Molecular characterization of distal 4q duplication in two patients using oligonucleotide array-based comparative genomic hybridization (oaCGH) analysis.

Pure/direct duplications on the long arm of chromosome 4 represent an infrequent chromosomal finding. Description of clinical findings in 30 patients has resulted in defining the 4q-associated phenotype. However, such duplications have not been molecularly or genomically characterized yet, limiting genotype-phenotype correlation. We report on the first two patients with a duplication involving the distal third of 4q that are characterized molecularly and genomically. Clinical features in our patients typical of 4q duplication syndrome included mild intellectual disability, cranial malformation, minor facial dysmorphism, and digital anomaly. Duplication of the segment 4q33-4q34, appears to be the critical region resulting in the phenotype associated with 4q duplication syndrome. The genes GLRA3, GMP6A that are invovled in neurogenesis and HAND2 in craniofacial development, within the duplicated region of 4q, may play a key role in the clinical phenotype. As more reporting on molecular characterization of 4q duplication becomes available, the role of these underlying genes may become clearer.

A novel insertion ins(18;5)(q21.1;q31.2q35.1) in acute myeloid leukemia associated with microdeletions at 5q31.2, 5q35.1q35.2 and 18q12.3q21.1 detected by oligobased array comparative genomic hybridization.

BACKGROUND: Nonrandom clonal chromosomal aberrations can be detected in approximately 55% of adult patients with acute myeloid leukemia (AML). Recurrent cytogenetic abnormalities play an important role in diagnosis, classification and prognosis of AML. However, several chromosomal abnormalities have not been completely determined or characterized, primarily because of their low incidence and limited amount of data. RESULTS: We characterized an AML patient with a novel apparently balanced insertion ins(18;5)(q21;q31.2q35.1) that was cryptic by G-banding. The rearrangement was further examined by molecular cytogenetic methods and oligobased high-resolution array CGH (oaCGH) analysis. We show that an approximately 31.8 Mb large segment from chromosome 5 bands q31.2 to q35.1 has been inserted, by a direct mechanism, into chromosome 18 between bands q12.3 and q21.1. The insertion was unbalanced with concurrent submicroscopic deletions at 5q31.2 (approximately 0.37 Mb in size), 5q35.1q35.2 (approximately 1.98 Mb in size), and 18q12.3q21.1 (approximately 2.07 Mb in size). The microdeletions affect genes on 5q and 18q that have been associated with hematological malignancy and other cancers. A novel juxtaposition of the genes NPM1 and HAUS1 at 5q35.1 and 18q21.1, respectively, was detected by FISH analysis. Searching the literature and the Mitelman database revealed no previously reported ins(18;5) cases. Interestingly, however, two AML patients with translocation t(5;18)(q35;q21) encompassing the 5q35 and 18q21 breakpoint regions as detected in our present ins(18;5) patient have been reported. CONCLUSIONS: It is well-known that cytogenetic abnormalities on the long arm of chromosome 5 affect hematopoiesis. However, the precise mechanism of their involvement in myeloid transformation is elusive. Our present data shed new light onto the frequent abnormalities on 5q as well as to the less frequent abnormalities observed on 18q in myeloid malignancies. In addition, we show that oaCGH analysis is a useful adjunct to revealing submicroscopic aberrations in regions of clinical importance. Reporting rare and nonrandom chromosomal abnormalities contribute to the identification of the whole spectrum of cytogenetic abnormalities in AML and their prognostic significance.

Cyclin B3 and dynein heavy chain cooperate to increase fitness in the absence of mdf-1/MAD1 in Caenorhabditis elegans.

Spindle assembly checkpoint (SAC) ensures genome stability by delaying anaphase onset until all the chromosomes have achieved proper spindle attachment. Once correct attachment has been achieved, SAC must be silenced. In the absence of mdf-1/MAD1, an essential SAC component, Caenorhabditis elegans cannot propagate beyond 3 generations. Previously, in a dog-1(gk10)/FANCJ mutator background, we isolated a suppressor of mdf-1(gk2) sterility (such-4) which allowed indefinite propagation in the absence of MDF-1. We showed that such-4 is a Cyclin B3 (cyb-3) duplication. Here we analyze mdf-1 such-4; dog-1, which we propagated for 470 generations, with freezing of samples for long time storage at F170 and F270. Phenotypic analysis of this strain revealed additional suppression of sterility in the absence of MDF-1, beyond the effects of such-4. We applied oligonucleotide array Comparative Genomic Hybridization (oaCGH) and whole genome sequencing (WGS) and identified a further amplification of cyb-3 (triplication) and a new missense mutation in dynein heavy chain (dhc-1). We show that dhc-1(dot168) suppresses the mdf-1(gk2), and is the second cloned suppressor, next to cyb-3 duplication, that does not cause a delay in anaphase onset. We also show that amplification of cyb-3 and dhc-1(dot168) cooperate to increase fitness in the absence of MDF-1.