RESUMO
In children with cancer, the heterogeneity in ototoxicity occurrence after similar treatment suggests a role for genetic susceptibility. Using a genome-wide association study (GWAS) approach, we identified a genetic variant in TCERG1L (rs893507) to be associated with hearing loss in 390 non-cranial irradiated, cisplatin-treated children with cancer. These results were replicated in two independent, similarly treated cohorts (n = 192 and 188, respectively) (combined cohort: P = 5.3 × 10-10, OR 3.11, 95% CI 2.2-4.5). Modulating TCERG1L expression in cultured human cells revealed significantly altered cellular responses to cisplatin-induced cytokine secretion and toxicity. These results contribute to insights into the genetic and pathophysiological basis of cisplatin-induced ototoxicity.
RESUMO
Here we report a 12 year old male with an extreme presentation of spastic paraplegia along with autism and dysmorphisms. Whole exome sequencing identified a predicted pathogenic pair of missense variants in SPAST at the same chromosomal location, each with a different alternative allele, while a chromosome microarray identified a 1.73 Mb paternally inherited copy gain of 1q21.1q21.2 resulting in a blended phenotype of both Spastic paraplegia 4 and 1q21.1 microduplication syndrome. We believe that the extreme phenotype observed is likely caused by the presence of cells which contain only mutant SPAST, but that the viability of the patient is possible due mosaicism of mutant alleles observed in different proportions across tissues.
Assuntos
Transtorno do Espectro Autista/genética , Cardiopatias Congênitas/genética , Deficiência Intelectual/genética , Mosaicismo , Paraplegia/genética , Fenótipo , Transtorno do Espectro Autista/diagnóstico , Transtorno Autístico/diagnóstico , Transtorno Autístico/genética , Criança , Deleção Cromossômica , Duplicação Cromossômica , Cromossomos Humanos Par 1/genética , Cardiopatias Congênitas/diagnóstico , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Mutação de Sentido Incorreto , Paraplegia/diagnóstico , Herança Paterna , Espastina/genéticaAssuntos
Epilepsia/genética , Canal de Potássio Kv1.2/genética , Mutação , Espasmos Infantis/genética , Feminino , Humanos , MasculinoRESUMO
BACKGROUND: Variegate porphyria (VP) is due to a partial deficiency of protoporphyrinogen oxidase (PPOX), the seventh enzyme in the haem biosynthetic pathway. Clinically, VP is characterized by photosensitivity and acute neurovisceral attacks that can manifest separately or together in affected individuals. The disease is inherited in an autosomal dominant fashion with incomplete penetrance and PPOX gene mutations associated with VP are usually unique to patients and their families. In South Africa, however, VP is highly prevalent as the result of a founder mutation, designated p.R59W. Previous genealogical and haplotype studies showed a link between South African and Dutch carriers of p.R59W and it was suggested that this mutation was introduced to South Africa by Dutch settlers at the end of the 17th century. OBJECTIVES: To perform extended haplotype analysis in six South African and Dutch VP families with the p.R59W mutation. METHODS: Haplotyping of 13 microsatellite markers flanking the PPOX gene on chromosome 1q22-23 and five informative single nucleotide polymorphisms within and around the gene. RESULTS: A core haplotype cosegregated in all families studied. CONCLUSIONS: Our data deliver further confirmation that the South African and Dutch VP families carrying mutation p.R59W shared a common ancestor.
Assuntos
Cromossomos Humanos Par 1/genética , Flavoproteínas/genética , Haplótipos/genética , Proteínas Mitocondriais/genética , Mutação/genética , Polimorfismo de Nucleotídeo Único/genética , Porfiria Variegada/genética , Protoporfirinogênio Oxidase/genética , Frequência do Gene/genética , Heterozigoto , Humanos , Repetições de Microssatélites/genética , Países Baixos/etnologia , Linhagem , África do Sul/etnologiaRESUMO
Psychiatric disorders place a considerable healthcare burden on South African society. Incorporating genetic technologies into future treatment plans offers a potential mechanism to reduce this burden. This review focuses on psychiatric genetic research that has been performed in South African populations with regards to obsessive-compulsive disorder, schizophrenia and bipolar disorder. Preliminary findings from these studies suggest that data obtained in developed countries cannot necessarily be extrapolated to South African population groups. Psychiatric genetic studies in South Africa seem to involve relatively low-cost methodologies and only a limited number of large national collaborative studies. Future research in South Africa should therefore aim to incorporate high-throughput technologies into large scale psychiatric studies through the development of collaborations. On a global level, the vast majority of psychiatric genetic studies have been performed in non-African populations. South Africa, as the leading contributor to scientific research in Africa, may provide a foundation for addressing this disparity and strengthening psychiatric genetic research on the continent. Although the elucidation of the genetic architecture of psychiatric disorders has proved challenging, examining the unique genetic profiles found in South African populations could provide valuable insight into the genetics of psychiatric disorders.
