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Pediatric toe-walking cohort with heterozygous SBF1 variants: A phenotypic description
David Pomarino1, Amel Sidi Athmane1, Bastian Fregien2
1Pomarino Praxis für Ganganomalien, Hamburg, Germany.
Global Medical Genetics
|February 25, 2026
Summary
Genetic testing in children with persistent toe walking identified heterozygous SBF1 variants, often classified as variants of uncertain significance (VUS). Further research is needed to clarify their clinical relevance and potential role in neuromuscular conditions.
Area of Science:
- Genetics
- Neurology
- Pediatrics
Background:
- Persistent toe walking is often idiopathic, but genetic factors may be involved.
- SBF1 gene variants are linked to autosomal recessive Charcot-Marie-Tooth disease type 4B3 (CMT4B3).
- The clinical significance of heterozygous SBF1 variants, particularly variants of uncertain significance (VUS), is not well understood.
Purpose of the Study:
- To explore the clinical features of children with persistent toe walking and heterozygous SBF1 variants.
- To compare these features with published CMT4B3 families and Human Phenotype Ontology (HPO) data.
Main Methods:
- Retrospective analysis of 86 children with persistent toe walking.
- Standardized blinded clinical assessment and targeted 49-gene next-generation sequencing.
- Comparison of phenotypic frequencies with existing CMT4B3 data and HPO.
Main Results:
- Heterozygous SBF1 variants, predominantly VUS, were identified in the cohort.
- Skeletal features like pes cavus were common.
- Muscle weakness and reflex abnormalities were less frequent than in recessive CMT4B3.
Conclusions:
- Heterozygous SBF1 variants were observed in children with toe walking and mild neuromotor/musculoskeletal features.
- These findings are descriptive and do not establish causality.
- Further studies are required to determine clinical significance and potential genetic mechanisms.
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