humanos , Masculino
10.
Indian J Med Res ; 140(6): 736-43, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25758572

RESUMEN

BACKGROUND & OBJECTIVES: Schizophrenia, the debilitating neuropsychiatric disorder, is known to be heritable, involving complex genetic mechanisms. Several chromosomal regions associated with schizophrenia have been identified during the past; putative gene (s) in question, to be called the global signature for the pathophysiology of the disease, however, seems to evade us. The results obtained from the several population-wise association-non association studies have been diverse. w0 e therefore, undertook the present study on Tamil speaking population in south India to examine the association between the single nucleotide polymorphisms (SNPs) at the serotonin receptor gene (5HT2A) and the occurrence of the disease. METHODS: Blood samples collected from 266 cases and 272 controls were subjected to genotyping (PCR amplification of candidate SNPs, RFLP and sequencing). The data on the SNPs were subjected to statistical analysis for assessing the gene frequencies in both the cases and the controls. RESULTS: The study revealed significant association between the genotypic frequencies of the serotonin receptor polymorphism and schizophrenia. SNP analysis revealed that the frequencies of GG (30%, rs6311) and CC genotypes (32%, rs6313), were higher in patients (P<0.05) than in controls. The study also showed presence of G and C alleles in patients. s0 ignificant levels of linkage disequilibrium (LD) were found to exist between the genotype frequencies of rs6311 and rs6313. INTERPRETATION & CONCLUSIONS: This study indicated an association between the SNPs (rs6311 and rs6313) of the serotonin receptor 5HT2A and schizophrenia. HapMap analysis revealed that in its genotype distribution, the Tamil speaking population was different from several other populations across the world, signifying the importance of such ethnicity-based studies to improve our understanding of this complex disease.


Asunto(s)
Receptor de Serotonina 5-HT2A/genética , Esquizofrenia/genética , Serotonina/genética , Adulto , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , India , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Esquizofrenia/patología
11.
Neurol India ; 72(2): 384-387, 2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-38817175

RESUMEN

There are a few comprehensive genetic studies on autism spectrum disorders (ASD) in India. Children of multiple births are valuable for genomics studies of complex disorders such as ASD. We report whole-exome sequencing (WES) in a triplet family in which only one among the triplet has ASD. The objective of this study was to identify potential candidate genes for ASD. Exome DNA was enriched using a twist human customized core exome kit, and paired-end sequencing was performed. Proband-specific de novo variants included 150 single nucleotide polymorphisms (SNPs) and 74 indels. Thirteen SNPs were in exonic regions, 7 of them being missense variations. Seventeen variants were previously reported in ASD. Genes harboring variants have functions in the development and maintenance of the central nervous system and are enriched in biological processes involving cell adhesion. This is the first comprehensive genetic study of a monozygotic triplet in ASD.


Asunto(s)
Trastorno del Espectro Autista , Niño , Humanos , Trastorno del Espectro Autista/genética , Secuenciación del Exoma , Polimorfismo de Nucleótido Simple/genética , Trillizos/genética
12.
Front Psychiatry ; 15: 1297760, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38516266

RESUMEN

Schizophrenia is a complex condition with entwined genetic and epigenetic risk factors, posing a challenge to disentangle the intermixed pathological and therapeutic epigenetic signatures. To resolve this, we performed 850K methylome-wide and 700K genome-wide studies on the same set of schizophrenia patients by stratifying them into responders, non-responders, and drug-naïve patients. The key genes that signified the response were followed up using real-time gene expression studies to understand the effect of antipsychotics at the gene transcription level. The study primarily implicates hypermethylation in therapeutic response and hypomethylation in the drug-non-responsive state. Several differentially methylated sites and regions colocalized with the schizophrenia genome-wide association study (GWAS) risk genes and variants, supporting the convoluted gene-environment association. Gene ontology and protein-protein interaction (PPI) network analyses revealed distinct patterns that differentiated the treatment response from drug resistance. The study highlights the strong involvement of several processes related to nervous system development, cell adhesion, and signaling in the antipsychotic response. The ability of antipsychotic medications to alter the pathology by modulating gene expression or methylation patterns is evident from the general increase in the gene expression of response markers and histone modifiers and the decrease in class II human leukocyte antigen (HLA) genes following treatment with varying concentrations of medications like clozapine, olanzapine, risperidone, and haloperidol. The study indicates a directional overlap of methylation markers between pathogenesis and therapeutic response, thereby suggesting a careful distinction of methylation markers of pathogenesis from treatment response. In addition, there is a need to understand the trade-off between genetic and epigenetic observations. It is suggested that methylomic changes brought about by drugs need careful evaluation for their positive effects on pathogenesis, course of disease progression, symptom severity, side effects, and refractoriness.

