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Contribution of Noncanonical Splice Variants to TTN Truncating Variant Cardiomyopathy
Parth N Patel1,2, Kaoru Ito1,3, Jon A L Willcox1
1Department of Genetics (P.N.P., K.I., J.A.L.W., A.H., M.Y.J., J.M.G., S.R.D., L.L., B.M., C.E.S., J.G.S.), Harvard Medical School, Boston, MA.
Circulation. Genomic and Precision Medicine
|August 31, 2021
Summary
Noncanonical splice-altering variants in TTN (titin) explain 1-2% of idiopathic dilated cardiomyopathy (DCM) cases. These findings increase TTN sequencing diagnostic power by 10-20% for DCM patients.
Area of Science:
- Genetics
- Molecular Biology
- Cardiology
Background:
- Heterozygous TTN truncating variants are implicated in 10-20% of idiopathic dilated cardiomyopathy (DCM).
- Canonical splice signal disruption is recognized, but the impact of nearby sequence variations on splicing and disease contribution remains unclear.
Purpose of the Study:
- To investigate the role of rare variants of unknown significance in TTN splice regions in DCM.
- To assess the effect of these variants on splicing using in vitro assays.
Main Methods:
- Identified rare variants in TTN splice regions from DCM cases and controls.
- Utilized an in vitro splice assay to evaluate variant effects on splicing.
- Analyzed variant locations and employed SpliceAI for in silico prediction.
Main Results:
- Splice-altering variants were enriched in DCM cases (2% of patients) compared to controls.
- Noncanonical splice-altering variants were frequently found at specific donor (+5) and acceptor (-3) sites.
- SpliceAI showed high specificity but low sensitivity for detecting these variants.
Conclusions:
- Noncanonical splice-altering TTN variants account for 1-2% of DCM cases, enhancing diagnostic yield by 10-20%.
- Established rules may aid in detecting splice-altering variants in other genes.
- Provides potential explanation for low splicing efficiency in alternate TTN exons.
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