Titin-Truncating Variant Associated With Late-Onset Dilated Cardiomyopathy

Dilated cardiomyopathy (DCM) is frequently caused by genetic factors. Studies identifying deleterious rare variants have predominantly focused on early-onset cases, and little is known about the genetic underpinnings of the growing numbers of patients with DCM who are diagnosed when they are older than 60 years (i.e., late-onset DCM).

An international team of medical scientists collaborating with Cardiologists at the University of Trieste (Trieste, Italy) investigated the prevalence, type, and prognostic impact of disease-associated rare variants in patients with late-onset DCM. A population of patients with late-onset DCM who had undergone genetic testing in seven international tertiary referral centers worldwide were enrolled from March 1990 to August 2020. A positive genotype was defined as the presence of pathogenic or likely pathogenic (P/LP) variants. A total of 184 patients older than 60 years were studied, that included 103 female (56%); age, 67 ± 6 years; left ventricular ejection fraction, 32% ± 10%.

The investigators reported that the most common variants in this cohort were a Titin-truncating variant (TTNtvs), which affected 46 patients, or 69% of those with a genetic diagnosis. TTNtvs appeared nearly twice as common among this late-onset dilated cardiomyopathy cohort as has been reported among younger-onset dilated cardiomyopathy cohorts. The remaining 20 cases had other P/LP variants (motor sarcomeric genes, 8%; LMNA, 6%; FLNC, 6%; desmosomal genes, 6%, and other variants, 3%). Investigators observed patients with positive genetic testing more frequently had a family history of DCM compared to patients with negative genetic testing (76% versus 59%). During a median (interquartile range) follow-up of 42 (10-115) months, 23 patients (13%) died; 17 (25%) of these were carriers of P/LP variants, while six patients (5.1%) were genotype-negative.

The authors concluded that late-onset DCM might represent a distinct subgroup characterized by and a high genetic variation burden, largely due to titin-truncating variants. Patients with a positive genetic test had higher mortality than genotype-negative patients. These findings support the extended use of genetic testing also in older patients. The study was published on February 9, 2022 in the journal JAMA Cardiology.

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