Paediatric B lymphoblastic leukaemia with hyperdiploidy and a false-positive KMT2A fluorescence in situ hybridization result.

The dramatic improvement in the event-free survival of paediatric B-lymphoblastic leukaemia (B-ALL) has led to risk-stratified treatment. Through a combination of clinical features, cytogenetic abnormalities and assessment of treatment response, patients are stratified to receive different intensities of therapy. The presence of high hyperdiploidy (>50 chromosomes) is considered a favourable genetic feature. Conversely, KMT2A fusion genes in B-ALL are associated with a poor prognosis, resulting in intensification of treatment. We present a seven-year-old female with B-ALL, a high hyperdiploid karyotype (56 chromosomes) and KMT2A rearrangement detected on FISH, but with no productive fusion identified. Single nucleotide polymorphism (SNP) array suggested the KMT2A rearrangement was due to chromosome 11 chromothripsis. Subsequent targeted RNA fusion panel and whole transcriptomic sequencing (mRNA-seq) did not detect an expressed KMT2A fusion. Differential expression analyses of the mRNA-seq data led to clustering of this case with other hyperdiploid cases, consistent with the hyperdiploid cytogenetic results. Given the additional intensity and potential toxicity of high-risk treatment, unusual findings by chromosome analysis, FISH and/or chromosomal microarray should prompt consideration of testing for a KMT2A fusion by another method to avoid misclassification.

A comparative study of standard cytogenetic evaluation and molecular karyotyping for products of conception.

Genetic analysis of fetal tissue provides valuable information regarding the underlying causes of miscarriage. However, current analysis techniques are limited and expensive. This trial compared a molecular multiplex, bead-based suspension array, KaryoLite Bacs on Beads, with conventional tissue culture and G-banded karyotype techniques. A 92% overall success rate was achieved. This method detected a cryptic deletion of a 7q subtelomeric region, a case of 25% mosaic trisomy 14, and 2 unbalanced subtelomeric rearrangements due to familial balanced translocations. Twenty (24%) of the 83 samples analyzed, that failed to yield a cytogenetic result due to culture failure, were successfully assayed using the suspension array. Genomic imbalances including trisomies and subtelomeric deletions were detected in 3 cases (15%) of previously failed cases. This method is limited by its inability to detect polyploidy, which is significant in first trimester loss. However, this can be readily overcome by prescreening using florescent in situ hybridization. Data indicates that KaryoLite BoBs molecular testing is superior to conventional cytogenetic evaluation in several key areas, including success rate (95% vs. 76%, for this study group), cost, turnaround time (2 vs. up to 28 d), and subjective result interpretation.