Challenges of Genetic Testing
Genetic testing in all-comers with AF remains challenging for several reasons, in part due to logistic issues with genetic testing, including lack of universal access and high financial cost.70Additionally, there are several AF-specific factors that limit universal genetic testing among patients with AF, in addition to lack of clinical outcome data to support its use. Foremost, widespread genetic testing in AF is limited by an unknown prevalence of rare, potentially pathogenic variants in all-comers with AF. In patients with very early-onset lone AF only 15% may carry a recognized pathologic mutation in a panel of genetic mutations, including various ion channel genes, associated with AF development30; this finding has been replicated in broader context of all lone-AF patients.49 These rates are similar in very-early onset AF patients with regards to TTNmutations, with a prevalence of 16%.71 These estimates are much lower when considering genes associated with long-QT syndrome72 and laminopathies (which are associated with mutations in Lamin A/C, nuclear membrane filaments)73, which are associated with higher rates of AF.74,75 Additionally, discovery of carrier status of these genes in family members does not imply 100% penetrance.17,76
Widespread genetic testing in AF has the potential to uncover multiple variants of uncertain significance (VUS). Yoneda et al. found that in a cohort of 1,293 early onset AF subjects, 812 (63%) carried a VUS in an inherited cardiomyopathy or arrhythmia syndrome gene.49 Universal genetic testing would likely lead to a high number of VUS detected, and, currently, there is limited data to adjudicate how these variants affect disease state, which is also a problem for other inherited cardiomyopathy syndromes.77Additionally, widespread genetic testing may be limited by the ability of positive AF family history in predicting AF occurrence in unaffected family members and in outcomes for patients with AF. Positive family history of AF confers an approximate 2-fold relative risk of developing AF in unaffected family members.78 Family history of AF is also more commonly seen in patients with early-onset lone AF.79 Additionally, a positive family history of AF diagnosed in a first-degree relative at ≤65 years old is associated with an increased risk of atrial arrhythmia recurrence in drug-refractory AF post-ablation.80 Similarly, patients with a positive family history of AF occurring in a first-degree relative ≤65 years old are more likely to receive a permanent pacemaker or implantable cardioverter-defibrillator (ICD).81 Taken together, this stresses the importance of gathering a thorough family history in patients that are newly diagnosed with AF.