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Large duplications of distal 3q are associated with ASD, VSD, Tetralogy of Fallot (TOF) and AVSB. A smaller duplication of 3q25.3q26.2 was independently ascertained through a girl of 11 years with TOF and mild dysmorphism, and a 9 year old girl with microcephaly. The same duplication was found in the mother of the first child who had otosclerosis and no CHD, and the father of the second girl who was also deaf. Five additional duplication carriers showed variable phenotypes that included one or more of CriB, deafness, brachydactyly, shod stature and developmental delay. The dysmorphic features were consistent and included hypertelorism with upslanting palpebral fissures and small low set ears. The critical region was further refined using a 3000 BAC clone genome-wide microarray with BACs spaced at approximately 1 megabase intervals. DNA from duplicated and control individuals was labelled with Cy3 and Cy5 respectively and hybridised. The array accurately defined the position of the duplicated region and showed it has a maximal size of 17 megabases. It is expected that this work will lead to the identification of novel dosage sensitive loci associated with CHD and deafness. [ABSTRACT FROM AUTHOR]

We have constructed a genomic clone microarray consisting of the complete tiling path of chromosome 22q and have used it to study patients with known chromosome 22q 11 deletions in order to validate this method for the detection of small chromosomal deletions in general. The tiling path microarray was constructed using sequenced golden path clones from chromosome 22q. DNA from patients with known FISH-confirmed 22q11 deletions was labeled with Cy3 and hybridized to the array together with Cy 5-labeled control DNA from a pooled panel of normal DNA samples extracted from whole blood. We found that 22q11 deletions were easily identified from a lowering of the fluorescence ratio of patient to control DNA compared to surrounding undeleted regions. We are also using an array constructed from a clone set with an average resolution of 1 megabase across the entire genome. We are currently using this array to evaluate a panel of patients with mental retardation and dysmorphic features, but with a normal karyotype and FiSH studies. In one patient with microcephaly, dysmorphic features and developmental delay, we have identified, and verified by FISH, a small duplication in chromosome 3p. This duplication is not visible on repeat karyotype analysis. We conclude that microarray-CGH is valid for the detection of small chromosomal deletions and duplications and will prove useful particularly for diagnosis in suitable patients with a normal G-banded karyotype and negative FISH studies. [ABSTRACT FROM AUTHOR]