NATIONAL HARBOR, MD. – Testing to identify mutations in the gene that codes for the muscle protein titin is now a reasonable step in routine clinical practice for selected people with either early-onset atrial fibrillation (AFib) or a family history of atrial fibrillation, or other cardiac disorders that have been strongly linked with titin-gene mutations, Patrick T. Ellinor, MD, said at the annual International AF Symposium.
About one out of every 250 people carries a loss of function (LOF) mutation in one of their TTN genes that codes for the titin protein, making these mutations about as common as mutations for familial hypercholesterolemia, noted Dr. Ellinor, professor of medicine at Harvard Medical School in Boston and director of the Cardiovascular Disease Initiative at the Broad Institute in Cambridge, Mass. TTN LOF mutations are “bad and very frequent,” he said in an interview. “This is evolving quickly as we start to appreciate how frequent these mutations are.”
Several commercial genetic testing companies now offer testing of blood specimens for TTN LOF mutations, often as part of an “arrhythmia test” panel, with a turnaround time of about 4 weeks at a cost to the patient of about $100, noted Dr. Ellinor, who said that he has begun to discuss such testing with a small number of patients in his practice. “It’s reasonable for selected people; the jury is still out on which ones,” a subject that guideline writers will soon need to address, he said.
Patients already diagnosed with early-onset atrial fibrillation (AFib) could benefit from knowing if they had a TTN LOF mutation because that diagnosis would warrant a magnetic resonance scan to look for “subtle myopathies” not detectable with echocardiography, Dr. Ellinor explained. Identification of a TTN LOF would also be a reason to then test the patient’s children. “Perhaps we should offer testing to everyone 40 years old or younger with AFib,” Dr. Ellinor suggested. Many of these patients are now getting genetic testing for TTN on their own “whether or not their physician wants it done,” he noted.
The most recent, and perhaps most persuasive evidence for the link between TTN LOF mutations and AFib came from a recent report from Dr. Ellinor and associates that examined genome-wide associations in 1,546 people with AFib and 41,593 controls using information contained in the UK Biobank, which holds complete gene sequencing data for about half a million U.K. residents (Circ Res. 2020 Jan 17;126: 200-9). The results showed that just under 0.5% of the entire population carried a TTN LOF mutation, and among patients with AFib the prevalence of a TTN LOF mutation was about 2%, but among people who carry this type of mutation 14% were diagnosed with AFib. This penetrance of 14% for AFib among people with a TTN LOF mutation makes AFib the most frequent clinical consequence identified so far for people with this type of mutation. Other cardiac disorders linked with TTN LOF mutations include heart failure and nonischemic cardiomyopathy. The Biobank study findings showed a penetrance for heart failure of about 7% among those with a TTN LOF mutation, and a penetrance of these mutations for nonischemic cardiomyopathy of about 3%.
Dr. Ellinor cited three other recently published studies with consistent results documenting a strong link between TTN LOF mutations and AFib: a study he worked on with lead author Seung H. Choi, Ph.D., and associates that ran an analysis on 2,781 AFib patients and 4,959 controls in a U.S. database of people who underwent whole-genome sequencing (JAMA. 2018 Dec 11; 320:2354-64); a study of 24 Danish families with clusters of three or more affected members with AFib as well as 399 Danish residents with lone, early-onset AFib (Nat Commun. 2018 Oct 17;9:4316); and a study of 25 patients with “very early onset” (less than 45 years old) AFib, which identified four of the 25 patients with a TTN LOF mutation (Circ Genom Precis Med. 2019 Nov 12; 526-8).
Titin is the largest protein in humans and is critical for normal myocardial function. Titin acts as a molecular scaffold for sarcomere assembly and signaling, providing passive stiffness to the sarcomere. Mutations in TTN have been associated with tibial muscular dystrophy, hypertrophic cardiomyopathy, and dilated cardiomyopathy. The relationship now established between TTN mutations and AFib, cardiomyopathy, and heart failure may in the future help explain the tight clinical association of AFib and heart failure, Dr. Ellinor noted. The TTN gene is also notable as the largest gene in the human genome.
Dr. Ellinor has received research funding from Bayer, and he has served as an adviser or consultant to Bayer, Quest Diagnostics, and Novartis.
SOURCE: Choi SH et al. Circ Res. 2020 Jan 17;126: 200-9.