Toe Walking: a Regional Analysis of TTN Variants Between c.10,000 and c.99,999 in a Cohort of Children

Background Persistent toe walking is traditionally considered idiopathic when no neurological or orthopedic cause is identified. Emerging evidence suggests genetic contributors, including TTN, but genotype–phenotype relationships remain poorly understood in affected children. Methods This retrospective descriptive study evaluated children with persistent toe walking assessed between November 2022 and April 2026 at a specialized physiotherapy practice. All participants underwent standardized clinical assessment and targeted next-generation sequencing. Individuals carrying TTN variants within the c.10,000–99,999 region were stratified into nine predefined cDNA intervals. Demographic characteristics, gait features, musculoskeletal findings, neurological signs, and variant distributions were summarized descriptively. Results The cohort comprised 581 individuals carrying 509 TTN variants. Most variants were classified as variants of uncertain significance, while likely pathogenic variants were uncommon. Male predominance was observed across all intervals. Mean age at assessment, age at independent walking, age at toe-walking onset, and toe-walking frequency were highly consistent between groups. Reduced ankle dorsiflexion was the most frequent examination finding, affecting 88.2–97.4% of participants. Muscle pain, cramps, fatigue, spinal abnormalities, heel-walking impairment, pes cavus, tremor, and other associated features demonstrated modest variation across intervals without a consistent regional pattern. Several recurrent TTN variants were identified, most notably c.32624 C>T, c.48727 C>T, and c.73825 G>C. Conclusions Children carrying TTN variants within the c.10,000–99,999 region exhibited broadly similar clinical phenotypes characterized by persistent toe walking and reduced ankle dorsiflexion. Stratification by cDNA location did not reveal clear genotype–phenotype clustering, suggesting limited predictive value of variant position alone and supporting the need for functional and segregation-based studies in future research.