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Recently, a new genetic test has been developed that allows a more detailed examination of the genome when compared with a standard chromosome analysis. Array comparative genomic hybridization (CGH microarray; also known as chromosome microarray analysis) in effect, combines chromosome and fluorescence in situ hybridization analyses allowing detection not only of aneuploidies, but also of all known microdeletion and microduplication disorders, including telomere rearrangements. Since 2004, this testing has been available in the Medical Genetics Laboratory at Baylor College of Medicine for postnatal evaluation and diagnosis of individuals with suspected genomic disorders. Subsequently, to assess the feasibility of offering CGH microarray for prenatal diagnosis, a prospective study was conducted on 98 pregnancies in a clinical setting comparing the results obtained from array CGH with those obtained from a standard karyotype. This was followed by the availability of prenatal testing on a clinical basis in 2005. To date, we have analyzed over 8000 cases referred to our clinical laboratory, including approximately 300 prenatal cases. With the clinical introduction of any new testing strategy, and particularly one focused on genetic disorders, issues of patient education, result interpretation, and genetic counseling must be anticipated and strategies adopted to allow the implementation of the testing with maximum benefit and minimum risk. In this article, we describe our experience with over 8000 clinical prenatal and postnatal cases of CGH microarray ordered by our clinical service or referred to the Baylor Medical Genetics Laboratory and describe the strategies used to optimize patient and provider education, facilitate clinical interpretation of results, and provide counseling for unique clinical circumstances.

We report clinical findings and molecular cytogenetic analyses for two patients with translocations [t(14;17)(p12;p12) and t(15;17)(p12;p13.2)], in which the chromosome 17 breakpoints map at a large low-copy repeat (LCR) and a breakage-prone TRE-2 (USP6) oncogene, respectively. In family 1, a 6-year-old girl and her 5-year-old brother were diagnosed with mental retardation, short stature, dysmorphic features, and Charcot-Marie-Tooth disease type 1A (CMT1A). G-banding chromosome analysis showed a der(14)t(14;17)(p12;p12) in both siblings, inherited from their father, a carrier of the balanced translocation. Chromosome microarray and FISH analyses revealed that the PMP22 gene was duplicated. The chromosome 17 breakpoint was mapped within an approximately 383 kb LCR17pA that is known to also be the site of several breakpoints of different chromosome aberrations including the evolutionary translocation t(4;19) in Gorilla gorilla. In family two, a patient with developmental delay, subtle dysmorphic features, ventricular enlargement with decreased periventricular white matter, mild findings of bilateral perisylvian polymicrogyria and a very small anterior commissure, a cryptic duplication including the Miller-Dieker syndrome region was identified by chromosome microarray analysis. The chromosome 17 breakpoint was mapped by FISH at the TRE-2 oncogene. Both partner chromosome breakpoints were mapped on the short arm acrocentric heterochromatin within or distal to the rRNA cluster, distal to the region commonly rearranged in Robertsonian translocations. We propose that TRE-2 together with LCR17pA, located approximately 10 Mb apart, also generated the evolutionary gorilla translocation t(4;19). Our results support previous observations that the USP6 oncogene, LCRs, and repetitive DNA sequences play a significant role in the origin of constitutional chromosome aberrations and primate genome evolution.

Purpose: We developed a microarray for clinical diagnosis of chromosomal disorders using large insert genomic DNA clones as targets for comparative genomic hybridization (CGH)., Methods: The array contains 362 FISH-verified clones that span genomic regions implicated in over 40 known human genomic disorders and representative subtelomeric clones for each of the 41 clinically relevant human chromosome telomeres. Three or four clones from almost all deletion or duplication genomic regions and three or more clones for each subtelomeric region were included. We tested chromosome microarray analysis (CMA) in a masked fashion by examining genomic DNA from 25 patients who were previously ascertained in a genetic clinic and studied by conventional cytogenetics. A novel software package implemented in the R statistical programming language was developed for normalization, visualization, and inference., Results: The CMA results were entirely consistent with previous cytogenetic and FISH findings. For clone by clone analysis, the sensitivity was estimated to be 96.7% and the specificity was 99.1%. Major advantages of this selected human genome array include the following: interrogation of clinically relevant genomic regions, the ability to test for a wide range of duplication and deletion syndromes in a single analysis, the ability to detect duplications that would likely be undetected by metaphase FISH, and ease of confirmation of suspected genomic changes by conventional FISH testing currently available in the cytogenetics laboratory., Conclusion: The array is an attractive alternative to telomere FISH and locus-specific FISH, but it does not include uniform coverage across the arms of each chromosome and is not intended to substitute for a standard karyotype. Limitations of CMA include the inability to detect both balanced chromosome changes and low levels of mosaicism.