Over‐Representation of <i>TTN</i> Truncating Variants in a Finnish Cohort of Patients With Axial Myopathy

Abstract

<h3>Background</h3><p>Axial myopathies present with late onset selective paravertebral weakness causing bent spine/camptocormia or dropped head, and the genetic basis remains currently only partially understood. Truncating variants in <em>TTN</em> (TTNtv) are found in about 1% of the general population and, when biallelic, cause recessive titinopathies. Also, TTNtv located in cardiac exons are known to confer an increased risk of cardiomyopathy, with incomplete penetrance.</p><h3>Methods</h3><p>We retrospectively analyzed 55 Finnish adults with late-onset axial myopathy evaluated at the Tampere Neuromuscular Center (2015–2025). Clinical, imaging, and histopathological data were collected, and genetic testing was performed using the MYOcap targeted next-generation sequencing panel.</p><h3>Results</h3><p>Heterozygous TTNtv were identified in 9 of 55 patients (16%), representing a significant enrichment compared with the general population (odds ratio = 14.1; <em>p</em> ≈5 × 10⁻⁸). The variants were ultra-rare, distributed across different exons expressed in skeletal muscle, and five were absent from gnomAD. Mean age at onset was 60 ± 11 years; six patients were female, and five reported a positive family history. Camptocormia was the main presentation, with muscle MRI showing a consistent fatty-fibrous replacement of paravertebral muscles in all cases. Muscle biopsies revealed either myopathic or myofibrillar changes without a uniform pattern.</p><h3>Conclusions</h3><p>Heterozygous TTNtv are significantly enriched in patients with late-onset axial myopathy, suggesting a potential contribution to this phenotype. These findings broaden the clinical spectrum of titin-related diseases and support inclusion of <em>TTN</em> in genetic testing for idiopathic axial myopathies.</p>