Prevalence of the GJB2 mutations and the del(GJB6-D13S1830) mutation in Brazilian patients with deafness

Mutations in the GJB2 gene are the most common cause of sensorineural non-syndromic deafness in different populations. One specific mutation, 35delG, has accounted for the majority of the mutations detected in the GJB2 gene in many countries. The aim of this study was to determine the prevalence of GJB2 mutations and the del(GJB6-D13S1830) mutation in non-syndromic deaf Brazilians. The 33 unrelated probands were examined by clinical evaluation to exclude syndromic forms of deafness. Mutation analysis in the GJB2 gene and the testing for the del(GJB6-Dl3S1830) were performed in both the patients and their family members. The 35delG mutation was found in nine of the probands or in 14 of the mutated alleles. The V371 mutation and the del(GJB6-D13S1830) mutation were also found in two patients, both are compound heterozygote with 35delG mutation. These findings strengthen the importance of genetic diagnosis, providing early treatment, and genetic counseling of deaf patients. (C) 2004 Elsevier B.V. All rights reserved.19641671879

The association between pro- and anti-inflammatory cytokine polymorphisms and periventricular leukomalacia in newborns with hypoxic-ischemic encephalopathy

Marta Lúcia Gabriel,1 Fernanda Braojos Braga,1 Mariana Rodero Cardoso,1 Ana Cláudia Lopes,2 Vânia Belintani Piatto,2 Antônio Soares Souza1 1Radiology Department, 2Morphology Department, São José do Rio Preto Medical School, FAMERP, São Paulo, BrazilBackground: Periventricular leukomalacia (PVL) is a frequent consequence of hypoxic-ischemic injury. Functional cytokine gene variants that result in altered production of inflammatory (tumor necrosis factor-alpha [TNF-α] and interleukin-1beta [IL-1β]) or anti-inflammatory (interleukin-10 [IL-10]) cytokines may modify disease processes, including PVL.Objective: The aim of this study was to evaluate if there is a relationship between the two proinflammatory polymorphisms (TNF-σ-1031T/C and IL-1 β-511C/T) and the anti-inflammatory polymorphism IL-10-1082G/A and PVL risk in Brazilian newborns with and without this injury.Materials and methods: A cross-sectional case-control study performed at the Neonatal Intensive Care Unit of the Children's Hospital and Maternity of the São José do Rio Preto Medical School (FAMERP). Fifty preterm and term newborns were examined as index cases and 50 term newborns as controls, of both sexes for both groups. DNA was extracted from peripheral blood leukocytes, and the sites that encompassed the three polymorphisms were amplified by polymerase chain reaction-restriction fragment length polymorphism.Results: Gestational age ranged from 25 to 39 weeks, in the case group, and in the control group it ranged from 38 to 42.5 weeks (P<0.0001). Statistically significant association was found between TNF-α-1031T/C high expression genotype TC (odds ratio [OR], 2.495; 95% confidence interval [CI], 1.10–5.63; P=0.043) as well as between genotypes (TC + CC) (OR, 2.471; 95% CI, 1.10–5.55; P=0.044) and risk of PVL. Statistically significant association was found between IL-1β-511C/T high expression genotypes (CT + TT) (OR, 23.120; 95% CI, 1.31–409.4; P=0.003) and risk of PVL. Statistically significant association between IL-10-1082G/A high expression genotype GG (OR, 0.07407; 95% CI, 0.02–0.34; P<0.0001) as well as between IL-10-1082G high expression allele (OR, 0.5098; 95% CI, 0.29–0.91; P=0,030) and PVL reduced risk was observed. There was a statistically significant association between TC/CT/GA genotype combination and the risk of PVL (OR, 6.469; 95% CI, 2.00–20.92; P=0.001).Conclusion: There is evidence of an association between the polymorphisms TNF-α-1031T/C, IL-1β-511C/T, and IL-10-1082G/A and PVL risk in this Brazilian newborn population studied.Keywords: leukomalacia periventricular, tumor necrosis factor-alpha, interleukin-10, interleukin-1beta, polymorphism single nucleotid

