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

ImportanceHereditary hematopoietic malignancies (HHMs) are hereditary cancer syndromes that constitute at least 14% of all myeloid malignancies, but genetic assays used to diagnose HHMs have historically been of variable quality. Here, we demonstrate that HHM assays continue to have persistent shortcomings. These diagnostic gaps place patients with HHMs at high risk for missed diagnoses, missed opportunities for cancer screening, and donor-derived leukemias following stem cell transplant. ObjectiveTo determine if the quality of HHM diagnostic assays has improved since 2020, when our group first demonstrated that most HHM diagnostic tests were insufficient for the accurate diagnosis of these syndromes. We hypothesized that the number of genes tested on each HHM assay increased from 2020 to 2022, in keeping with a more comprehensive sequencing approach. Design, Setting, and ParticipantsWe analyzed assays from eight commercial laboratories to determine which HHM-related genes were sequenced by these assays. We compared these assays to panels from 2020 to determine trends in sequencing quality. ResultsThe majority of HHM diagnostic assays did not change over time and are insensitive for the detection of the full spectrum of HHM-related mutations. The majority (75%) of HHM assays do not sequence CHEK2, the gene most frequently mutated in HHMs, and 25% of HHM assays do not sequence DDX41, the second most frequently mutated HHM gene. ConclusionsThe quality of HHM diagnostic assays has stagnated despite the discovery of novel HHM-related genes as well as prior work demonstrating heterogeneity in quality of HHM testing. The majority of commercially available HHM tests remain insufficient for the diagnosis of the full spectrum of HHM-related germline mutations. Key PointsO_ST_ABSQuestionC_ST_ABSHow have diagnostic assays for hereditary hematopoietic malignancies (HHMs) changed since 2020, when most HHM diagnostic assays were inadequate for the accurate diagnosis of HHMs? FindingsMost HHM assays have significant deficiencies in quality and do not sequence the most relevant HHM-related genes. No meaningful improvements in the quality of HHM diagnostic testing have occurred since 2020. MeaningThe quality of HHM diagnostic testing must be improved to universally include the most common HHM-related germline mutations. This will reduce the risk for false negatives, donor derived leukemias, improve genetic counseling, and improve screening for other HHM-related malignancies.