The upcoming 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours is part of an effort to hierarchically catalogue human cancers arising in various organ systems within a single relational database. This paper summarizes the new WHO classification scheme for myeloid and histiocytic/dendritic neoplasms and provides an overview of the principles and rationale underpinning changes from the prior edition. The definition and diagnosis of disease types continues to be based on multiple clinicopathologic parameters, but with refinement of diagnostic criteria and emphasis on therapeutically and/or prognostically actionable biomarkers. While a genetic basis for defining diseases is sought where possible, the classification strives to keep practical worldwide applicability in perspective. The result is an enhanced, contemporary, evidence-based classification of myeloid and histiocytic/dendritic neoplasms, rooted in molecular biology and an organizational structure that permits future scalability as new discoveries continue to inexorably inform future editions.

Cytogenetics has long represented a critical component in the clinical evaluation of hematologic malignancies. Chromosome banding studies provide a simultaneous snapshot of genome-wide copy number and structural variation, which have been shown to drive tumorigenesis, define diseases, and guide treatment. Technological innovations in sequencing have ushered in our present-day clinical genomics era. With recent publications highlighting novel sequencing technologies as alternatives to conventional cytogenetic approaches, we, an international consortium of laboratory geneticists, pathologists, and oncologists, describe herein the advantages and limitations of both conventional chromosome banding and novel sequencing technologies and share our considerations on crucial next steps to implement these novel technologies in the global clinical setting for a more accurate cytogenetic evaluation, which may provide improved diagnosis and treatment management. Considering the clinical, logistic, technical, and financial implications, we provide points to consider for the global evolution of cytogenetic testing.

Background/Objectives: Optical genome mapping (OGM) has recently emerged as a new technology in the clinical cytogenomics laboratories. This methodology has the ability to detect balanced and unbalanced structural rearrangements using ultra-high molecular weight DNA. This article discusses the uses of this new technology in both constitutional and somatic settings, its advantages as well as opportunity for improvements. Methods: We reviewed the medical and scientific literature for methodology and current clinical uses of OGM. Results: OGM is a recent addition to the methods used in cytogenomics laboratories and can detect a wide range of structural and copy number variations across a plethora of diseases. Conclusions: Clinical cytogenomics is an important laboratory specialty for which various technologies have been validated over the last several decades to improve detection of copy number and structural variations and their association to human disease. OGM has proven to be a powerful tool in the arsenal of clinical laboratories and provides a unified workflow for the detection of chromosomal aberrations across a wide range of diseases.

Background: Throughout history, the field of cytogenetics has witnessed significant changes due to the constant evolution of technologies used to assess chromosome number and structure. Similar to the evolution of single nucleotide variant detection from Sanger sequencing to next-generation sequencing, the identification of chromosome alterations has progressed from banding to fluorescence in situ hybridization (FISH) to chromosomal microarrays. More recently, emerging technologies such as optical genome mapping and genome sequencing have made noteworthy contributions to clinical laboratory testing in the field of cytogenetics. Content: In this review, we journey through some of the most pivotal discoveries that have shaped the development of clinical cytogenetics testing. We also explore the current test offerings, their uses and limitations, and future directions in technology advancements. Summary: Cytogenetics methods, including banding and targeted assessments like FISH, continue to hold crucial roles in cytogenetic testing. These methods offer a rapid turnaround time, especially for conditions with a known etiology involving recognized cytogenetic aberrations. Additionally, laboratories have the flexibility to now employ higher-throughput methodologies to enhance resolution for cases with greater complexity.

Traditionally, prenatal genetic testing has included karyotyping (KT), fluorescence in situ hybridization, and, more recently, chromosomal microarray analysis (CMA) and whole-exome/-genome sequencing. Together, these methodologies have improved the detection rate of disease-causing structural rearrangements and copy-number abnormalities, particularly in pregnancies with structural ultrasound abnormalities ( 1–3). These diagnostic tests are ordered either concurrently or sequentially, which results in increased costs and/or longer turnaround times (TAT), especially with the time constraints for clinical decision-making in the prenatal setting. In consideration of these limitations, optical genome mapping (OGM) has emerged as a significant advancement in genomic testing, offering higher resolution analysis for both copy-number and structural aberrations and a tool to streamline and automate laboratory workflows. Based on optical imaging of ultra-high molecular weight labeled DNA, OGM allows for the identification of the different classes of structural variants: deletions, gains, translocations, inversions, insertions, and large repeat expansions. Indeed, several groups have published studies on the utility of OGM in several disease settings including retrospective prenatal studies as well as oncology ( 4–9). In the latter, identification of diagnostic, prognostic, and therapeutically actionable targets within a relatively short TAT have been shown to be critical for patient management.