RESUMO
BACKGROUND: Duplications and deletions in the human genome can cause disease or predispose persons to disease. Advances in technologies to detect these changes allow for the routine identification of submicroscopic imbalances in large numbers of patients. METHODS: We tested for the presence of microdeletions and microduplications at a specific region of chromosome 1q21.1 in two groups of patients with unexplained mental retardation, autism, or congenital anomalies and in unaffected persons. RESULTS: We identified 25 persons with a recurrent 1.35-Mb deletion within 1q21.1 from screening 5218 patients. The microdeletions had arisen de novo in eight patients, were inherited from a mildly affected parent in three patients, were inherited from an apparently unaffected parent in six patients, and were of unknown inheritance in eight patients. The deletion was absent in a series of 4737 control persons (P=1.1x10(-7)). We found considerable variability in the level of phenotypic expression of the microdeletion; phenotypes included mild-to-moderate mental retardation, microcephaly, cardiac abnormalities, and cataracts. The reciprocal duplication was enriched in nine children with mental retardation or autism spectrum disorder and other variable features (P=0.02). We identified three deletions and three duplications of the 1q21.1 region in an independent sample of 788 patients with mental retardation and congenital anomalies. CONCLUSIONS: We have identified recurrent molecular lesions that elude syndromic classification and whose disease manifestations must be considered in a broader context of development as opposed to being assigned to a specific disease. Clinical diagnosis in patients with these lesions may be most readily achieved on the basis of genotype rather than phenotype.
Assuntos
Transtorno Autístico/genética , Aberrações Cromossômicas , Cromossomos Humanos Par 1/genética , Anormalidades Congênitas/genética , Deficiência Intelectual/genética , Catarata/congênito , Catarata/genética , Criança , Deleção Cromossômica , Feminino , Duplicação Gênica , Rearranjo Gênico , Variação Genética , Cardiopatias Congênitas/genética , Humanos , Masculino , Microcefalia/genética , Fenótipo , Recombinação GenéticaRESUMO
PURPOSE: Previous studies did not discriminate wild-type from hemizygous genotypes of GSTM1 and GSTT1. In this study, we investigated wild-type, hemizygous deletion, and homozygous deletion genotypes of GSTM1 and GSTT1 and lung cancer risk. METHODS: We conducted a nested case-control study of 143 primary incident lung cancer cases matched to 447 cancer-free controls. Genotyping was carried out using a real-time polymerase chain reaction (PCR)-based assay. Conditional logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Compared to GSTM1 wild-type carriers, the relative odds of lung cancer increased from 1.49 (95% CI=0.66-3.40) to 1.80 (95% CI=0.81-4.02) for the hemizygous and homozygous deletion genotypes, respectively (p-trend=0.13). The strongest associations were seen among those who smoked less than one pack per day and had greater than or equal to one deletion variant of GSTM1 (OR=3.25; 95% CI=0.93-11.34; p-trend=0.07) whereas the reverse was observed for smokers who smoked greater than or equal to one pack per day (OR=0.80; 95% CI=0.24-2.67; p-interaction=0.08). No clear associations were observed for GSTT1 genotypes. CONCLUSIONS: Risk of lung cancer increased as the number of deletion variants increased for GSTM1, although the associations were nonsignificant. Discriminating between the wild-type, hemizygous, and homozygous deletion GSTM1 genotypes permitted a more precise characterization of the associations between GSTM1 deletion variants and lung cancer.