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

Abstract

Purpose 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.

Methods 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.

Results 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.

Conclusions 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.

Keywords

Genetic Testing / Toe Walking / Neurology / Pediatrics / SBF1 / Mutations

Author contribution

David Pomarino contributed to the conceptualization of the study, data curation, and formal analysis. Amel Sidi Athmane contributed to data curation and investigation and drafted the original manuscript. Bastian Fregien and Alexander Nazarkin contributed to the study methodology and validation. Kevin M. Rostásy contributed to formal analysis, supervision, validation, and manuscript review and editing. All authors reviewed and approved the final manuscript.

Ethical statement

This study was conducted in accordance with the ethical principles of the World Medical Association Declaration of Helsinki. All procedures were performed in compliance with relevant laws and institutional guidelines and were approved by the ethical board of the Deutschen Verbandes für Physiotherapie an der Physio-Akademie in Wremen, Germany (project number 2025-02).

Prior to participation, written informed consent was obtained from all subjects. The consent process included explanations of the study's purpose, procedures, and any potential implications of the results. All data collected were formally anonymized to protect participant confidentiality.

This manuscript was prepared in accordance with the International Committee of Medical Journal Editors (ICMJE) recommendations.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Declaration of Competing Interest

The Authors declare that there is no conflict of interest.

Declaration of generative AI and AI-assisted technologies in the writing process

Generative AI Deepseek was used in the writing phase of this manuscript exclusively for linguistic polishing and enhancing clarity. All scientific reasoning, data analysis, and intellectual substance remain the sole contribution of the authors. The AI was not employed in the research process itself.

Acknowledgments

We extend our sincere gratitude to the children and their families whose participation made this study possible. We also thank the medical professionals involved for their expert clinical assessments, thoughtful project oversight, and constructive feedback throughout the course of this research.

We are particularly grateful to the administrative, technical, and support staff at Pomarino Praxis für Ganganomalien in Hamburg for their careful data acquisition and coordination of the study. We further acknowledge Labor Dr. Heidrich & Colleagues for providing specialized genetic testing and expert analytical support.

Appendix A. Supplementary material

Supplementary data associated with this article can be found in the online version at doi:10.1016/j.gmg.2026.100095.

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