Array-Based Comparative Genomic Hybridization for the Genomewide Detection of Submicroscopic Chromosomal Abnormalities

Microdeletions and microduplications, not visible by routine chromosome analysis, are a major cause of human malformation and mental retardation. Novel high-resolution, whole-genome technologies can improve the diagnostic detection rate of these small chromosomal abnormalities. Array-based comparative genomic hybridization allows such a high-resolution screening by hybridizing differentially labeled test and reference DNAs to arrays consisting of thousands of genomic clones. In this study, we tested the diagnostic capacity of this technology using ∼3,500 flourescent in situ hybridization–verified clones selected to cover the genome with an average of 1 clone per megabase (Mb). The sensitivity and specificity of the technology were tested in normal-versus-normal control experiments and through the screening of patients with known microdeletion syndromes. Subsequently, a series of 20 cytogenetically normal patients with mental retardation and dysmorphisms suggestive of a chromosomal abnormality were analyzed. In this series, three microdeletions and two microduplications were identified and validated. Two of these genomic changes were identified also in one of the parents, indicating that these are large-scale genomic polymorphisms. Deletions and duplications as small as 1 Mb could be reliably detected by our approach. The percentage of false-positive results was reduced to a minimum by use of a dye-swap-replicate analysis, all but eliminating the need for laborious validation experiments and facilitating implementation in a routine diagnostic setting. This high-resolution assay will facilitate the identification of novel genes involved in human mental retardation and/or malformation syndromes and will provide insight into the flexibility and plasticity of the human genome

SUBGOVERNMENTS AND THE IMPACT OF POLICY FRAGMENTATION AND ACCOMMODATION

For many years political scientists have utilized the subgovernment model of policy-making to explain certain types of policy output. Recently a number of scholars have argued that the traditional conceptualization of subgovernments was simplistic and incomplete. They view subgovernments as a complex and integral part of the larger policy-making environment. This paper examines this "new" subgovernment by analyzing its role in contemporary public policy-making. If subgovernments have lost their autonomy and been exposed to the complex demands of the larger political system, what impact does this have on policy outputs? Relying upon the literature on subgovernments and their principal components, the paper offers an interpretation of how subgovernments have potentially expanded their influence on public policy as a result of two contemporary developments: policy-making fragmentation, and the accommodation of policy outputs. Copyright 1988 by The Policy Studies Organization.

Characteristics, management, and outcomes of patients with left‐sided infective endocarditis complicated by heart failure: a substudy of the ESC‐EORP EURO‐ENDO (European infective endocarditis) registry

International audienc