International journal of cardiology · 2025
Identification of the non-canonical splice-disrupting variants of TTN in dilated cardiomyopathy.
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Wang Linlin, Liu Hao, Zhao Qu, Chen Yanghui, Sun Yang, Li Rui, Yu Ting, Chen Chen, Wang Dao Wen
Аннотация
BACKGROUND: Titin truncating variants (TTNtvs) are the most common genetic cause of dilated cardiomyopathy (DCM). However, the pathogenicity of non-canonical splicing variants remains unknown.
METHODS AND RESULTS: By integrating bioinformatics predictions and minigene functional assays, we systematically evaluated 78 TTN non-canonical splicing variants and identified 16 splice-disrupting variants in 17 individuals. This finding increased the total number of TTNtvs by 14.5 % (16/110) and genetic diagnostic yield in the Chinese DCM cohort by 1.6 % (17/1041). Distribution analysis showed high positive rates in the core acceptor (47 %, 8/17) and donor (25 %, 1/4) regions. Comparison between patients carrying splicing variants (canonical and non-canonical) and those harboring other truncating mutations (nonsense and frameshift) revealed that the latter exhibited a significantly shorter time to heart transplantation (37.73 ± 18.96 vs. 16.21 ± 15.08; p = 0.002), whereas no significant difference in survival time was observed between the two groups (34.36 ± 17.38 vs. 39.56 ± 30.41; p = 0.594). Mechanistic studies on the c.45617-12G > A variant revealed enhanced binding to heterogeneous nuclear ribonucleoprotein A1 by generating a novel splice acceptor site, leading to partial intron retention.
CONCLUSIONS: By systematically screening for non-canonical splicing variants, this study improved the genetic diagnostic yield in the DCM cohort by 1.6 %. Overall, this study highlights the contribution of non-canonical splicing variants to TTN pathogenicity and refines the genetic architecture of DCM, supporting the development of more comprehensive genetic testing strategies to improve molecular diagnosis and genetic counseling.
METHODS AND RESULTS: By integrating bioinformatics predictions and minigene functional assays, we systematically evaluated 78 TTN non-canonical splicing variants and identified 16 splice-disrupting variants in 17 individuals. This finding increased the total number of TTNtvs by 14.5 % (16/110) and genetic diagnostic yield in the Chinese DCM cohort by 1.6 % (17/1041). Distribution analysis showed high positive rates in the core acceptor (47 %, 8/17) and donor (25 %, 1/4) regions. Comparison between patients carrying splicing variants (canonical and non-canonical) and those harboring other truncating mutations (nonsense and frameshift) revealed that the latter exhibited a significantly shorter time to heart transplantation (37.73 ± 18.96 vs. 16.21 ± 15.08; p = 0.002), whereas no significant difference in survival time was observed between the two groups (34.36 ± 17.38 vs. 39.56 ± 30.41; p = 0.594). Mechanistic studies on the c.45617-12G > A variant revealed enhanced binding to heterogeneous nuclear ribonucleoprotein A1 by generating a novel splice acceptor site, leading to partial intron retention.
CONCLUSIONS: By systematically screening for non-canonical splicing variants, this study improved the genetic diagnostic yield in the DCM cohort by 1.6 %. Overall, this study highlights the contribution of non-canonical splicing variants to TTN pathogenicity and refines the genetic architecture of DCM, supporting the development of more comprehensive genetic testing strategies to improve molecular diagnosis and genetic counseling.