Clinical and Genetic Spectrum of Titinopathy: A Turkish Pediatric Case Series

Our aim is to contribute to the literature by presenting pediatric titinopathy cases with different clinical and genetic profiles, including the newly identified homozygous TTN mutation.

We retrospectively evaluated five pediatric patients with genetically confirmed titinopathy who presented to the Cukurova University Pediatric Neurology Department between January 2015 and May 2025. Clinical features, pattern of muscle weakness, electromyography (EMG), creatine kinase (CK) levels, muscle biopsy findings, cardiac and respiratory involvement, and genetic analyses via next-generation sequencing (NGS) were documented.

Five pediatric patients from three consanguineous families were diagnosed with titinopathy. Patients' median age was 14 years (30 months-17 years). The mean age of walking in the patients was 28.5 months. Four patients from two consanguineous families carried a novel homozygous c.15218-2A>G mutation in the TTN gene, not previously reported as pathogenic. These cases exhibited a wide spectrum of muscle involvement, variable facial, respiratory, and cardiac manifestations, and histopathological features of myotubular or centronuclear myopathy. One unrelated patient had a known pathogenic homozygous c.35296G>A mutation, associated with limb-girdle and facial muscle weakness and mild cardiomyopathy. Despite genetic similarities, phenotypic expression varied even within families. All CK levels were normal.

This study expands the clinical and molecular understanding of titinopathies by identifying a novel TTN mutation associated with marked phenotypic variability, even within the same family. The findings underscore the significant heterogeneity of TTN-related myopathies and reinforce the necessity of comprehensive clinical and genetic evaluations for accurate diagnosis and effective genetic counseling.