Title : Importance of genetic testing in patients referred for heart transplant or durable mechanical circulatory support
Abstract:
Purpose: Genetic abnormalities are found in 5 to >20% of cases of dilated cardiomyopathy (DCM), depending on the population studied. Truncating variants of TTN (TTNtv) are the most common genetic cause of DCM, accounting for up to 25% of cases with familial inheritance. Lifetime risk for DCM is high but recent studies have shown that treatment of TTNtv pre-DCM may delay development of symptoms.
Methods: We studied 201 patients (pts) with non-ischemic DCM and end stage heart failure defined by need for heart transplantation or durable mechanical support (Tx/VAD). Presumed etiology was malignancy (1), congenital (3), anthracycline (4), myocarditis (2), peripartum (2), hypertrophic (4), valvular (1), infiltrative (2), mixed ischemic/nonischemic (2) and
familial (14). The remaining pts had no etiology identified.
Results: Pts were 65% male; mean age 51 years; 56% were Black and 39% were White. Initial treatment was VAD in 32 pts and tx in169 pts. Pts were studied using the Invitae/Labcorp cardiomyopathy panel (121 genes) in 167 pts, the Ambry panel (92 genes) in 33 pts and Boston University genetic testing in 1 pt. Pathogenic or potentially pathogenic variants were noted in 67/201 (33.3%) of patients. Variants of the TTN gene were seen in 33/201 (16.4%) pts. No single variant appeared in more than 1 pt. TTR variants (all Val142Ile) were seen in 9/201pts (5.5%). Among pts with a family history of DCM, 10/14 had variants of genes associated with DCM. Among the 187 patients with no family history of DCM, 33 had TTNtv. Other pathogenic variants included ACTC1 (1), AGL (2), BAG3 (1), CPT2 (1), DMD (2), DNAJC19 (1), FKTN (1), FLNC (3), LMNA (3), LZTR1 (2), MTO1 (1), MYBPC3 (3), MYH7(4), PCCA (1), PCCB (1), PKP2 (2), PLN (1), PRKAG2 (1), SDHA (1), SLC22A5 (1), TCAP (1), TNNI3 (1), CAV3 (1), and TRDN (1). Only 3/33 patients with TTNtv had family histories of DCM. Among patients with pathogenic or potentially pathogenic variants, 237 siblings and 152 children were identified. Among the 62 family members tested, 36 had shared genes.
Conclusions:
- Genetic abnormalities are common in patients with end-stage cardiomyopathy even in the absence of a family history.
- Variants of the TTN gene are the most common genetic cause for nonischemic cardiomyopathy, occurring in 16.4% of patients with DCM undergoing Tx/VAD.
- Genetic testing will identify high risk family members of TTNtv patients and allow early potentially life-saving treatment.
- Genetic testing should be extended to all patients with dilated cardiomyopathy referred for Tx/VAD.
