Genetic testing may be considered in patients with early-onset atrial fibrillation (AF), particularly those with a positive family history and lack of conventional clinical risk factors, because specific genetic variants may underlie AF as well as “potentially more sinister cardiac conditions,” a new white paper from the Canadian Cardiovascular Society suggested.
“Given the resources and logistical challenges potentially imposed by genetic testing (that is, the majority of cardiology and arrhythmia clinics are not presently equipped to offer it), we have not recommended routine genetic testing for early-onset AF patients at this time,” lead author Jason D. Roberts, MD, associate professor of medicine at McMaster University in Hamilton, Ontario, Canada, told this news organization.
“We do, however, recommend that early-onset AF patients undergo clinical screening for potential coexistence of a ventricular arrhythmia or cardiomyopathy syndrome through careful history, including family history, and physical examination, along with standard clinical testing, including ECG, echocardiogram, and Holter monitoring,” he said.
The white paper was published online in the Canadian Journal of Cardiology.
Routine Testing Unwarranted
The Canadian Cardiovascular Society reviewed AF research in 2022 and concluded that a guideline update was not yet warranted. One area meriting consideration but lacking sufficient evidence for a formal guideline was the clinical application of AF genetics.
Therefore, the society formed a writing group to assess the evidence linking genetic factors to AF, discuss an approach to using genetic testing for early-onset patients with AF, and consider the potential value of genetic testing in the foreseeable future.
The resulting white paper reviews familial and epidemiologic evidence for a genetic contribution to AF. As an example, the authors pointed to work from the Framingham Heart Study showing a statistically significant risk for AF among first-degree relatives of patients with AF. The overall odds ratio (OR) for AF among first-degree relatives was 1.85. But for first-degree relatives of patients with AF onset at younger than age 75 years, the OR increased to 3.23.
Other evidence included the identification of two rare genetic variants: KCNQ1 in a Chinese family and NPPA in a family with Northern European ancestry. In case-control studies, a single gene, titin (TTN), was linked to an increased burden of loss-of-function variants in patients with AF compared with controls. The variant was associated with a 2.2-fold increased risk for AF.
For example, loss-of-function SCN5A variants are implicated in Brugada syndrome and cardiac conduction system disease, whereas gain-of-function variants cause long QT syndrome type 3 and multifocal ectopic Purkinje-related premature contractions. Each of these conditions was associated with an increased prevalence of AF.
Similarly, genes implicated in various other forms of ventricular channelopathies also have been implicated in AF, as have ion channels primarily expressed in the atria and not the ventricles, such as KCNA5 and GJA5.
Nevertheless, in most cases, AF is diagnosed in the context of older age and established cardiovascular risk factors, according to the authors. The contribution of genetic factors in this population is relatively low, highlighting the limited role for genetic testing when AF develops in the presence of multiple conventional clinical risk factors.