Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 4 de 4
Filtrar
Más filtros











Base de datos
Intervalo de año de publicación
1.
Mol Genet Genomics ; 298(3): 721-733, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-37020053

RESUMEN

DNA methylation may be involved in the development of osteosarcomas. Osteosarcomas commonly arise during the bone growth and remodeling in puberty, making it plausible to infer the involvement of epigenetic alterations in their development. As a highly studied epigenetic mechanism, we investigated DNA methylation and related genetic variants in 28 primary osteosarcomas aiming to identify deregulated driver alterations. Methylation and genomic data were obtained using the Illumina HM450K beadchips and the TruSight One sequencing panel, respectively. Aberrant DNA methylation was spread throughout the osteosarcomas genomes. We identified 3146 differentially methylated CpGs comparing osteosarcomas and bone tissue samples, with high methylation heterogeneity, global hypomethylation and focal hypermethylation at CpG islands. Differentially methylated regions (DMR) were detected in 585 loci (319 hypomethylated and 266 hypermethylated), mapped to the promoter regions of 350 genes. These DMR genes were enriched for biological processes related to skeletal system morphogenesis, proliferation, inflammatory response, and signal transduction. Both methylation and expression data were validated in independent groups of cases. Six tumor suppressor genes harbored deletions or promoter hypermethylation (DLEC1, GJB2, HIC1, MIR149, PAX6, and WNT5A), and four oncogenes presented gains or hypomethylation (ASPSCR1, NOTCH4, PRDM16, and RUNX3). Our analysis also revealed hypomethylation at 6p22, a region that contains several histone genes. Copy-number changes in DNMT3B (gain) and TET1 (loss), as well as overexpression of DNMT3B in osteosarcomas provide a possible explanation for the observed phenotype of CpG island hypermethylation. While the detected open-sea hypomethylation likely contributes to the well-known osteosarcoma genomic instability, enriched CpG island hypermethylation suggests an underlying mechanism possibly driven by overexpression of DNMT3B likely resulting in silencing of tumor suppressors and DNA repair genes.


Asunto(s)
Neoplasias Óseas , MicroARNs , Osteosarcoma , Humanos , Neoplasias Óseas/genética , Neoplasias Óseas/patología , Islas de CpG/genética , Metilación de ADN/genética , Epigénesis Genética , Oxigenasas de Función Mixta/genética , Osteosarcoma/genética , Osteosarcoma/patología , Regiones Promotoras Genéticas/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Supresoras de Tumor/genética , ADN (Citosina-5-)-Metiltransferasas/metabolismo
2.
Am J Med Genet A ; 191(2): 570-574, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36333968

RESUMEN

The causal link between variants in the SCAF4 gene and a syndromic form of intellectual disability (ID) was established in 2020 by Fliedner et al. Since then, no additional cases have been reported. We performed exome sequencing in a 16-year-old Brazilian male presenting with ID, epilepsy, behavioral problems, speech impairment, facial dysmorphisms, heart malformations, and obesity. A de novo pathogenic variant [SCAF4(NM_020706.2):c.374_375dup(p.Glu126LeufsTer20)] was identified. This is the second study reporting the involvement of SCAF4 in syndromic ID, and the description of the patient's clinical features contributes to defining the phenotypic spectrum of this recently described Mendelian disorder.


Asunto(s)
Epilepsia , Discapacidad Intelectual , Problema de Conducta , Humanos , Masculino , Adolescente , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Epilepsia/genética , Secuenciación del Exoma , Síndrome , Fenotipo , Factores de Empalme Serina-Arginina/genética
3.
Int J Obes (Lond) ; 46(9): 1582-1586, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35597848

RESUMEN

BACKGROUND: Syndromic obesity (SO) refers to obesity with additional phenotypes, including intellectual disability (ID)/developmental delay (DD), dysmorphic features, or organ-specific abnormalities. SO is rare, has high phenotypic variability, and frequently follows a monogenic pattern of inheritance. However, the genetic etiology of most cases of SO has not been elucidated. SUBJECTS AND METHODS: In this study, we investigated 20 SO patients by whole-exome sequencing (WES) trios to identify causal genetic variants. RESULTS: 4/20 patients had negative results for array comparative genomic hybridization (aCGH) analyses. In the remaining 15 patients, in addition to SNVs and indels, CNVs were also evaluated. Pathogenic/likely pathogenic (P/LP) SNVs/indels were detected in 6/20 patients (involving MED13L, AHDC1, EHMT1, MYT1L, GRIA3, and SETD1A), while two patients carried an inherited VUS. In addition, P/LP CNVs were observed in 3/15 patients (involving SATG2, KIAA0442, and MEIS2). CONCLUSIONS: All nine detected P/LP variants involved genes already known to lead to syndromic ID/DD; however, for only two genes (EHMT1 and MYT1L) is the link with obesity well established. This is the first study applying a comprehensive genomic investigation of an SO cohort, showing a high diagnostic yield (~47%). Additionally, our findings suggested that several known ID/DD genes may also predispose individuals to SO.


Asunto(s)
Discapacidades del Desarrollo , Discapacidad Intelectual , Niño , Hibridación Genómica Comparativa , Variaciones en el Número de Copia de ADN , Proteínas de Unión al ADN/genética , Discapacidades del Desarrollo/genética , N-Metiltransferasa de Histona-Lisina/genética , Humanos , Discapacidad Intelectual/genética , Obesidad/genética , Obesidad/patología
4.
Clin Genet ; 101(1): 134-141, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34664255

RESUMEN

Prediction of pathogenicity of rare copy number variations (CNVs), a genomic alteration known to contribute to the etiology of autism spectrum disorder (ASD), represents a serious limitation to interpreting genetic tests, particularly for genetic counseling purposes. Chromosomal microarray analysis (CMA) was conducted in a unique collection of 144 Brazilian individuals with ASD of strong European and African ancestries. Rare CNVs were detected in 39 patients: 41 of unknown significance (VUS), four pathogenic and one likely pathogenic CNVs (clinical yield of 4.1%; 5/122). Based on gene content and recurrence in three large cohorts [a Brazilian neurodevelopmental disorder cohort, the autism MSSNG cohort, and the Canadian-based Centre for Applied Genomics microarray database], this work strengthened the pathogenicity of 14 genes (FAT1, CAMK4, BIRC6, DPP6, CSMD1, CTNNA3, CDH8/CDH11, CDH13, OR1C1, CNTN6, CNTNAP4, FGF2 and PTPRN2) within 14 CNVs. Notably, enrichment of cell adhesion proteins to ASD etiology was identified (p < 0.05), highlighting the importance of these gene families in the etiology of ASD.


Asunto(s)
Alelos , Trastorno del Espectro Autista/diagnóstico , Trastorno del Espectro Autista/genética , Adhesión Celular/genética , Variaciones en el Número de Copia de ADN , Predisposición Genética a la Enfermedad , Adolescente , Adulto , Brasil , Niño , Preescolar , Mapeo Cromosómico , Hibridación Genómica Comparativa , Femenino , Estudios de Asociación Genética , Humanos , Lactante , Masculino , Fenotipo , Adulto Joven
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA