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INTRODUCTION
Dilated cardiomyopathy (DCM) is characterized by the dilation of one or both ventricles and reduced systolic function, occurring in the absence of abnormal loading conditions or significant coronary artery disease that would explain such remodeling [1]. To date, over 50 genes have been implicated in the development of DCM, reflecting the complexity of its genetic architecture [2]. Among these, the TTN gene is the most frequent genetic contributor, accounting for approximately 25% of cases [3].
The TTN gene encodes titin, a giant sarcomeric protein essential for maintaining cardiomyocyte stiffness and sensing cardiac strain [4]. Titin is divided into four distinct regions: the Z-disc, Iband, A-band, and M-band. Each region plays specific roles in muscle contraction and elasticity [5]. Most TTN truncating variants associated with DCM are located in the A-band. In contrast, variants in other regions, such as the I-band, are less frequently associated with clinical disease, highlighting the pathogenic significance of the A-band in DCM development [3, 6, 7].
Here, we report a case of DCM caused by a novel TTN frameshift variant located in the A-band of titin, underscoring the importance of variant location in determining DCM pathogenesis. This study was approved by the Institutional Review Board of Kangbuk Samsung Hospital (IRB No. 2024-09-009).
CASE REPORT
A 51-year-old woman presented with dyspnea on exertion and a 20 kg weight gain over the previous three months. Physical examination revealed signs of heart failure, including peripheral edema and abdominal distention. Laboratory tests showed significantly elevated N-terminal pro B-type natriuretic peptide (NT-proBNP) levels (2,426.0 pg/mL), indicating severe heart failure. The electrocardiogram showed sinus tachycardia and multiple ventricular premature complexes (Fig. 1A). Transthoracic echocardiography revealed severe left ventricular systolic dysfunction with an ejection fraction of 23.2% and left ventricular enlargement with normal wall thickness, consistent with a diagnosis of DCM (Fig. 1B). Coronary angiography revealed no significant atherosclerosis, ruling out ischemic causes for the DCM (Fig. 1C).
To investigate the genetic etiology of DCM, next-generation sequencing targeting 139 cardiomyopathy-related genes was performed (Table 1). A novel heterozygous frameshift variant in the TTN gene was identified: NM_001267550.2(TTN):c.70236dup (p.Phe23413Ilefs*6), which was confirmed by Sanger sequencing (Fig. 2). This variant is located in exon 326 within the A-band of titin, a known hotspot for DCM (Fig. 3). The frameshift introduces a premature stop codon, likely triggering nonsense-mediated decay of the mRNA. This variant was absent from major population databases, including the Genome Aggregation Database (gnomAD) and the Korean Variant Archive (KOVA), and has not been previously reported in the literature. According to the 2015 American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines [8], this variant was classified as likely pathogenic. Given the clinical presentation and genetic findings, the patient was diagnosed with DCM caused by this novel TTN frameshift variant.
DISCUSSION
DCM is a genetically heterogeneous disorder, with TTN truncating variants being the most prevalent genetic cause, accounting for a significant proportion of cases [3]. These variants are distributed across different regions of the titin protein, but their pathogenic impact highly depends on their specific location within the gene. In patients with DCM, TTN truncating variants are nonrandomly distributed throughout the titin protein, showing a significant overrepresentation in the A-band [3, 6, 7]. Understanding the nonrandom distribution of truncating variants and the location-dependent pathogenicity is essential for interpreting TTN variants, particularly when evaluating novel ones.
According to a study by Schafer et al. [7], truncating variants in the A-band are associated with the highest odds ratio of 49.8 for developing DCM. In contrast, those located in the central I-band have the lowest odds ratio of 1.5. Many truncating variants found in the general population are in the I-band and do not typically lead to DCM. This may be due to the lower proportion spliced-in (PSI) score of the exons in the I-band [6]. The PSI score reflects the proportion of TTN transcripts that include the exon where the truncating variant is located. A PSI score of 100% indicates a constitutively expressed exon, while a score lower than 100% suggests that an exon is variably skipped during splicing [9]. Many exons in the I-band have a low PSI score, indicating that truncating variants in this region are often skipped during splicing, reducing their pathogenic potential [6]. Consequently, truncating variants in the I-band are less likely to contribute to the development of DCM.
In contrast, all exons in the A-band have a PSI score of 100%, suggesting that truncating variants in this region are more likely to have deleterious effects and significantly increase the risk of developing DCM [6]. Therefore, the PSI score is a valuable tool for interpreting TTN truncating variants, providing insights into exon usage and the potential impact of such variants. The PSI score for TTN exons can be accessed via the Titin Variants in Dilated Cardiomyopathy database, available at [https://www.cardiodb.org/titin/index.php].
In this case, the patient presented with symptoms and signs consistent with DCM, and a novel frameshift variant was identified in exon 326 within the A-band of titin. Given that exon 326 has a PSI score of 100%, indicating it is constitutively expressed, this variant is likely to contribute to the patient’s clinical presentation. Additionally, the absence of this variant from population databases such as gnomAD and KOVA supports its pathogenicity. These findings emphasize the critical role of the A-band in the pathogenesis of DCM and highlight the necessity of considering variant location in the interpretation of TTN truncating variants.
The limitation of this study is the inability to obtain a detailed family history or perform genetic testing on family members, which could have provided further insights into the clinical relevance of the identified variant.
In conclusion, this case underscores the significance of the TTN gene, especially the A-band of titin, in the pathogenesis of DCM. The location of truncating variants within titin, particularly the PSI scores of these regions, is crucial for assessing variant pathogenicity and clinical relevance. Furthermore, the identification of this novel frameshift variant expands the genetic landscape of DCM.
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