Secondary complex chromosome rearrangement identified by chromosome analysis and FISH subsequent to detection of an unbalanced derivative chromosome 12 by SNP array analysis.

Microarray analysis is used to detect small copy number changes (deletions and duplications) that may be associated with genetic syndromes and phenotypic abnormalities. However, there are limitations to what microarrays are able to detect. We present a patient referred for microarray in whom chromosome analysis identified a more complex structural rearrangement than was indicated by the microarray. Our studies included Affymetrix Cytoscan HD array, chromosome analysis and fluorescence in situ hybridization (FISH) using a subtelomere probe targeting chromosome 3. Array analysis revealed a 6.45-Mb terminal duplication of 3q28q29 and a 1.02-Mb terminal deletion of 12p13.33. This suggested an unbalanced translocation derivative. In order to investigate visibility of the rearrangement, chromosome analysis was performed, revealing an additional balanced complex chromosome rearrangement involving chromosomes 3 and 11, including a translocation with breakpoints at 3p13 and 11p11.2, as well as a paracentric inversion of segment 3p25p13 translocated onto chromosome 11. Subtelomere FISH confirmed that the duplicated chromosome 3q material observed in the array analysis was localized to distal 12p. This case clearly illustrates the combined utilization of classic cytogenetics, FISH and array technologies to better characterize chromosomal abnormalities.

Interstitial deletion of proximal 8q including part of the centromere from unbalanced segregation of a paternal deletion/marker karyotype with neocentromere formation at 8p22.

BACKGROUND/AIMS: The 'McClintock mechanism' of chromosome breakage and centromere misdivision, in which a deleted chromosome with its concomitant excised marker or ring chromosome is formed, has been described in approximately one dozen reports. We report a case of a girl with short stature, developmental delay, and dysmorphic features. METHODS: Analysis was performed on the proband and father using cytogenetic chromosome analysis and the Affymetrix 6.0 SNP microarray. Fluorescence in situ hybridization (FISH) using a chromosome 8 alpha-satellite probe and immunofluorescence with antibodies to CENP-C were used to examine the centromere positions in these chromosomes. RESULTS: An abnormal chromosome 8 with a cytogenetically visible deletion was further defined by SNP array as a 10.6-Mb deletion from 8q11.1→q12.1. FISH with a chromosome 8 alpha-satellite probe demonstrated that the deletion removed a significant portion of the pericentromeric alpha-satellite repeat sequences and proximal q arm. The deleted chromosome 8 appeared to have a constriction at 8p22, suggesting the formation of a neocentromere, even though alpha-satellite sequences still appeared at the normal location. Chromosome analysis of the phenotypically normal father revealed the same deleted chromosome 8, as well as an apparently balancing mosaic marker chromosome 8. FISH studies revealed that the majority of the chromosome 8 alpha-satellite DNA resided in the marker chromosome. Immunofluorescence studies with antibodies to CENP-C, a kinetochore protein, proved the presence of a neocentromere at 8p22. The excision of the marker from the deleted chromosome 8 likely necessitated the formation of a new kinetochore at the 8p22 neocentromere to stabilize the chromosome during mitosis. CONCLUSION: This case clearly illustrates the utilization of classic cytogenetics, FISH, and array technologies to better characterize chromosomal abnormalities and provide information on recurrence risks. It also represents a rare case where a neocentromere can form even in the presence of existing alpha-satellite DNA.