13.
Seizure ; 115: 81-86, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38232648

RESUMEN

OBJECTIVE: We aimed to compare the electroclinical correlates of truncating and missense variants of SCN1A variants in children with Dravet syndrome (DS) and to determine phenotypic features in relation to variants identified and seizure outcomes. METHODS: A single center prospective study was carried out on a South Indian cohort. Patients below 18 years of age who met the clinical criteria for DS who had undergone genetic testing and completed a minimum of one year follow up were included. We compared the differences in clinical profile, seizure outcome, developmental characteristics and anti-seizure medication (ASM) responsiveness profiles between patients with missense and truncating variants. RESULTS: Out of a total of 3967 children with drug-resistant epilepsy during the period 2015-2021, 49 patients who fulfilled the inclusion criteria were studied. Thirty-seven had positive genetic tests, out of which 29 were SCN1A variants and 9 were other novel variants. The proportion of missense (14; 48.3%) and truncating SCN1A variants (15; 51.7%) was similar. A significant trend for developing multiple seizure types was noted among children with truncating variants (p = 0.035) and seizure freedom was more likely among children with missense variants (p = 0.042). All patients with truncating variants had ASM resistant epilepsy (p = 0.020). Developmental outcomes did not differ between the variant subtypes. CONCLUSION: Our results show that children harbouring missense variants demonstrated a significantly lower propensity for multiple seizure subtypes and a higher proportion with seizure freedom. However developmental implications appear to be independent of variant subtype.


Asunto(s)
Epilepsia Refractaria , Epilepsias Mioclónicas , Niño , Humanos , Estudios de Cohortes , Estudios Prospectivos , Epilepsias Mioclónicas/genética , Epilepsias Mioclónicas/tratamiento farmacológico , Canal de Sodio Activado por Voltaje NAV1.1/genética , Fenotipo , Convulsiones , Mutación/genética
14.
Pediatr Neurol ; 158: 113-123, 2024 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-39038432

RESUMEN

BACKGROUND: Autism spectrum disorder (ASD) is a childhood-onset complex neurodevelopmental disorder characterized by problems with communication and social interaction and restricted, repetitive, stereotyped behavior. The prevalence of ASD is one in 36 children. The genetic architecture of ASD is complex in spite of its high heritability. To identify the potential candidate genes of ASD, we carried out a comprehensive genetic study of monozygotic (MZ) twins concordant or discordant for ASD. METHODS: Five MZ twins and their parents were recruited for the study. Four of the twins were concordant, whereas one was discordant for ASD. Whole exome sequencing was conducted for the twins and their parents. The exome DNA was enriched using Twist Human Customized Core Exome Kit, and paired-end sequencing was performed on HiSeq system. RESULTS: We identified several rare and pathogenic variants (homozygous recessive, compound heterozygous, de novo) in ASD-affected individuals. CONCLUSION: We report novel variants in individuals diagnosed with ASD. Several of these genes are involved in brain-related functions and not previously reported in ASD. Intriguingly, some of the variants were observed in the genes involved in sensory perception (auditory [MYO15A, PLEC, CDH23, UBR3, GPSM2], olfactory [OR9K2], gustatory [TAS2R31], and visual [CDH23, UBR3]). This is the first comprehensive genetic study of MZ twins in an Indian population. Further validation is required to determine whether these variants are associated with ASD.

15.
Epilepsy Res ; 201: 107341, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38447235

RESUMEN

Genetic advances over the past decade have enhanced our understanding of the genetic landscape of childhood epilepsy. However a major challenge for clinicians ha been understanding the rationale and systematic approach towards interpretation of the clinical significance of variant(s) detected in their patients. As the clinical paradigm evolves from gene panels to whole exome or whole genome testing including rapid genome sequencing, the number of patients tested and variants identified per patient will only increase. Each step in the process of variant interpretation has limitations and there is no single criterion which enables the clinician to draw reliable conclusions on a causal relationship between the variant and disease without robust clinical phenotyping. Although many automated online analysis software tools are available, these carry a risk of misinterpretation. This guideline provides a pragmatic, real-world approach to variant interpretation for the child neurologist. The focus will be on ascertaining aspects such as variant frequency, subtype, inheritance pattern, structural and functional consequence with regard to genotype-phenotype correlations, while refraining from mere interpretation of the classification provided in a genetic test report. It will not replace the expert advice of colleagues in clinical genetics, however as genomic investigations become a first-line test for epilepsy, it is vital that neurologists and epileptologists are equipped to navigate this landscape.


