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PURPOSE: Autosomal recessive nonsyndromic deafness (ARNSD) is characterized by a high degree of genetic heterogeneity, with reported mutations in 58 different genes. This study was designed to detect deafness-causing variants in a multiethnic cohort with ARNSD by using whole-exome sequencing (WES). METHODS: After excluding mutations in the most common gene, GJB2, we performed WES in 160 multiplex families with ARNSD from Turkey, Iran, Mexico, Ecuador, and Puerto Rico to screen for mutations in all known ARNSD genes. RESULTS: We detected ARNSD-causing variants in 90 (56%) families, 54% of which had not been previously reported. Identified mutations were located in 31 known ARNSD genes. The most common genes with mutations were MYO15A (13%), MYO7A (11%), SLC26A4 (10%), TMPRSS3 (9%), TMC1 (8%), ILDR1 (6%), and CDH23 (4%). Nine mutations were detected in multiple families with shared haplotypes, suggesting founder effects. CONCLUSION: We report on a large multiethnic cohort with ARNSD in which comprehensive analysis of all known ARNSD genes identifies causative DNA variants in 56% of the families. In the remaining families, WES allows us to search for causative variants in novel genes, thus improving our ability to explain the underlying etiology in more families.Genet Med 18 4, 364-371.
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Surdez/diagnóstico , Surdez/genética , Exoma , Genes Recessivos , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/genética , Sequenciamento de Nucleotídeos em Larga Escala , Alelos , Estudos de Coortes , Etnicidade/genética , Genótipo , Humanos , MutaçãoRESUMO
Atherothrombosis is the cornerstone of cardiovascular diseases and the primary cause of death worldwide. Genetic contribution to disturbances in lipid metabolism, coagulation, inflammation and oxidative stress increase the susceptibility to its development and progression. Given its multifactorial nature, the multiloci studies have been proposed as potential predictors of susceptibility. A cross-sectional study was conducted to explore the contribution of nine genes involved in oxidative stress, inflammatory and thrombotic processes in 204 subjects with atherothrombosis matched by age and gender with a healthy group (n = 204). To evaluate the possibility of spurious associations owing to the Mexican population genetic heterogeneity as well as its ancestral origins, 300 unrelated mestizo individuals and 329 Native Americans were also included. ALOX5, LPA, MMP9 and TPO gene polymorphisms, as well as their multiallelic combinations, were twice to four times more frequent in those individuals with clinical manifestations of atherothrombosis than in the healthy group. Once adjusting for population stratification was done, these differences remained. Our results add further evidence on the contribution of ALOX5, LPA, MMP9 and TPO polymorphisms to atherothrombosis development in the middle-aged group, emphasizing the multiethnic studies in search of gene risk polymorphisms.
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[This corrects the article DOI: 10.1098/rsos.190775.].
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OBJECTIVE: The aim of this study was to elucidate the involvement of mutations in three relatively common deafness genes in Mexican individuals with non-syndromic hearing loss. METHODS: We sequenced GJB2 for mutations, screened for two deletions involving GJB6, del(GJB6-D13S1830) and del(GJB6-D13S1854), and for the m.1555A>G mutation in the MTRNR1 gene in 76 (71 simplex and 5 multiplex) unrelated Mexican probands with prelingual non-syndromic hearing loss. Samples were obtained from the Department of Genetics at Instituto Nacional de Rehabilitacion in Mexico City. RESULTS: Eight previously reported pathogenic variants and two polymorphic variants in GJB2 were identified. The two screened GJB6 deletions and the m.1555A>G mutation were not detected. Eight cases (10.6%) were found to have bi-allelic mutations in GJB2 and six (7.9%) were found to have a monoallelic GJB2 mutation. Of the six monoallelic mutations, one (p.R184Q) was a previously reported autosomal dominant variant. The most frequent pathological allele detected in this population was the c.35delG mutation in the GJB2 gene. The p.V27I polymorphic variant was also detected, with an allele frequency of 0.24. All eight probands with GJB2 mutations had symmetric profound deafness, whereas patients without GJB2 mutations had moderate, severe or profound hearing loss. CONCLUSIONS: This study shows that GJB2 mutations are an important cause of prelingual deafness in the Mexican population.
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Conexinas/genética , Perda Auditiva/genética , Mutação , Conexina 26 , Conexina 30 , Surdez/genética , Deleção de Genes , Frequência do Gene , Heterozigoto , Humanos , México , Polimorfismo GenéticoRESUMO
Capillary electrophoresis (CE) may replace many conventional clinical laboratory methods, such as electrophoresis, Southern blotting, sequencing and HPLC (High-performance liquid chromatography). It is an ideal technique due to analytical speed, the possibility of handling great amount of samples, its capacity to separate small molecules according to their size, charge, hydrophobic and stereo-specificity its good reproducibility the use of small amounts of sample and reagents, its low costs and easy handling. The diagnosis of hereditary diseases or the predisposition to polygenic diseases related to specific mutations or polymorphisms can be carried out with this method. In clinical laboratories, this technique is being used for the analysis of several substrates present in urine or serum and for the diagnosis of some infectious agents. It is also a firsthand tool in forensic medicine for human identification and anthropology.
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Eletroforese Capilar/métodos , Genética Forense/métodos , Humanos , Técnicas de Diagnóstico Molecular/métodosRESUMO
Charcot-Marie-Tooth (CMT) disease is the most common inherited disorder of the human peripheral nerve, with an estimated overall prevalence of 17-40/10 000 [1]. The typical phenotype presents peroneal muscular atrophy and pes cavus [2]. CMT is usually divided into two large types, about two-thirds of the patients have CMT type 1 (CMT1), that affects the layer of myelin (demyelination). In type 2 (CMT2) the nerve fibers are affected (axonal). CMT diseases have autosomal dominant, autosomal recessive, and X-linked inheritance [1]. The most frequent subtype is 1A (CMT1A) with autosomal dominant transmission, secondary in most cases to a tandem duplication of a 1.5 Mb DNA fragment on chromosome 17p11.2-p12 [4-7]. In this region, the codification of the peripheral myelin protein 22 (PMP22) takes place. The severity of the disease varies among patients, even within the same family, from almost no symptoms to severe foot-drop and sensory loss. The PMP22 gene has four exons and is regulated by two promoters located toward the extreme 5'. The origin of the duplication that causes the disease is an uneven exchange of the chromatids during the meiosis. This unequal recombination occurs between two regions that limit the PMP22 gene, described as REP places of 24 kb, proximal and distal [3, 4].