Investigação genética da surdez hereditária: mutação do gene da Conexina 26 Genetic investigation of hereditary deafness: connexin 26 gene mutation

Nos últimos anos houve grande progresso na localização de genes associados à deficiência auditiva hereditária, possibilitando diagnósticos cada vez mais precisos e precoces. Mutações no gene da Conexina 26 (GJB2 - Cx26) causam deficiência auditiva. Pela facilidade e benefício do rastreamento de mutações no gene GJB2, o teste genético está se tornando um importante recurso na saúde pública. O objetivo foi realizar pesquisa bibliográfica sobre a mutação do gene da Conexina 26 e sua influência na audição. Foi realizado um levantamento bibliográfico por meio de busca eletrônica utilizando os descritores: perda auditiva, genética, triagem genética, Conexina 26, nas bases de dados MEDLINE, SciELO e LILACS, desde a década de 90 até os dias atuais. Concluiu-se que a mutação 35delG da Conexina 26 está potencialmente vinculada a alguns casos de perda auditiva não esclarecida. A pesquisa desta mutação poderia ser incluída na bateria de exames de investigação etiológica da surdez indeterminada, uma vez que esclarece a etiologia de alguns casos e a sua identificação possibilita o aconselhamento genético.<br>In the last few years, great progress has been made in the search for genes associated to hereditary hearing impairment, allowing more precise and earlier diagnosis. Connexin 26 gene mutations (GJB2 - Cx26) cause hearing impairment. Due to the easiness and benefits of the screening of mutations on the gene GJB2, genetic testing is becoming an important resource in public health. The aim of the present study was to conduct a literature research about the mutation of the Connexin 26 gene and its influence in hearing. It was carried out a literature review through electronic search using the keywords: hearing loss, genetics, genetic screening, and Connexin 26, at the databases MEDLINE, SciELO and LILACS, from the 90s to the present days. The results indicate that the 35delG mutation of Connexin 26 is potentially associated to some cases of hearing loss that were not justified. The research regarding this mutation could be included in the battery of tests for etiologic investigation of undetermined deafness, possibly elucidating the etiology of some cases and allowing genetic counseling

Homozygosity mapping in a family presenting with schizophrenia, epilepsy and hearing impairment

Homozygosity mapping within consanguineous families is a powerful method of localising genes for autosomal recessive disease. We investigated a family from Punjab, Pakistan, a region where consanguineous marriages are frequent. The parents have no detectable clinical disorders. However, five out of six children present with schizophrenia, epilepsy or hearing impairment either alone or in combination. This unusual phenotype in several offspring of first cousins is strongly suggestive of a rare, Mendelian recessive disorder. Two genome-wide scans initially using low-density microsatellites, and subsequently high-density SNP markers were used to map homozygous-by-descent regions in affected individuals. Candidate genes within these loci were subsequently screened for mutations. Homozygosity analysis and inbreeding coefficients were investigated to give an estimate of consanguinity. Two putative disease loci were mapped to 22q12.3–q13.3 and 2p24.3. The candidate locus on chromosome 2p24 overlaps with a deafness locus, DFNB47, linked to autosomal recessive hearing impairment, while positive findings reported for affective psychosis and schizophrenia cluster in a region of 4–5 cM on 22q13.1 within our second candidate locus. Sequence analysis of three candidate genes (KCNF1 (2p); ATF4, CACNG2 (22q)) did not reveal any exonic mutations. Inbreeding coefficients calculated for each family member support a very high degree of ancestral and recent inbreeding. The screening of other candidate genes located within these newly identified disease intervals on Chr2p24.3 and 22q12.3-q13.3 may lead to the discovery of causative variants, and consequent disrupted molecular pathways associated with this rare phenotype