Asunto(s)
Epilepsia , Neurólogos , Niño , Humanos , Pruebas Genéticas , Epilepsia/diagnóstico , Epilepsia/genética , Estudios de Asociación Genética , Secuenciación de Nucleótidos de Alto Rendimiento
16.
Seizure ; 115: 20-27, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38183824

RESUMEN

PURPOSE: Drug-resistant epilepsy is seen in patients with inborn errors of metabolism and metabolic dysfunction in neurons is crucial to brain disorders associated with psychomotor impairment. Diagnostic rates of metabolic causes of developmental and epileptic encephalopathy (DEE) using next generation sequencing have been rarely studied in literature. METHODS: A prospective hospital study was carried out in 384 children with DEE, who underwent genetic testing. Metabolic disorders were evaluated with biochemical blood/urine assays and when required CSF estimations performed. RESULTS: A total of 154 pathogenic/likely pathogenic variants in 384 children were identified. Out of 384 children, 89 were clinically suspected to have probable or possible metabolic disorders. Pathogenic/likely pathogenic variants in metabolic genes were identified in 39 out of 89 (43.8 %) and promising VUS in 28 (31.4 %). These included variants for progressive myoclonus epilepsies (21; 53.8 %), DEE with focal/multifocal seizures (8; 20.5 %), generalized epilepsy (5;12.8 %), early myoclonic encephalopathy (2; 5.1 %), LGS (1; 2.6 %) and West syndrome (2; 5.1 %). CONCLUSION: Our cohort demonstrates for the first time from the Indian subcontinent that identification of metabolic variants can guide investigations and has therapeutic implications in patients with variable DEE phenotypes. A high utility is noted with regard to diagnosis and prognostication, given the low yield of available biochemical tests, indicating cost-effectiveness of this approach.


Asunto(s)
Encefalopatías , Enfermedades Metabólicas , Espasmos Infantiles , Niño , Humanos , Estudios Prospectivos , Espasmos Infantiles/diagnóstico , Convulsiones/complicaciones , Encefalopatías/genética , Enfermedades Metabólicas/complicaciones
17.
Pharmacogenet Genomics ; 23(11): 605-10, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-24061200

RESUMEN

OBJECTIVE: Several antiepileptic drugs (AEDs) are known to target the GABA(A) receptor through positive allosteric modulation of the receptors, thereby enhancing GABA(A) receptor-mediated inhibition. The large diversity of GABA(A) receptors has been reported in the central nervous system; some of these have been implicated in epilepsy susceptibility and AED resistance, which we aimed to examine. MATERIALS AND METHODS: We investigated the association of single-nucleotide polymorphisms in GABA(A) receptor subunit subtype genes namely; rs2279020 (GABRA1), rs3219151 (GABRA6), rs2229944 (GABRB2), and rs211037 (GABRG2) with predisposition to epilepsy and AED resistance. This was assessed in three cohorts of ethnically matched South Indian ancestry: mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) (prototype of AED-resistant epilepsy syndrome), juvenile myoclonic epilepsy (prototype of AED-responsive epilepsy syndrome), and nonepilepsy controls. RESULTS: A significant allelic (P=0.0006, odds ratio=1.6, 95% confidence interval=1.22-2.08) and genotypic (P=0.001) association of a synonymous variant in GABRG2, rs211037 (Asn196Asn) was observed with epilepsy irrespective of its phenotype, that is, MTLE-HS or juvenile myoclonic epilepsy. However, this association was not retained in epilepsy patients with a history of febrile seizures. The GABA(A) receptor subunit subtype genes were not found to have any association with AED resistance. In-silico analysis indicated that rs211037 plays a significant role in the transcriptional regulation and splicing regulation. CONCLUSION: We could substantiate that among the GABA(A) receptor subunit gene cluster polymorphisms, the GABRG2, rs211037 predisposes susceptibility to epilepsy, irrespective of its phenotype, but not to AED resistance.


Asunto(s)
Anticonvulsivantes/uso terapéutico , Resistencia a Medicamentos/genética , Epilepsia/genética , Receptores de GABA-A/genética , Convulsiones Febriles/tratamiento farmacológico , Convulsiones Febriles/genética , Adolescente , Adulto , Estudios de Casos y Controles , Epilepsia del Lóbulo Temporal/tratamiento farmacológico , Epilepsia del Lóbulo Temporal/genética , Femenino , Predisposición Genética a la Enfermedad , Variación Genética , Genotipo , Hipocampo/patología , Humanos , India , Masculino , Epilepsia Mioclónica Juvenil/tratamiento farmacológico , Epilepsia Mioclónica Juvenil/genética , Fenotipo , Polimorfismo de Nucleótido Simple , Esclerosis , Adulto Joven
18.
Mol Biol Rep ; 40(10): 5869-74, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-24065528

RESUMEN

Intracranial aneurysm (IA) accounts for 85 % of haemorrhagic stroke and is mainly caused due to weakening of arterial wall. Lysyl oxidase (LOX) is a cuproenzyme involved in cross linking structural proteins collagen and elastin, thus providing structural stability to artery. Using a case-control study design, we tested the hypothesis whether the variants in LOX gene flanking the two LD block, can increase risk of aSAH among South Indian patients, either independently, or by interacting with other risk factors of the disease. SNPs were genotyped by fluorescence-based competitive allele-specific PCR (KASPar) chemistry. We selected 200 radiologically confirmed aneurysmal cases and 235 ethnically and age and gender matched controls from the Dravidian Malayalam speaking population of South India. We observed marked interethnic differences in the genotype distribution of LOX variants when compared to Japanese and African populations. However, there was no significant association with any of the LOX variants with IA. This study also could not observe any significant role of LOX polymorphisms in influencing IA either directly or indirectly through its confounding factors such as hypertension and gender in South Indian population.


