JACC. Advances · 2025
Truncating Titin and Lamin A/C Variants in Anthracycline-Induced Cardiomyopathy.
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Advani Pooja P, McPherson Alyssa D, Reddy Joseph S, Schneider Jay W, Baheti Saurabh, Nguyen Thien D, Ray Jordan C, Norton Nadine
Аннотация
BACKGROUND: Anthracycline chemotherapy-related cardiomyopathy (CCM) is a serious adverse event that can occur several years after completion of therapy. Demographic and clinical risk factors have failed to predict which patients will experience CCM. Genetic variants may account for a significant proportion of interindividual variation and CCM.
OBJECTIVES: This study aimed to identify genetic variants in the known idiopathic cardiomyopathy genes that predispose patients to CCM.
METHODS: We developed a cardiotoxicity registry. Patients were (and continue to be) enrolled and consented for chart review and DNA sequencing. We sequenced whole exomes of the first 136 patients (anthracycline, n = 55; anti-HER2 [no anthracycline], n = 71; other chemotherapy, n = 10), primarily focusing on titin (TTN) truncating variants, known to be present in ∼25% of patients with primary dilated cardiomyopathy, and previously reported in 7.5% of patients with CCM, followed by exploration of rare nonsynonymous variants in 62 established genes for idiopathic cardiomyopathy.
RESULTS: Eighteen of 55 patients treated with anthracycline experienced CCM. TTN truncating variants were identified in 2 of 18 (11%) CCM patients and absent in 37 patients who did not experience CCM. We identified a pathogenic variant in lamin A/C (p.Arg190Gln) in 1/18 (5.5%) patients and the same rare (p.Glu1127Gly) variant in ryanodine receptor 2 occurred in 2/18 (11%) of patients. We observed enrichment of rare missense variants in patients with anthracycline CCM compared to anti-HER2 therapy without anthracycline CCM (P < 0.00001).
CONCLUSIONS: Three of 18 anthracycline CCM patients carried likely pathogenic variants in the most common causative genes for idiopathic dilated cardiomyopathy, TTN, and lamin A/C. Rare nonsynonymous variants in ryanodine receptor 2 and other idiopathic cardiomyopathy genes warrant further investigation.
OBJECTIVES: This study aimed to identify genetic variants in the known idiopathic cardiomyopathy genes that predispose patients to CCM.
METHODS: We developed a cardiotoxicity registry. Patients were (and continue to be) enrolled and consented for chart review and DNA sequencing. We sequenced whole exomes of the first 136 patients (anthracycline, n = 55; anti-HER2 [no anthracycline], n = 71; other chemotherapy, n = 10), primarily focusing on titin (TTN) truncating variants, known to be present in ∼25% of patients with primary dilated cardiomyopathy, and previously reported in 7.5% of patients with CCM, followed by exploration of rare nonsynonymous variants in 62 established genes for idiopathic cardiomyopathy.
RESULTS: Eighteen of 55 patients treated with anthracycline experienced CCM. TTN truncating variants were identified in 2 of 18 (11%) CCM patients and absent in 37 patients who did not experience CCM. We identified a pathogenic variant in lamin A/C (p.Arg190Gln) in 1/18 (5.5%) patients and the same rare (p.Glu1127Gly) variant in ryanodine receptor 2 occurred in 2/18 (11%) of patients. We observed enrichment of rare missense variants in patients with anthracycline CCM compared to anti-HER2 therapy without anthracycline CCM (P < 0.00001).
CONCLUSIONS: Three of 18 anthracycline CCM patients carried likely pathogenic variants in the most common causative genes for idiopathic dilated cardiomyopathy, TTN, and lamin A/C. Rare nonsynonymous variants in ryanodine receptor 2 and other idiopathic cardiomyopathy genes warrant further investigation.