Stagnation in quality of next‐generation sequencing assays for the diagnosis of hereditary hematopoietic malignancies

Abstract

AbstractHereditary hematopoietic malignancies (HHMs) are inherited syndromes that confer the risk of blood cancer development. With the rapid acceleration of next‐generation sequencing (NGS) into commercial biotechnology markets, HHMs are increasingly recognized by genetic counselors and clinicians. In 2020, it was demonstrated that most diagnostic test offerings for HHMs were insufficient for accurate diagnosis, failing to sequence the full spectrum of genetic events known to cause HHMs. We hypothesized the number of genes on commercially available HHM assay increased from 2020 to 2022, consistent with a more comprehensive sequencing approach. Here, we analyzed assays from eight commercial laboratories to determine the HHM‐related genes sequenced by these assays. We compared these assays with panels from 2020 to determine trends in sequencing quality. Most HHM diagnostic assays did not change and remain insensitive for the detection of all HHM‐related variants. Most (75%) HHM assays do not sequence CHEK2, the gene most frequently mutated in HHMs, and 25% of HHM assays does not sequence DDX41, the second most frequent HHM driver. The quality of HHM diagnostic assays stagnated despite the discovery of novel HHM‐related genes and prior work demonstrating heterogeneity in the quality of HHM testing. Most commercially available HHM tests remain insufficient.