Clinical and regional distribution of TTN variants in toe walking: A descriptive cohort study

The TTN gene encodes titin, a key structural protein of the sarcomere. Variants in TTN are frequently identified in genetic testing, but their clinical interpretation remains challenging due to their high prevalence in the general population and frequent classification as variants of uncertain significance (VUS). Toe walking is often considered idiopathic; however, emerging evidence suggests a potential genetic contribution.

To provide a descriptive analysis of TTN variants in children presenting with persistent toe walking, using a region-based approach to explore variant distribution and associated clinical features.

This retrospective study included children with persistent toe walking following exclusion of known neurological, neuromuscular, and orthopedic causes. All patients underwent standardized clinical assessment and targeted next-generation sequencing using a 49-gene panel. TTN variants were grouped into predefined cDNA intervals (c.1-c.9000). Clinical and genetic data were analyzed descriptively.

Fifty-five patients carrying 43 TTN variants were included (mean age 7.3 years; 71% male). Variants were unevenly distributed, with clustering in the c.1001-2000 (22.4%) and c.3001-4000 (19.0%) regions. All variants were classified as VUS. A consistent clinical phenotype was observed across groups, including persistent toe walking, reduced ankle dorsiflexion, and a frequent positive foot drop test. Group-specific differences were noted but remained inconsistent and descriptive.

TTN variants in children with toe walking show heterogeneous distribution but a largely consistent clinical presentation. No clear genotype-phenotype correlation was identified. These findings highlight the need for cautious interpretation of TTN VUS and further studies to clarify their clinical significance.