RESUMEN
BACKGROUND: Recent studies suggest that epigenetic factors may play an important role in the pathogenesis of Parkinson's disease (PD). In our previous work, we sequenced the exomes of sixteen patients from eight Chinese PD families using whole exome sequencing technology, consequently three patients from different pedigrees were found sharing the variant c.1460C > T (rs150689919) in the coding region of the Tet methyl cytosine dioxygenase 1 (TET1) gene. METHODS: In order to evaluate the possible association between sporadic PD and the single nucleotide polymorphism (SNP) rs150689919 in TET1, a case-control cohort study was conducted in 514 sporadic PD patients and 529 normal controls. Genotyping was determined by PCR and direct sequencing. Statistical significance was analyzed by the Chi-squared test. RESULTS: There was no statistical significance in TET1 rs150689919 genotype or allele frequencies between the PD cases and healthy controls, even after being stratified by gender and age at onset. CONCLUSIONS: Our findings suggest that rs150689919 in TET1 may not be associated with PD in Chinese population. However, due to the limited data in this study, replication studies in larger sample and other populations are required.
Asunto(s)
Pueblo Asiatico/etnología , Metilación de ADN/genética , Proteínas de Unión al ADN/genética , Predisposición Genética a la Enfermedad , Enfermedad de Parkinson/genética , Polimorfismo de Nucleótido Simple/genética , Proteínas Proto-Oncogénicas/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Pueblo Asiatico/genética , Distribución de Chi-Cuadrado , Niño , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Oxigenasas de Función Mixta , Adulto JovenRESUMEN
Introduced in 2009, whole-exome sequencing (WES) is a technology in which target capture methods are used to enrich sequences of coding regions of genes from fragmented total genomic DNA, which is followed by high-throughput sequencing of the captured fragments. As reported, WES has been successfully applied for discovering genes underlying several Mendelian diseases, especially autosomal recessive types. In this review, authors have summarized the main computational strategies which have been applied to identify novel autosomal recessive diseases genes using whole-exome data.
Asunto(s)
Exoma , Enfermedades Genéticas Congénitas/genética , Clonación Molecular , Genes Recesivos , Humanos , Análisis de Secuencia de ADNRESUMEN
Genetic heterogeneity is common in many Mendelian disorders such as hereditary spastic paraplegia (HSP), which makes the genetic diagnosis more complicated. The goal of this study was to investigate a Chinese family with recessive hereditary spastic paraplegia, of which causative mutations could not be identified using the conventional PCR-based direct sequencing. Next-generation sequencing of all the transcripts of whole genome exome, after on-array hybrid capture, was performed on two affected male subjects (the proband and his brother). A missense mutation (c.1661G>A, p.R554H) was identified in ABCD1. Subsequently, PCR-based direct sequencing of other family members revealed that the mutation was co-segregating with the disease, indicating that ABCD1 mutation was the pathogenic event for this family. Very long-chain fatty acids (VLCFA) assay in the two affected cases confirmed X-ALD. Our study suggests exome sequencing can be used not only to find a novel causative gene, but also to quickly identify mutations of known genes when the clinical elements are etiologically misleading.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Adrenoleucodistrofia/diagnóstico , Exoma/genética , Paraplejía Espástica Hereditaria/diagnóstico , Miembro 1 de la Subfamilia D de Transportador de Casetes de Unión al ATP , Adrenoleucodistrofia/genética , Adulto , Diagnóstico Diferencial , Femenino , Heterogeneidad Genética , Humanos , Masculino , Mutación Missense , Linaje , Análisis de Secuencia de ADN , Paraplejía Espástica Hereditaria/genéticaRESUMEN
BACKGROUND: Hereditary spastic paraplegia type 6 (SPG6) is caused by mutations in the NIPA1 gene, this is a rare cause of HSP, until now, all the affected individuals reported displayed "pure" spastic paraplegia. OBJECTIVES: To analyze the genotype/phenotype correlation of mutations so far described in NIPA1. METHODS: Eighty-six Chinese Han HSP patients were investigated for SPG6 mutations by direct sequencing of the NIPA1 gene. RESULTS: One heterozygous missense mutation c.316G>C/p.G106R was identified in a complicated form of ADHSP family with peripheral nerves disease, and SPG6 mutation in our sample accounted for 3.6% (1/28) of ADHSP families and 1.1% (1/86) of non-ARHSP patients who were negative for SPG4, SPG3A and SPG31 mutations. CONCLUSIONS: We report the first complicated case of SPG6 in the world by the presence of peripheral neuropathy, which extends the phenotype initially described.