Global medical genetics · 2026
Exploring EPHB4 in gait disorders: VUS detection and phenotypic characterization in a toe-walking cohort.
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Pomarino David, Rostásy Kevin M, Fregien Bastian, Sidi Athmane Amel, Nazarkin Alexander
Аннотация
BACKGROUND: Idiopathic toe walking (ITW) is a gait abnormality with a suspected genetic contribution, although its underlying mechanisms remain poorly understood. While ephrin type-B receptor 4 (EPHB4) is primarily recognized for its role in vascular development, this study explored whether EPHB4 variants identified in children with ITW were associated with specific clinical characteristics.
METHODS: We retrospectively analyzed the clinical and genetic data of 20 children with toe walking who harbored EPHB4 variants identified using a targeted 49-gene next-generation sequencing (NGS) panel.
RESULTS: Genetic analysis identified 18 distinct EPHB4 variants, all of which were classified as variants of uncertain significance (VUS) according to the five-tier sequence variant classification system. The most common clinical findings were pes cavus (40%), clinodactyly/brachydactyly (40%), and speech or language delay (40%). Notably, only 10% of patients exhibited the venous anomalies typically associated with pathogenic EPHB4 variants.
CONCLUSIONS: This study identified a recurrent occurrence of EPHB4 variants in children with idiopathic toe walking. However, these findings should be interpreted with caution because all identified variants were classified as VUS, no clear genotype-phenotype correlation was observed, and ascertainment bias cannot be excluded. Further functional studies and familial segregation analyses are required to determine whether these findings represent a true biological association or incidental observations. These results highlight the complexity of investigating potential genetic contributors to common pediatric gait disorders such as idiopathic toe walking.
CLINICAL TRIAL REGISTRATION: not applicable.Retrospective cohort analysis of existing clinical data. Not prospectively registered as no interventions were performed.
METHODS: We retrospectively analyzed the clinical and genetic data of 20 children with toe walking who harbored EPHB4 variants identified using a targeted 49-gene next-generation sequencing (NGS) panel.
RESULTS: Genetic analysis identified 18 distinct EPHB4 variants, all of which were classified as variants of uncertain significance (VUS) according to the five-tier sequence variant classification system. The most common clinical findings were pes cavus (40%), clinodactyly/brachydactyly (40%), and speech or language delay (40%). Notably, only 10% of patients exhibited the venous anomalies typically associated with pathogenic EPHB4 variants.
CONCLUSIONS: This study identified a recurrent occurrence of EPHB4 variants in children with idiopathic toe walking. However, these findings should be interpreted with caution because all identified variants were classified as VUS, no clear genotype-phenotype correlation was observed, and ascertainment bias cannot be excluded. Further functional studies and familial segregation analyses are required to determine whether these findings represent a true biological association or incidental observations. These results highlight the complexity of investigating potential genetic contributors to common pediatric gait disorders such as idiopathic toe walking.
CLINICAL TRIAL REGISTRATION: not applicable.Retrospective cohort analysis of existing clinical data. Not prospectively registered as no interventions were performed.