Genetic Testing in Early AF May Reveal More Serious Congenital Problems

By Marilynn Larkin

September 22, 2021

NEW YORK (Reuters Health) - Genetic testing in patients with early-onset atrial fibrillation (AF) identified a more serious disease-associated variant in 10% of cases, researchers found.

"Research over the past several years has raised the concern that AF may be an early sign of more serious inherited cardiomyopathy or arrhythmia syndromes," Dr. Benjamin Shoemaker of Vanderbilt University in Nashville told Reuters Health by email. "We conducted this study to inform clinicians about the yield of genetic testing among different age groups and to identify the most common genes that harbor disease-associated variants."

"The prevalence of disease-associated variants didn't really surprise us, but the extent to which they were predominately from cardiomyopathy genes may have," he said. "These results further suggest that early-onset AF is often an atrial myopathy."

As reported in JAMA Cardiology, Dr. Shoemaker and colleagues analyzed data on individuals who received an AF diagnosis before age 66 and underwent whole genome sequencing between 1999-2015.

Rare variants were identified by a panel of 145 genes that are included on cardiomyopathy and arrhythmia panels used by commercial clinical genetic testing laboratories.

The primary outcome was classification of rare variants using American College of Medical Genetics and Genomics criteria: benign, likely benign, variant of undetermined significance, likely pathogenic, or pathogenic. Disease-associated variants were defined as pathogenic/likely pathogenic variants in genes associated with autosomal dominant or X-linked dominant disorders.

A total of 1,293 individuals were included in the analysis. The median age at enrollment in the genomic sequencing cohort was 56; 72% were men; the median age at AF diagnosis was 50.

Genetic testing identified 10.1% with a disease-associated variant; 62.8% with a variant of undetermined significance; 7.1% as heterozygous carriers for an autosomal recessive disorder; and 20% with no suspicious variant.

The likelihood of a disease-associated variant was highest in participants with AF diagnosed before the age of 30 (16.8%) and lowest after age 60 (7.1%).

Disease-associated variants were more often associated with inherited cardiomyopathy syndromes compared with inherited arrhythmias. Specifically, 7.2% had a disease-associated variant for dilated cardiomyopathy, 3.3% for hypertrophic cardiomyopathy; and 2.9% for arrhythmogenic cardiomyopathy.

By contrast, rates for inherited arrhythmias were 0.2% for Brugada syndrome, 0.9% for long QT syndrome, and 0.1% for catecholaminergic polymorphic ventricular tachycardia.

The most common affected genes were TTN, MYH7, MYH6, LMNA, and KCNQ1.

The authors conclude, "These results support the use of genetic testing in early-onset AF."

Dr. Shoemaker said, "A next step is to do detailed clinical phenotyping, which might involve MRI or drug challenges depending on the variant identified, and we've recently received an NIH grant to do that. Those results will help us better understand whether the genetic variants we identify actually increase AF risk and so will determine how important genetic testing (in) early-onset AF will become in the future.

Dr. Gordon Tomaselli of Albert Einstein College of Medicine in New York City, coauthor of a related editorial, commented in an email to Reuters Health, "AF is often a consequence of age or other cardiovascular diseases such as hypertension and heart failure, so the contribution of single gene variants is difficult to interpret."

"In this study, gene variants associated with heart muscle disease and other arrhythmias were more prevalent than expected, particularly in patients who experience AF at a younger age," he said. "The suggestion is that genetic testing may be useful in younger patients with AF, especially in patients without risk factors for this arrhythmia such as hypertension or obesity."

"The promissory is that the identification of a genetic cause of heart disease or potentially lethal arrhythmias may allow for early treatment and prevention," he said. "This will need to be tested prospectively in larger, more diverse populations."

SOURCE: https://bit.ly/3zekGZO and https://bit.ly/2VO9XHJ JAMA Cardiology, online September 8, 2021.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....