AUTHOR=Xiao Lei , Li Chenze , Sun Yang , Chen Yanghui , Wei Haoran , Hu Dong , Yu Ting , Li Xianqing , Jin Li , Shi Leming , Marian Ali J. , Wang Dao Wen 

TITLE=Clinical Significance of Variants in the TTN Gene in a Large Cohort of Patients With Sporadic Dilated Cardiomyopathy

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=8

YEAR=2021

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2021.657689

DOI=10.3389/fcvm.2021.657689

ISSN=2297-055X

ABSTRACT=<p><bold>Background:</bold> Mutations in the <italic>TTN</italic> gene are the most common causes of dilated cardiomyopathy (DCM). The clinical significance of <italic>TTN</italic> gene variants remains inadequately understood.</p><p><bold>Methods:</bold> Whole-exome sequencing and phenotypic characterisation were performed, and patients were followed up for a median of 44 months.</p><p><bold>Results:</bold> We analyzed the association of the <italic>TTN</italic> variants with the clinical outcomes in a prospective study of 1,041 patients with sporadic DCM. <italic>TTN</italic> truncating variants (tTTN) were detected in 120 (11.5%) patients as compared with 2.4/10,000 East Asian populations in the Genome Aggregation Database (GnomAD; <italic>p</italic> &lt; 0.0001). Pathogenic <italic>TTN</italic> missense variants were also enriched in DCM as compared with the GnomAD populations (27.6 vs. 5.9%, <italic>p</italic> &lt; 0.0001). DCM patients with tTTN had a lower left ventricular ejection fraction (28.89 ± 8.72 vs. 31.81 ± 9.97, <italic>p</italic> = 0.002) and a lower frequency of the left bundle branch block (3.3 vs. 11.3%, <italic>p</italic> = 0.011) than those without or with mutations in other known causal genes (OCG). However, tTTN were not associated with the composite primary endpoint of cardiac death and heart transplantation during the follow-up period [adjusted hazard ratio (HR): 0.912; 95% confidence interval: 0.464–1.793; <italic>p</italic> = 0.790]. There was also no sex-dependent effect. Concomitant tTTN and pathogenic variants in OCG were present in only eight DCM patients and did not affect the outcome.</p><p><bold>Conclusion:</bold> The phenotype of DCM caused by tTTN, major causes of sporadic DCM, is not distinctly different from those caused by other causal genes for DCM.</p>