Toe walking in children with variants in myopathy-associated genes: A retrospective descriptive cohort study

Tip-toe walking may occur in children carrying variants associated with, neuromuscular disorders, but characteristics of children carrying variants in selected, muscle-related genes remain insufficiently characterized. We characterized children, with tip-toe walking carrying variants in CAV3, CLCN1, COL6A2, or COL6A3.

This retrospective study included children assessed at a referral center, between November 2022 and June 2026. Clinical and genetic data were reviewed from, a 49-gene next-generation sequencing panel. Demographic, developmental, toewalking, caregiver-reported, and clinical characteristics were summarized descriptively.

The cohort comprised 288 children carrying variants in CAV3, CLCN1, COL6A2, or COL6A3. Demographic characteristics, age at independent walking, age, at onset of tip-toe walking, tip-toe walking proportion, and clinical course were, comparable across cohorts. Independent walking occurred at 12-13 months, while tiptoe, walking began during the second year of life and accounted for approximately 80%, of daily walking. Family history of tip-toe walking was reported in one-third to one-half, of participants. Pain, cramps, fatigue, and speech difficulties were reported across all, cohorts. Restricted ankle mobility was consistently documented, while pes cavus, littlefinger, shortening/curvature, and chest wall abnormalities were frequent. VUS, predominated in CAV3, COL6A2, and COL6A3.

Children carrying variants in these four genes showed similar tip-toe, walking characteristics. Additional findings occurred in a minority. Findings should be, interpreted within the limitations of the retrospective, single-center design, unequal, cohort sizes, reliance on caregiver-reported and observational data, limited, segregation analysis, and predominance of VUS in three cohorts. Results do not.