Functional Validation of a Novel Homozygous TTN Splice-Site Variant Reveals Aberrant Splicing in Hypertrophic Cardiomyopathy.
Xiaoyun Sun, Dandan Wang, Shujuan Wang et al.
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Case in brief
A 42-year-old male with nonobstructive hypertrophic cardiomyopathy (HCM) and paroxysmal atrial arrhythmias underwent whole-exome sequencing, revealing a novel homozygous TTN splice-site variant. This variant was predicted to cause aberrant splicing, confirmed by minigene assays, leading to an in-frame protein alteration. The variant was classified as a variant of uncertain significance, with two asymptomatic offspring identified as heterozygous carriers.
Diagnostic / clinical pearl
Clinicians should consider the potential for TTN splice-site variants to contribute to HCM, as demonstrated by the functional validation of this novel variant.
Why it matters
This case highlights the importance of functional assays in interpreting variants of uncertain significance, particularly in the context of genetic cardiomyopathies.