Should variants of unknown significance (VUS) be disclosed to patients in cardiogenetics or not; only in case of high suspicion of pathogenicity?
In an adult/pediatric patient with a suspected inherited cardiac disease, genetic testing to clarify the clinical condition is nowadays part of standard routine clinical care. Apart from identifying a likely or clear disease causing genetic variant (respectively a class 4 or class 5 which means that the variant is more than 90% likely or certain to cause the disease), test results can also be confusing when a variant of unknown significance (VUS, class 3) is identified. In cardiogenetics this happens in ~35–40% of patients. In our experiences in Sweden and the Netherlands, it can be hard for both healthcare professionals and patients to distinguish the difference between a VUS and a (likely) disease causing variant, sometimes leading to communication difficulties regarding the possibility of genetic testing in the family. In general, VUS indicate that the correlation between the identified genetic variants in the patient and the disease remains unclear. In this case predictive genetic testing in families is not advisable.
The value of a VUS, however, is not always the same. Suspicion of association with disease can vary from low (~5%) to high (~90%) and highly depends on the type of genetic variation, what is known about the gene and whether it could fit the cardiac abnormalities in the patient. If the suspicion that the association between the genetic variant and the disease in the patient is strong, the VUS is classified as “hot”. In this case an advice to both do genetic testing plus cardiological examination in the family is given to increase the strength of the finding. If association between the genetic variant and the disease becomes stronger, the variant can be reclassified into a likely or certain disease causing variant. From then genetic testing via a blood test can be performed in the family.
Although it can be expected that in the nearby future artificial intelligence can play a role in detecting the true meaning of this variants, we propose for now, to decrease both confusion, time and costs to, like in Sweden, only share a genetic variant of unknown significance with a patient when it is “hot”. The classification of a “hot” VUS can only be given after the variant has been weighed by a multidisciplinary team in a center of expertise considering the difficulties of the interpretation. Furthermore, we propose testing and cardiological screening of the family within this multidisciplinary team to see what the true value of this genetic variant is and accordingly share that with the family.
Translated by Saskia van der Crabben, Amsterdam UMC, Amsterdam, The Netherlands
van der Crabben SN, Mörner S, Lundström AC, Jonasson J, Bikker H, Amin AS, Rydberg A, Wilde AAM. Should variants of unknown significance (VUS) be disclosed to patients in cardiogenetics or not; only in case of high suspicion of pathogenicity? Eur J Hum Genet. 2022 Nov;30(11):1208-1210. doi: 10.1038/s41431-022-01173-z. Epub 2022 Aug 26. PMID: 36008533; PMCID: PMC9626604.