Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 7 de 7
Filtrar
Más filtros

Banco de datos
País/Región como asunto
Tipo del documento
Intervalo de año de publicación
1.
Cleft Palate Craniofac J ; 59(11): 1329-1339, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-34787502

RESUMEN

BACKGROUND: Pierre Robin Sequence (PRS) affects approximately 1 per 8500 to 14000 new-borns worldwide. Although the clinical entity is well defined, the pathogenesis of PRS is debated. The present study aims to understand the contribution of genomic imbalances and genetic variants in patients clinically diagnosed of PRS. METHODOLOGY: A total of 7 independent patients with nonsyndromic PRS thoroughly evaluated by a medical geneticist at a tertiary care hospital, were included in the study. Blood samples were collected from these patients and their family members. Array CGH was performed on all 7 patients and their respective family members for detection of underlying cytogenetic defects. Whole exome sequencing (WES) was performed for 5 families to capture single nucleotide variants or small indels. RESULTS: Cytogenetic analyses did not detect any previously reported gross chromosomal aberrations for PRS in the patient cohort. However, copy number variations (CNVs) of size <1 Mb were detected in patients which may have implications in PRS. The present study provided evidence for the occurrence of de novo deletions at 7p14.1 locus in PRS patients: further validating the candidate loci susceptibility in oral clefts. WES data identified LOXL3 as candidate gene, carrying novel deleterious variant, which is suggestive of the role of point mutations in the pathogenesis of PRS. CONCLUSION: The present study offered considerable insight into the contribution of cytogenetic defects and novel point mutation in the etiology of nonsyndromic PRS. Studies comprising large number of cases are required to fully elucidate the genetic mechanisms underlying the PRS phenotype.


Asunto(s)
Variaciones en el Número de Copia de ADN , Síndrome de Pierre Robin , Aminoácido Oxidorreductasas/genética , Análisis Citogenético , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Mutación , Nucleótidos , Síndrome de Pierre Robin/diagnóstico , Síndrome de Pierre Robin/genética
2.
Neurogenetics ; 22(4): 271-285, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34333724

RESUMEN

Twelve patients from seven unrelated South Indian families with a limb-girdle muscular dystrophy-congenital myasthenic syndrome (LGMD/CMS) phenotype and recessive inheritance underwent deep clinical phenotyping, electrophysiological evaluation, muscle histopathology, and next-generation sequencing/Sanger sequencing-based identification of the genetic defect. Homozygosity mapping was performed using high-throughput genome-wide genotyping for mapping the mutation and to evaluate the founder effect. The age of disease onset among patients ranged from childhood to 40 years of age. The key clinical manifestations observed were progressive fatigable limb-girdle weakness, muscle hypertrophy/atrophy, and preferential weakness in a dystrophic pattern. The ages at last follow-up ranged from 30 to 64 years; nine were independently ambulant, two required assistance, and one was wheelchair-bound. Lower limb muscle MRI showed varying degrees of fat replacement in the glutei, hamstrings, anterior leg muscles, and medial gastrocnemius. All patients showed significant decrement on repetitive nerve stimulation (RNS). Muscle biopsy in 7 patients revealed varying degrees of dystrophic and neurogenic changes. Treatment with pyridostigmine and/or salbutamol resulted in variable improvement in 10 patients. Genetic analysis showed an identical homozygous GMPPB mutation c.1000G > A (p.Asp334Asn) in all affected patients. A region of homozygosity (6Mbp) was observed flanking the c.1000G > A change in carrier chromosomes. This study identifies c.1000G > A in GMPPB as a common founder mutation in an ethnic community of South Indian descent with milder yet variable degree of clinical presentation of GMPPB-associated LGMD-CMS.


