Investigation of 15q11-q13, 16p11.2 and 22q13 CNVs in Autism Spectrum Disorder Brazilian Individuals with and without Epilepsy

Copy number variations (CNVs) are an important cause of ASD and those located at 15q11-q13, 16p11.2 and 22q13 have been reported as the most frequent. These CNVs exhibit variable clinical expressivity and those at 15q11-q13 and 16p11.2 also show incomplete penetrance. In the present work, through multiplex ligation-dependent probe amplification (MLPA) analysis of 531 ethnically admixed ASD-affected Brazilian individuals, we found that the combined prevalence of the 15q11-q13, 16p11.2 and 22q13 CNVs is 2.1% (11/531). Parental origin could be determined in 8 of the affected individuals, and revealed that 4 of the CNVs represent de novo events. Based on CNV prediction analysis from genome-wide SNP arrays, the size of those CNVs ranged from 206 kb to 2.27 Mb and those at 15q11-q13 were limited to the 15q13.3 region. In addition, this analysis also revealed 6 additional CNVs in 5 out of 11 affected individuals. Finally, we observed that the combined prevalence of CNVs at 15q13.3 and 22q13 in ASD-affected individuals with epilepsy (6.4%) was higher than that in ASD-affected individuals without epilepsy (1.3%; p<0.014). Therefore, our data show that the prevalence of CNVs at 15q13.3, 16p11.2 and 22q13 in Brazilian ASD-affected individuals is comparable to that estimated for ASD-affected individuals of pure or predominant European ancestry. Also, it suggests that the likelihood of a greater number of positive MLPA results might be found for the 15q13.3 and 22q13 regions by prioritizing ASD-affected individuals with epilepsy.Support was provided by FAPESP-INCT - grant number: 2008/57899-7; FAPESP-CEPID - grant number: 2013/08028-1; CNPq [http://www.fapesp.br/]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

A importância do gene p53 na carcinogênese humana The importance of the p53 gene in human carcinogenesis

Existem várias razões que justificam o título de "guardião do genoma" do gene P53. Seu envolvimento, direto ou indireto, tem sido observado na etiopatogenia de praticamente todas as neoplasias humanas, incluindo as leucemias e linfomas. Conhecer seus mecanismos de ação é fundamental para compreender os aspectos moleculares da carcinogênese. O presente trabalho apresenta uma revisão sobre as características deste gene e sua importância no diagnóstico, prognóstico e terapêutica, o que faz dele um alvo em potencial das estratégias de terapia gênica.<br>There are several reasons which justify the name of 'guardian of the genome' given to the P53 gene. Its involvement either directly or indirectly has been observed in the pathology of practically all human neoplasias, including leukemia and lymphomas. Knowledge of its mechanisms of action is fundamental to understand molecular aspects of carcinogenesis. This work presents a revision of the characteristics of this gene and its importance in the diagnosis, prognosis and treatment and why this makes it a potential target for gene therapy strategies

Diagnóstico de hemoglobinopatias em recém-nascidos do Hospital de Base de São José do Rio Preto-SP

The neonatal period is considered the most effective for the screening of hemoglobinopathies. This allows prophylaxis and prevention, improving the patient's survival and guidance of parents and heterozygote carriers. The present work aims at the early detection of abnormal hemoglobins, the establishment of standard analysis and to examine the viability of the prevention program. Blood samples were collected by heel stick and from blood cord of children born in the Hospital de Base São José do Rio Preto, from April 1998 to November 1999. Electrophoresis and cytological, biochemical, cromatographic analyses were made for abnormal hemoglobin characterization. A total of 1,478 neonatal blood samples were analyzed in which 14.62% presented with hemoglobins alterations: 3.32% had Hb S; 0.61% had Hb C; 7.44% were suggestive of alpha thalassemia; 1.55% were suggestive of beta thalassemia, and 1.70% had alpha/beta thalassemia interactions. The samples collected from the blood cord showed better results in all analyses while the blood samples collected by heel stick on filter paper, were applicable to only specific methodologies. The routine laboratory methods allowed identification of the thalassemic and variant forms, and isoelectric focusing presented sensitivity only for variant identification in this age range. The suspected cases were reassessed after six months, which permitted genetic counseling of their family members and clinic attendance. A multidisciplinary approach in programs of this kind is fundamental for its success

Hemoglobina Köln diagnosticada em programa de triagem neonatal em São José do Rio Preto, SP Köln Hemoglobin found in Neonatal Screening Program in São José do Rio Preto, São Paulo, Brazil

