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.