A genomic perspective of benign hematological disorders in the era of next-generation sequencing

Next-generation sequencing (NGS) has revolutionized the diagnostic approach to hematological disorders, enabling precise identification of genetic alterations that underlie both benign and malignant conditions. By detecting single-nucleotide variants, insertions/deletions, structural rearrangements, and copy number changes, NGS provides unparalleled diagnostic accuracy. This technology encompasses various techniques, including targeted sequencing, whole exome sequencing (WES), whole genome sequencing (WGS), and transcriptome analysis, each suited to specific clinical applications. Targeted NGS focuses on clinically relevant genes, offering a cost-effective approach for diseases with established genetic bases, while WES and WGS allow for broader analyses to uncover novel mutations in cases of uncertain genetic etiology. NGS surpasses single-gene testing by addressing the lack of specificity in clinical and laboratory features, facilitating the analysis of multiple candidate genes simultaneously. Studies highlight that relying solely on phenotype and traditional methods can result in misdiagnoses in 10–40% of cases, leading to inadequate treatment and increased patient burden. NGS mitigates these risks by providing a comprehensive and efficient diagnostic strategy. Despite its advantages, NGS interpretation poses challenges, particularly in classifying variants according to the American College of Medical Genetics and Genomics guidelines. Variants are categorized into five classes, ranging from pathogenic to benign, with many novel variants remaining of uncertain significance. Advanced tools and population databases, such as SIFT, PolyPhen-2, and ExAC, aid in variant assessment. This review underscores the transformative role of NGS in diagnosing inherited benign hematological disorders. By improving diagnostic precision, understanding disease mechanisms, and enabling genetic counseling, NGS fosters the advancement of personalized medicine. Its integration into routine diagnostics enhances cost-effectiveness and expands the potential for updating targeted panels as new genes are discovered, solidifying its pivotal role in modern healthcare.