RESUMEN
Technological innovation related to the advent and development of the Next-Generation Sequencing (NGS) has provided significant advances in the diagnosis of disorders with genetic and phenotypic variability, such as neurodegenerative diseases. However, the interpretation of NGS data often remains challenging, although advanced prediction tools have contributed to primarily assess the impact of some missense variants. Here, we report a patient with Parkinson's disease (PD) and a family history of disease, in which a panel of 29 disease-causing or risk genes for PD were analyzed. We identified a new missense variant in the SNCA gene. Although this variant might be associated with PD in this family, it has been currently classified as a "Variant of Unknown Significance" because of the lack of segregation with disease. Indeed, we subsequently found the same mutation in an unaffected sister. Nevertheless, this finding may help clinicians and researchers in questioning the causative role of genetic variants within the daily clinical and diagnostic settings.
Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/genética , alfa-Sinucleína/genética , Predisposición Genética a la Enfermedad , Humanos , Mutación Missense , LinajeRESUMEN
Neurofibromatosis type 1 (NF1) is caused by mutations of the NF1 gene and is one of the most common human autosomal dominant disorders. The patient shows different signs on the skin and other organs from early childhood. The best known are six or more café au lait spots, axillary or inguinal freckling, increased risk of developing benign nerve sheath tumours and plexiform neurofibromas. Mutation detection is complex, due to the large gene size, the large variety of mutations and the presence of pseudogenes. Using Ion Torrent PGM™ Platform, 73 mutations were identified in 79 NF1 Italian patients, 51% of which turned out to be novel mutations. Pathogenic status of each variant was classified using "American College of Medical Genetics and Genomics" guidelines criteria, thus enabling the classification of 96% of the variants identified as being pathogenic. The use of Next Generation Sequencing has proven to be effective as for costs, and time for analysis, and it allowed us to identify a patient with NF1 mosaicism. Furthermore, we designed a new approach aimed to quantify the mosaicism percentage using electropherogram of capillary electrophoresis performed on Sanger method.
Asunto(s)
Manchas Café con Leche/genética , Neurofibromatosis 1/genética , Neurofibromina 1/genética , Anomalías Cutáneas/genética , Adolescente , Adulto , Manchas Café con Leche/patología , Niño , Preescolar , Análisis Mutacional de ADN , Femenino , Humanos , Lactante , Italia , Masculino , Persona de Mediana Edad , Mosaicismo , Mutación , Neurofibromatosis 1/patología , Análisis de Secuencia de ADN , Anomalías Cutáneas/patologíaRESUMEN
Down's syndrome (DS) is the most frequent genetic cause of intellectual disability and is a chromosomal abnormality of chromosome 21 trisomy. The pericentrin gene (PCNT) has sequenced in 21q22.3 inside of the minimal critical region for Down's syndrome. Alterations of PCNT gene are associated with dwarfism, cardiomyopathy and other pathologies. In this study, we have evaluated the possible differential expression of PCNT mRNA, by qRT-PCR, in peripheral blood leukocytes of DS subjects compared with the normal population. In the present case-control study, PCNT gene expression was increased by 72.72% in 16 out 22 DS samples compared with normal subjects. Our data suggest that changes in the expression levels of PCNT in DS subjects may be involved into the molecular mechanism of Down's syndrome.
Asunto(s)
Antígenos/genética , Síndrome de Down/genética , Adulto , Estudios de Casos y Controles , Femenino , Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , ARN Mensajero/metabolismo , Adulto JovenAsunto(s)
Síndrome de Down/genética , Regulación de la Expresión Génica , Leucocitos/metabolismo , Proteínas Nucleares/genética , Proteínas Supresoras de Tumor/genética , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas Nucleares/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Adulto JovenAsunto(s)
Antígenos/genética , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Cromosómicas no Histona/genética , Síndrome de Down/genética , Perfilación de la Expresión Génica , Cinesinas/genética , Leucocitos/metabolismo , Receptores Adrenérgicos beta 2/genética , Antígenos/metabolismo , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Cromosomas Humanos Par 21/genética , Humanos , Cinesinas/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Receptores Adrenérgicos beta 2/metabolismo , Reproducibilidad de los Resultados , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Regulación hacia Arriba/genéticaRESUMEN
SOX-3 is a transcription factor expressed throughout the developing central nervous system and is involved in maintenance of pluripotency in self-renewing stem cells, specification events, lineage progression, and terminal differentiation. An association between growth hormone deficiency, mental retardation, and Sox-3 mutations in humans was previously reported. The occurrence of abnormalities affecting the polyalanine tract of the Sox-3 gene was determined in a group of 77 unrelated mentally retarded patients without a definite genetic diagnosis and in 84 control subjects. A new SOX-3 polyalanine tract deletion was identified in a mentally impaired boy, in his mother (homozygous), and in 2 healthy brothers of the proband. This new mutation does not segregate with mental retardation.
Asunto(s)
Proteínas de Unión al ADN/genética , Proteínas del Grupo de Alta Movilidad/genética , Discapacidad Intelectual/genética , Péptidos , Eliminación de Secuencia , Factores de Transcripción/genética , Adolescente , Adulto , Anciano , Secuencia de Bases , Niño , Preescolar , Femenino , Homocigoto , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Valores de Referencia , Factores de Transcripción SOXB1RESUMEN
The cell division cycle 2 (CDC2) gene is a candidate susceptibility gene for Alzheimer's disease (AD). We investigated the CDC2 genotype, and allele and haplotype frequencies in AD patients and matched controls, distinguishing between apolipoprotein E (APOE) epsilon4 allele carriers and non-carriers. APOE epsilon4 is an established predictor of AD risk. APOE and CDC2 genotypes were examined in 109 sporadic AD patients and in 110 healthy age- and sex-matched controls from Sicily. The epsilon4 allele of APOE was predictive of AD risk in our study group (odds ratio: 5.37, 95% CI 2.77-10.41; P<0.0001). Genotype and allele frequencies of the three tested CDC2 polymorphisms (Ex6+7I/D, Ex7-15 G>A, Ex7-14 T>A) were not significantly different between AD patients and controls. However, a significant different distribution of a specific CDC2 haplotype (I-G-T) was found between AD patients and controls when analyzing APOE epsilon4-positive subjects (P=0.0288). Moreover, the combined presence of the I-G-T haplotype and the epsilon4 allele almost doubled the risk of AD (odds ratio: 10.09, 95% CI 3.88-26.25; P<0.0001) compared to carriers of epsilon4 alone. This study suggests that the I-G-T haplotype of the CDC2 gene increases the risk of AD in APOE epsilon4 carriers.