Delivering on the Promise of Germline Genetic Testing for RUNX1 Variants
Project Description: Familial platelet disorder with associated myeloid malignancy (FPD/MM) is an inherited disease caused by harmful genetic mutations in the RUNX1 gene. FPD/MM patients bruise and bleed easily, due to both a lack of platelets (thrombocytopenia) and platelets that do not work correctly. Nearly half will develop blood cancer over their lifetime. Genetic testing is the cornerstone of diagnosis. Patients with blood cancers who have a RUNX1 mutation have an aggressive disease that does not respond well to traditional chemotherapy, and many will be treated with a bone marrow transplant. Correct identification of harmful mutations in RUNX1 is crucial to excluding relatives with the same genetic change as potential bone marrow donors. Relatives found to have the same harmful genetic change can be referred to genetic counselors and can be screened proactively for blood cancers.
Current strategies for understanding changes in RUNX1 are limited and leave many patients and families without answers. Understanding how a genetic change relates to disease is a complex process that relies heavily on how this change tracks with affected people in the same family. FPD/MM is rare, and many of the genetic changes we find are only present in a single patient or family. Therefore, most genetic changes in RUNX1 are classified as variants of uncertain significance (VUS). A genetic change receives a VUS classification when there is not enough information to determine if it is related to disease. These types of genetic changes cannot be used for clinical decision making.
Project Goal: Data generated from laboratory experiments are an additional source of information that can be used when evaluating a genetic change. Recent studies have shown that this type of data can be used to reclassify many VUS as either related to disease (pathogenic) or not related to disease (benign). Currently, data from laboratory experiments are only available for a handful of RUNX1 genetic changes. These experiments are time and labor intensive, and have historically been performed in a reactive manner, after a genetic change is found in a patient, often long after such information could benefit the patient or their family.
We propose taking a proactive approach and seek to generate a comprehensive catalog of RUNX1 genetic changes that can be used as a reference when evaluating a change found in a patient. To generate this catalog, we will measure the effects of RUNX1 genetic changes in a way that tests thousands of these changes in a single experiment. These experiments are called “high-throughput assays” and have been successfully used at our institution to determine the effects of changes in other genes related to inherited cancers. Our ultimate goal is to use the data generated in these experiments to reclassify current VUS and to reduce the probability that new RUNX1 genetic changes will receive a VUS classification.