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

ABSTRACT: Background: Mutations in the TTN gene are the most common causes of dilated cardiomyopathy (DCM). The clinical significance of TTN gene variants remains inadequately understood. Methods: Whole-exome sequencing and phenotypic characterisation were performed, and patients were followed up for a median of 44 months. Results: We analyzed the association of the TTN variants with the clinical outcomes in a prospective study of 1,041 patients with sporadic DCM. TTN 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; p < 0.0001). Pathogenic TTN missense variants were also enriched in DCM as compared with the GnomAD populations (27.6 vs. 5.9%, p < 0.0001). DCM patients with tTTN had a lower left ventricular ejection fraction (28.89 ± 8.72 vs. 31.81 ± 9.97, p = 0.002) and a lower frequency of the left bundle branch block (3.3 vs. 11.3%, p = 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; p = 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. Conclusion: 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.

SUBMITTER: Xiao L

PROVIDER: S-EPMC8120103 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Idiopathic dilated cardiomyopathy (DCM) is a common cardiomyopathy with the prevalence of 1:250, and at least one-third of all the cases are inherited. Mutations in the TTN gene are considered as the most frequent cause of inherited DCM and cover 10-30% of the cases. The studies were mainly focused on the adult or mixed age group of patients with DCM. The mutation rate in the TTN gene, the characteristics of manifestations and their prognostic significance in childhood have not been studied. To determine TTN mutation rate in children with DCM and the relevance of including this gene in the DNA diagnostic protocol for paediatric DCM, complete clinical and instrumental examination of 36 DCM patients (up to 18 years) with the manifestation of the disease was conducted in specialised cardiology centres. Molecular genetic testing included sequencing of coding and adjacent regulatory regions of the major cardiac TTN isoform N2BA using IonTorrent ™ semiconductor sequencing (for 25 isolated cases) and trio whole exome sequencing (trio WES)on the Illumina platform (for 11 family cases). Our pilot group included 36 probands with DCM diagnosis first established on the basis of the generally accepted criteria at the age of 5 days to 18 years(average age: 6.5 years). The sex ratio (M:F) was 23: 8. There were 25 sporadic DCM cases and 11 cases of familial DCM (at least one of the parents and/or siblings were also diagnosed with DCM). The only likely pathogenic truncating variant p.Arg33703*in the TTN gene (TTNtv) was found in a 16-year-oldmale proband out of 36 (3%). Apparently, TTN-dependent forms of DCMs manifest later at a young (but older than 18 years) or more mature age, and TTN gene cannot be considered as the first-line genetic testing for DCM in the paediatric group, despite several studies have reported a generally high mutation rate in this gene with DCM. Further research is needed to compare the representation of mutations in the TTN gene in different age groups of DCM patients.

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

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