RESUMO
Tourette Syndrome (TS) is a heritable, early-onset neuropsychiatric disorder that typically begins in early childhood. Identifying rare genetic variants that make a significant contribution to risk in affected families may provide important insights into the molecular aetiology of this complex and heterogeneous syndrome. Here we present a whole-genome sequencing (WGS) analysis from the 11-generation pedigree (>500 individuals) of a densely affected Costa Rican family which shares ancestry from six founder pairs. By conducting an identity-by-descent (IBD) analysis using WGS data from 19 individuals from the extended pedigree we have identified putative risk haplotypes that were not seen in controls, and can be linked with four of the six founder pairs. Rare coding and non-coding variants present on the haplotypes and only seen in haplotype carriers show an enrichment in pathways such as regulation of locomotion and signal transduction, suggesting common mechanisms by which the haplotype-specific variants may be contributing to TS-risk in this pedigree. In particular we have identified a rare deleterious missense variation in RAPGEF1 on a chromosome 9 haplotype and two ultra-rare deleterious intronic variants in ERBB4 and IKZF2 on the same chromosome 2 haplotype. All three genes play a role in neurodevelopment. This study, using WGS data in a pedigree-based approach, shows the importance of investigating both coding and non-coding variants to identify genes that may contribute to disease risk. Together, the genes and variants identified on the IBD haplotypes represent biologically relevant targets for investigation in other pedigree and population-based TS data.
Assuntos
Neurogênese , Síndrome de Tourette , Pré-Escolar , Humanos , Costa Rica , Haplótipos , Linhagem , Transdução de Sinais , Síndrome de Tourette/genética , Neurogênese/genética , Polimorfismo Genético , Sequenciamento Completo do Genoma , Fator 2 de Liberação do Nucleotídeo Guanina/genéticaRESUMO
BACKGROUND: It is not known whether immune dysfunction is associated with increased risk of death after cancer diagnosis in persons with HIV (PWH). AIDS-defining illness (ADI) can signal significant immunosuppression. Our objective was to determine differences in cancer stage and mortality rates in PWH with and without history of ADI. METHODS: PWH with anal, oropharynx, cervical, lung cancers, or Hodgkin lymphoma diagnoses from January 2000 to December 2009 in the North American AIDS Cohort Collaboration on Research and Design were included. RESULTS: Among 81,865 PWH, 814 had diagnoses included in the study; 341 (39%) had a history of ADI at time of cancer diagnosis. For each cancer type, stage at diagnosis did not differ by ADI (P > 0.05). Mortality and survival estimates for cervical cancer were limited by n = 5 diagnoses. Adjusted mortality rate ratios showed a 30%-70% increase in mortality among those with ADI for all cancer diagnoses, although only lung cancer was statistically significant. Survival after lung cancer diagnosis was poorer in PWH with ADI vs. without (P = 0.0001); the probability of survival was also poorer in those with ADI at, or before other cancers although not statistically significant. CONCLUSIONS: PWH with a history of ADI at lung cancer diagnosis had higher mortality and poorer survival after diagnosis compared to those without. Although not statistically significant, the findings of increased mortality and decreased survival among those with ADI (vs. without) were consistent for all other cancers, suggesting the need for further investigations into the role of HIV-related immune suppression and cancer outcomes.
Assuntos
Infecções por HIV/complicações , Neoplasias/mortalidade , Neoplasias/patologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Análise de SobrevidaRESUMO
Estudos epidemiológicos em esquizofrenia estabeleceram que a idade de início para o gênero masculino precede em alguns anos aquela para o feminino. No entanto, tal efeito de gênero não vem sendo observado para os casos de esquizofrenia familiar, em que pelo menos dois membros de uma mesma família recebam o mesmo diagnóstico. Nosso estudo examina pela primeira vez esta questão em uma população brasileira. Estudamos 31 pacientes com diagnóstico de esquizofrenia pelos critérios RDC, provenientes de 13 famílias com dois ou mais afetados. Nossos resultados confirmam os da literatura internacional, não encontrando diferenças entre gênero masculino e feminino na idade de aparecimento dos sintomas. Estes resultados indicam a possibilidade da existência de influência genética na idade de início do transtorno e devem receber atenção de estudos em genética molecular.