Proactive Variant Effect Mapping Aids Diagnosis in Pediatric Cardiac Arrest

摘要

Genetic testing is becoming mainstream in the management of cardiovascular disease. However, up to 80% of variants reported on genetic testing are classified as variants of uncertain significance (VUS), which cannot be acted upon with high confidence in the clinic.1 Conventionally, VUS are functionally investigated reactively, after they have been identified in a patient. This time- and labor-intensive approach represents a significant barrier to patient care. Here, we describe a first implementation of proactive variant effect mapping in clinical cardiovascular genetics. We show that prospective determination of the functions of large numbers of variants in calmodulin genes (CALM1, CALM2, and CALM3) allows rapid integration of functional data in clinical decision-making in pediatric cardiac arrest cases, illustrating the promise of this strategy in overcoming the VUS barrier toward widespread implementation of genomic medicine