Asunto(s)
Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Aneurisma Intracraneal/enzimología , Aneurisma Intracraneal/genética , Polimorfismo de Nucleótido Simple/genética , Proteína-Lisina 6-Oxidasa/genética , Estudios de Casos y Controles , Demografía , Femenino , Frecuencia de los Genes/genética , Humanos , India , Desequilibrio de Ligamiento/genética , Masculino , Persona de Mediana Edad
19.
Indian J Hum Genet ; 19(1): 58-64, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23901194

RESUMEN

BACKGROUND: Complex network of pro and anti-inflammatory cytokines are known to act in inflamed periodontal tissue. This study explores the distribution of interleukin (IL)-4 (+33 C/T) and IL-17F (7383A/G, 7488A/G) gene polymorphism in chronic and aggressive periodontitis subjects of Dravidian ethnicity. MATERIALS AND METHODS: This case control study consisted of 124 periodontitis individuals comprising of 63 chronic and 61 aggressive periodontitis subjects as cases, and control group consisted of 101 healthy subjects. All subjects were genotyped for IL-4 + 33C/T, IL-17F 7383A/G, 7488A/G by polymerase chain reaction amplification followed by TaqMan assay for IL-4 + 33C/T, restriction enzyme digestion and gel electrophoresis for IL-17F 7383A/G and sequencing for IL-17F 7488A/G. RESULTS: IL-4 + 33C/T was significantly associated with periodontitis (P < 0.05) at both allelic and genotypic level. In subgroup analysis also significant difference (P < 0.05) in allelic distribution between aggressive periodontitis and control group for loci IL-4 + 33C/T was noted. However, there was a lack of association between IL-17F 7383A/G and IL-17F 7488A/G with periodontitis and its sub-groups at both allelic and genotypic levels. CONCLUSIONS: In Malayalam speaking Dravidian population IL-4 + 33C/T loci appears to be an important risk factor for periodontal disease with a leaning towards aggressive periodontitis. The association between IL-17F at 7383A/G and 7488A/G loci with either chronic or an aggressive periodontitis could not be ascertained.

20.
Asian J Psychiatr ; 86: 103636, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37290243

RESUMEN

BACKGROUND: Schizophrenia is a complex neuropsychiatric disorder for which several etiopathological theories have been proposed, one of the prominent ones being immune dysfunction. Recent studies on yoga as an add-on therapy have shown improvement in negative symptoms, cognition, and quality of life in schizophrenia patients. However, the biological mechanism/s of action of yoga in schizophrenia are not clear. The current study was aimed at exploring the effects of long-term (6 months) add-on yoga therapy on the immune inflammatory pathway in schizophrenia patients. METHODS: Sixty schizophrenia patients were randomized to add-on yoga therapy (YT=30) and treatment-as-usual (TAU=30) groups of which 21 patients in YT and 20 in TAU group completed the study. Blood samples and clinical assessments were obtained at baseline and at the end of 6 months. The plasma levels of nine cytokines (IL-2, IL-4, IL-5, IL-10, IL-12(p70), IL-13, GM-CSF, IFN-γ, and TNF-α) were quantified using multiplex suspension array. The clinical assessments included SAPS, SANS, BPRS, PSS, CGI, SOFS and WHOQUOL-BREF. RESULTS: Patients in the yoga group showed significant reductions in plasma TNF-α (Z = 2.99, p = 0.003) and IL-5 levels (Z = 2.20, p = 0.03) and greater clinical improvements in SAPS, SANS, PSS, and SOFS scores as compared to TAU group. Further, plasma TNF-α levels exhibited a positive correlation with negative symptoms (rs =0.45, p = 0.02) and socio-occupational functioning (rs =0.61, p = 0.002) in the YT group. CONCLUSIONS: The findings of the study suggest that improvements in schizophrenia psychopathology with yoga interventions are associated with immuno-modulatory effects.


Asunto(s)
Antipsicóticos , Esquizofrenia , Yoga , Humanos , Yoga/psicología , Antipsicóticos/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Calidad de Vida , Interleucina-5/uso terapéutico , Factor de Necrosis Tumoral alfa , Resultado del Tratamiento
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