Alterações genéticas em que a mutação de aminoácidos nas globinas afeta a estrutura da molécula tornando-a instável são classificadas como hemoglobinas instáveis. Devido à grande diversidade dos pontos de mutações por substituições e deleções de aminoácidos, as formas de instabilização se apresentam muito variadas. A hemoglobina Köln é a variante instável descrita com maior freqüência na literatura e a terceira descoberta no Brasil, as outras são Hb Niterói e Hb Hasharon. Anemia moderada, icterícia e presença de urina escura caracterizam as manifestações clínicas da Hb Köln. Em programa de triagem neonatal identificamos uma criança com suspeita de heterozigose para hemoglobina Köln, confirmada por procedimentos eletroforéticos e HPLC. Avaliações por diferentes metodologias laboratoriais e estudo familiar auxiliam no diagnóstico precoce, possibilitando minimizar os sintomas decorrentes da hemoglobina anormal e a realização do aconselhamento genético e educacional destas alterações hereditárias.<br>Hemoglobinopathies are a diverse group of inherited recessive disorders that include thalassemias and sickle cell disease. They were the first genetic diseases to be characterized at the molecular level and consequently have been used repeatedly as a prototype for the development of new techniques of mutation detection. A major group of the structural hemoglobins exhibit the property of instability in solution, resulting from their altered molecular structures. Mutation of amino acids in the globin affects the structure of the molecule turning it unstable and they are classified as unstable hemoglobins. Due to the great diversity of the mutation points, substitutions and deletions of amino acids, the unstable forms are very varied. Hemoglobin Köln is the unstable variant most described in literature and the third discovered in Brazil, the others are Hb Niterói and Hb Hasharon. Moderate anemia, jaundice and the presence of dark urine characterize Hb Köln’s clinical manifestations. In a neonatal screening program we identified a child suspected of having hemoglobin Köln, which was confirmed by electrophoretic procedures and HPLC. Evaluations by different laboratory examinations and the family study aided in a precocious diagnosis, thereby facilitating to minimize the current symptoms of the abnormal hemoglobin, and thus the family received support with genetic and educational counseling of these hereditary alterations

Investigação de hemoglobinopatias em sangue de cordão umbilical de recém-nascidos do Hospital de Base de São José do Rio Preto

As hemoglobinopatias são as doenças genéticas mais freqüentes na população humana. Cerca de 12 a 15% da população é portadora de uma ou mais formas de hemoglobinas anormais, resultando em um grande problema de saúde pública. O diagnóstico neonatal possibilita o tratamento e o aconselhamento genético precoce, incluindo a conscientização dos portadores sobre o risco do nascimento de homozigotos. O objetivo deste trabalho é apresentar os resultados da investigação de hemoglobinopatias em recém-nascidos do Hospital de Base de São José do Rio Preto. O estudo foi realizado em 913 amostras de sangue de cordão umbilical, que foram submetidas a testes eletroforéticos, bioquímicos e citológicos, específicos para análise de hemoglobinas. Foram identificadas 100 (10,95%) amostras com hemoglobinas anormais, das quais 40 (4,38%) com Hb Bart's, sugerindo alfa talassemia, 34 (3,72%) com Hb S, 23 (2,52%) com beta talassemia, duas (0,22%) com Hb C e uma (0,11%) amostra apresentou Hb rápida. A frequência elevada de alterações encontradas evidencia a necessidade da triagem neonatal de hemoglobinopatias que pode resultar em amplos benefícios para os portadores destas patologias e seus familiares.Hemoglobinopathies are the most frequent genetic diseases in the human population. About 12 to 15% of the population have one or more forms of abnormal hemoglobins, which creates a huge public health problem. The neonatal diagnosis permits early treatment and genetic counselling also makes carriers aware of the risk of homozygote children. The purpose of this study is to present the results of the investigation of hemoglobinopathies in newborn babies in the Hospital de Base, São José do Rio Preto. The study was performed on 913 blood samples taken from umbilical cords, which were submitted to specific electrophoresis, biochemical and cytologic tests for hemoglobin analysis. The results showed one hundred samples (10.95%) had abnormal hemoglobins of which 40 (4.38%) were Hb Bart's suggesting alpha thalassaemia, 34 (3.72%) were Hb S, 23 (2.52%) were Beta thalassaemia, two (0.22%) were Hb C and one (0.11%) was fast hemoglobin. The high rate of abnormal hemoglobins shows the necessity of neonatal screening which can result in great benefits for carriers of these diseases and their relatives

Frequency of the BCR/ABL rearrangements and associated alterations detected by FISH during monitoring of patients taking imatinib mesylate in isolation

A introdução do mesilato de imatinibe como tratamento da leucemia mielóide crônica tem salvado muitos pacientes, mas o sucesso da terapia tem sido prejudicado pela resistência e possível não destruição do clone maligno. Este artigo descreve a resposta citogenética e padrões citogenéticos anormais envolvendo os genes ABL e BCR detectados por FISH em pacientes em uso exclusivo de imatinibe. Os resultados mostraram que outras alterações envolvendo os genes BCR e ABL não parecem estar relacionadas à resistência à droga, elas ocorrem em baixas freqüências e podem não estar associadas à resposta citogenética ou ao tempo de tratamento. Contudo, a resposta ao imatinibe parece ser individual e imprevisível, independente do tempo e do início do tratamento após o diagnóstico.The introduction of imatinib mesylate as treatment of chronic myelogenous leukemia has saved many patients, but the success of therapy is hampered by resistance and possible non-destruction of the malignant clone. This article describes the cytogenetic responses and abnormal cytogenetic patterns involving the ABL and BCR genes detected by FISH in patients who use exclusively imatinib. The results showed that other alterations involving the BCR and ABL genes do not seem to be related to resistance to the drug as they occur in low frequencies and can not be associated to the cytogenetic response or to the time of treatment. Moreover, the response to imatinib seems to be individual and unpredictable, independent of the time of treatment and of its initiation after diagnosis