Pediatric toe-walking cohort with heterozygous SBF1 variants: A phenotypic description

Persistent toe walking is frequently labeled idiopathic; however, targeted genetic testing in selected cohorts can identify variants in genes implicated in neuromuscular disease. SBF1 is a known cause of autosomal recessive Charcot-Marie-Tooth disease type 4B3 (CMT4B3), whereas the clinical relevance of heterozygous SBF1 variants-particularly variants of uncertain significance (VUS)-remains unclear. We aimed to describe, in an exploratory manner, the clinical features of children with persistent toe walking in whom heterozygous SBF1 variants were identified, and to contextualize these observations using published CMT4B3 families and Human Phenotype Ontology (HPO) feature frequencies.

We retrospectively analyzed children referred to a specialized toe-walking clinic who underwent a standardized blinded clinical assessment and targeted 49-gene next-generation sequencing. Individuals with alternative sequencing approaches or known non-genetic causes of toe walking were excluded. Heterozygous SBF1 variants were summarized using HGVS nomenclature, ACMG classification, population allele frequency, and report date. Phenotypic frequencies were compared with published SBF1-related CMT4B3 families and with HPO-reported feature frequencies for CMT4B3.

The cohort comprised 86 children (mean age 9.5 years), all with persistent toe walking. Common findings included skeletal features (e.g., pes cavus and lumbar hyperlordosis), whereas muscle weakness and deep tendon reflex abnormalities were less frequent than reported in recessive CMT4B3 families. Genetic testing identified a spectrum of heterozygous SBF1 variants, predominantly classified as VUS.

In this referral-based cohort, heterozygous SBF1 variants were observed in children with persistent toe walking and accompanying mild neuromotor/musculoskeletal features that partially overlap with reported CMT4B3 phenotypes; however, these findings are descriptive and do not establish causality or enrichment. Longitudinal follow-up, segregation/phase determination, and electrophysiological studies are needed to clarify clinical significance, potential biallelic configurations in some individuals, and possible gene-dosage or modifier effects.