1Anita Rauch, 2Franz Rueschendorf, 3Jing Huang, 1Udo Trautmann, 2Christian Becker, 3Keith Jones, 1Andre Reis, 2Peter Nuernberg
1Institute of Human Genetics, Schwabachanlage 10, 91054 Erlangen, Germany, 2Genome Mapping Center, MDC Robert-Roessle-Strasse 10, 13092 Berlin, Germany, 3Affymetrix inc., Santa Clara, CA 95051, U. S. A.
Subtle segmental chromosomal aneusomies (SCA) and microdeletions are a major cause of MR/MCA syndromes. With current techniques only a fraction of these aberrations can be detected, mainly those associated with characteristic clinical phenotypes or with subtelomeric rearrangements. New approaches to achieve a higher genome-wide detection rate of such aneusomies are mainly focused on matrix comparative genome hybridisation (CGH). However this technique is not routinely available. Therefore we evaluated an alternative method using commercially available, easy to handle SNP genotyping chip-arrays for parallel interrogation of 11,256 SNPs for the detection of such SCAs. We investigated 20 patients with previously confirmed cryptic aberrations of varying size and location together with both parents. Deletion sizes varied from 192kb to 12Mb. Of these deletions 8 lay in areas where the current version of the chip-array had no coverage. From the remaining 12 deletion areas, 5 had only a 1-5 SNP coverage. While the analysis of mendelian errors in the trios produced a high rate of false positive and false negative results, we were able to detect unambiguously 7 deletions using the meta-p-value analysis of hybridisation intensities of individual patients' chip hybridisations. Under a stringent cut off level not allowing for false positives, all deletions encompassing a minimum of 14 SNPs could be unambiguously detected and sized. Detection of deletions was only dependent on SNP coverage but not on deletion size. Thus, the 10K SNP is already a valuable tool to detect cryptic chromosomal deletions. However, most deletions should have been detectable using a denser array with 120K SNPs under development. We conclude that such a higher density SNP array with more even distribution of SNPs could be easily used for genome-wide detection of cryptic deletions.
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