Asunto(s)
Distrofia Muscular de Cinturas/genética , Distrofia Muscular de Cinturas/patología , Síndromes Miasténicos Congénitos/genética , Síndromes Miasténicos Congénitos/patología , Nucleotidiltransferasas/genética , Adulto , Niño , Femenino , Pruebas Genéticas/métodos , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Músculos/patología , Mutación/genética , Fenotipo
3.
Hum Mutat ; 41(11): 1833-1847, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32906206

RESUMEN

There have been concerted efforts toward cataloging rare and deleterious variants in different world populations using high-throughput genotyping and sequencing-based methods. The Indian population is underrepresented or its information with respect to clinically relevant variants is sparse in public data sets. The aim of this study was to estimate the burden of monogenic disease-causing variants in Indian populations. Toward this, we have assessed the frequency profile of monogenic phenotype-associated ClinVar variants. The study utilized a genotype data set (global screening array, Illumina) from 2795 individuals (multiple in-house genomics cohorts) representing diverse ethnic and geographically distinct Indian populations. Of the analyzed variants from Global Screening Array, ~9% were found to be informative and were either not known earlier or underrepresented in public databases in terms of their frequencies. These variants were linked to disorders, namely inborn errors of metabolism, monogenic diabetes, hereditary cancers, and various other hereditary conditions. We have also shown that our study cohort is genetically a better representative of the Indian population than its representation in the 1000 Genome Project (South Asians). We have created a database, ClinIndb, linked to the Leiden Open Variation Database, to help clinicians and researchers in diagnosis, counseling, and development of appropriate genetic screening tools relevant to the Indian populations and Indians living abroad.


Asunto(s)
Marcadores Genéticos , Genética de Población , Estudios de Cohortes , Etnicidad , Genómica , Genotipo , Humanos , India , Fenotipo
4.
Adv Genet (Hoboken) ; 3(2): 2100078, 2022 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-36618024

RESUMEN

Cerebellar ataxias (CAs) represent a group of autosomal dominant and recessive neurodegenerative disorders affecting cerebellum with or without spinal cord. Overall, CAs have preponderance for tandem nucleotide repeat expansions as an etiological factor (10 TREs explain nearly 30-40% of ataxia cohort globally). The experience of 10 years of common genetic ataxia subtypes for ≈5600 patients' referrals (Pan-India) received at a single center is shared herein. Frequencies (in %, n) of SCA types and FRDA in the sample cohort are observed as follows: SCA12 (8.6%, 490); SCA2 (8.5%, 482); SCA1 (4.8%, 272); SCA3 (2%, 113); SCA7 (0.5%, 28); SCA6 (0.1%, 05); SCA17 (0.1%, 05), and FRDA (2.2%, 127). A significant amount of variability in TRE lengths at each locus is observed, we noted presence of biallelic expansion, co-occurrence of SCA-subtypes, and the presence of premutable normal alleles. The frequency of mutated GAA-FRDA allele in healthy controls is 1/158 (0.63%), thus an expected FRDA prevalence of 1:100 000 persons. The data of this study are relevant not only for clinical decision making but also for guidance in direction of genetic investigations, transancestral comparison of genotypes, and lastly provide insight for policy decision for the consideration of SCAs under rare disease category.

5.
Neurobiol Aging ; 88: 156.e1-156.e9, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32035847

RESUMEN

Hexanucleotide repeat expansion in C9orf72 is defined as a major causative factor for familial amyotrophic lateral sclerosis (ALS). The mutation frequency varies dramatically among populations of different ethnicity; however, in most cases, C9orf72 mutant has been described on a common founder haplotype. We assessed its frequency in a study cohort involving 593 clinically and electrophysiologically defined ALS cases. We also investigated the presence of reported Finnish haplotype among the mutation carriers. The identified common haplotype region was further screened in 192 (carrying 2-6 G4C2 repeats) and 96 (≥7 repeats) control chromosomes. The G4C2 expansion was observed in 3.2% (19/593) of total cases where 9/19 (47.4%) positive cases belonged to the eastern region of India. Haplotype analysis revealed 11 G4C2-Ex carriers shared the common haplotype (haplo-A) background spanning a region of ∼90 kbp (rs895021-rs11789520) including rs3849942 (a well-known global at-risk loci with T allele for G4C2 expansion). The other 3 G4C2-Ex cases had a different haplotype (haplo-B) with core difference from haplo-A at G4C2-Ex flanking 31 kbp region between rs3849942 and rs11789520 SNPs (allele 'C' of rs3849942 which is a nonrisk allele). Out of other five G4C2-cases, four carried the risk allele T of rs3849942 while one harbored the non-risk allele. This study establishes the prevalence of C9orf72 expansion in Indian ALS cases providing further evidence for geographical predilection. The global core risk haplotype predominated C9orf72 expansion-positive ALS cases, yet the existence of a different haplotype suggests a second lineage (haplo B), which may have been derived from the Finnish core haplotype or may imply a unique haplotype among Asians. The association of risk haplotype with normal intermediate C9orf72 alleles reinforced its role in conferring instability to the C9orf72-G4C2 region. We thus present an effective support to interpret future burden of ALS cases in India.


Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Proteína C9orf72/genética , Expansión de las Repeticiones de ADN/genética , Estudios de Asociación Genética , Mutación , Alelos , Estudios de Cohortes , Haplotipos , Heterocigoto , India , Riesgo
6.
J Comp Neurol ; 452(4): 324-33, 2002 Oct 28.
Artículo en Inglés | MEDLINE | ID: mdl-12355416

RESUMEN

Most excitatory intrahippocampal pathways are characterized by significant, highly ordered projections into the long, or septotemporal, hippocampal axis. However, the mossy fiber system, the excitatory projection by which the dentate gyrus projects to hippocampal area CA3, is considered an exception, being organized to innervate exclusively transversely oriented cortical layers of the hippocampus. In the present study, the anatomy of the rat mossy fiber system was investigated using axonal tracing techniques, with an emphasis on determining its projection pattern into the long hippocampal axis. To this end, we used dual ipsilateral retrograde tracer injections to determine whether individual granule cells extend divergent axon collaterals to septotemporally distinct levels of hippocampal area CA3. We combined this technique with the fluorescent immunohistochemical detection of 5-bromo-2'-deoxyuridine (BrdU), a marker of granule cell precursors and their progeny, to address whether the divergence of mossy fiber collaterals within area CA3 might by related to ontogenic gradients in granule cell genesis. We observed single granule neurons that had retrogradely transported both tracers, indicating that they had axon collaterals passing through or terminating within the distinct levels of area CA3 into which tracer had been injected. By using BrdU labeling, we identified divergent granule neurons that were produced during embryonic and postnatal development. We observed no adult-generated granule neurons with significantly diverging mossy fiber collaterals. However, many fewer cells were labeled with BrdU in adult-exposed animals. Because of this smaller sample, we cannot rule out the possibility that small numbers of divergent adult-generated granule cells exist. We conclude that a proportion of the hippocampal mossy fiber projection extends septotemporally divergent axon collaterals to hippocampal area CA3.


Asunto(s)
Axones/fisiología , Hipocampo/citología , Hipocampo/embriología , Neuronas/ultraestructura , Ratas Sprague-Dawley/embriología , Animales , Antimetabolitos , Biomarcadores , Bromodesoxiuridina , División Celular , Giro Dentado/citología , Giro Dentado/embriología , Femenino , Inmunohistoquímica , Masculino , Fibras Musgosas del Hipocampo/ultraestructura , Vías Nerviosas , Embarazo , Ratas
7.
Proc Natl Acad Sci U S A ; 103(45): 17007-12, 2006 Nov 07.
Artículo en Inglés | MEDLINE | ID: mdl-17065322

RESUMEN

Central thalamic electrical stimulation has been proposed as a method for remediation of acquired cognitive disability. Long-standing experimental and clinical observations indicate a key role for neurons within the central thalamus in maintaining the alert waking state and facilitating attended behaviors. Here, we show that continuous high frequency (100 Hz) electrical stimulation of the central thalamus generates widespread cortical activation of c-fos across all cortical layers and a selective pattern of regulation of zif268 within the supragranular, granular, and infragranular cortical laminae. Significant elevation of both immediate early genes also is seen in the dentate gyrus of the hippocampus. Use of the same stimulation parameters is shown to facilitate untrained goal-directed seeking behavior and object recognition memory in rodents. An overall increase of exploratory motor behaviors and grooming activity also is observed, consistent with a global increase in arousal. Taken together, these studies indicate that electrical stimulation of the central thalamus may enhance cognitive performance through neocortical and hippocampal neuronal activation and specific regulation of gene expression.


Asunto(s)
Cognición/fisiología , Terapia por Estimulación Eléctrica/métodos , Animales , Trastornos del Conocimiento/psicología , Trastornos del Conocimiento/terapia , Proteína 1 de la Respuesta de Crecimiento Precoz/genética , Proteína 1 de la Respuesta de Crecimiento Precoz/metabolismo , Expresión Génica , Genes fos , Inmunohistoquímica , Masculino , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Sprague-Dawley , Tálamo/anatomía & histología , Tálamo/fisiología
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA