Figure 2.

Conceptual Framework for the Management of ACMG59 Disorders

The results of the clinical evaluation enable the clinician to determine whether or not an individual has a clinicomolecular diagnosis, but uncertainty may still exist. There is an overall positive correlation between the certainty of clinicomolecular diagnosis required for ongoing intervention (beyond the initial clinical evaluation) and the nature of that intervention. The nature of intervention includes consideration of medical risk, cost, and overall inconvenience. Malignant hyperthermia susceptibility can be managed with relatively low burden (avoiding triggering agents during surgery and communicating risk to clinicians) and therefore, even in the setting of an uncertain clinicomolecular diagnosis, these measures should be implemented. By contrast, an individual with Peutz-Jeghers syndrome would, at a minimum, undergo regular moderately invasive screening exams. Therefore, in this latter scenario, a higher degree of certainty is required for an individual to be considered to have a clinicomolecular diagnosis. Given both the catastrophic threat and diagnostic challenges associated with arrhythmogenic right ventricular cardiomyopathy, there are moderate intensity interventions that are acceptable for an individual even when there is uncertainty regarding a clinicomolecular diagnosis. The disorders noted are illustrative examples but are not the only disorders that fall into a given category. For any individual with a secondary finding, a clinician would weigh these factors for the given disorder and determine whether the results of the clinical evaluation meet a threshold for ongoing intervention. The categories are purposefully overlapping as they are not discrete entities but rather concepts for the clinician to be mindful of when establishing a long-term plan for an individual.