NGS-Panel Diagnosis Developed for the Differential Diagnosis of Idiopathic Toe Walking and Its Application for the Investigation of Possible Genetic Causes for the Gait Anomaly

Abstract

Idiopathic toe walking (ITW) describes a condition affecting approximately 4.5% of children. Toe walking is an accompanying symptom for many hereditary disorders. This retrospective study uses next-generation sequencing-panel-diagnosis to investigate the feasibility of genetic testing to research the possible genetic causes of ITW and for differential diagnosis.Data were taken from our inhouse database, the minimum age for participants was 3 years. Underlying neurological or orthopaedic conditions were tested for and ruled out prior to diagnosing ITW. Patients, who experienced complications before, during or immediately after birth, children with autism, and patients toe walking less than 50% of the time were excluded.Eighty-nine patients were included in the study, in which 66 (74.2%) patients were boys and 23 (25.8%) girls. Mean age at testing was 7.7 years (range: 3–17 years). Fifteen of the 89 patients included in the study (16.9%) had a genetic variant identified as likely pathogenic or pathogenic by the genetics laboratory. Additionally, we found 129 variants of uncertain significance. About 65.2% of patients showed a pes cavus foot deformity, 27% of patients reportedly had at least one relative who also displayed the gait anomaly, and 37.1% had problems with their speech development.Despite the limitations of the sample size and the scope of our genetic testing targets, our results indicate that research into the genetic causes of ITW could better our understanding of the causes of ITW in otherwise healthy children, to help develop novel methods to detect serious conditions early. ITW could be an early onset symptom for further hereditary conditions.

Gut Microbiome Dysbiosis as a Potential Risk Factor for Idiopathic Toe-Walking in Children: A Review

“…These findings suggest that the severity and clinical presentation of ITW may depend on a combination of mutated variants and various risk factors, such as perinatal factors [23,34,35], which may affect the development of sensorimotor impairment. Of note, showing the merit of continued genetic research into the genetic causes of ITW, the research has the potential to identify ITW as a symptom for further conditions, which it was not previously linked to.…”

“…Several mutations were found in addition to defects in the 129 genes of uncertain significance. These mutations may lead directly to toe walking lesions and gait abnormalities [23]. Of note, children who were found to have mutations that led to the development of ITW did not experience any birth-related complications before, during, or immediately after their birth [22,23].…”

“…The prevailing TW history among families with ITW strongly suggests the involvement of genetic factors in the manifestation of this condition within specific individuals [7,[19][20][21]. Indeed, Pomarino and his colleagues propose that genetic abnormalities may be the root cause of the frequent occurrence of ITW in children during their developmental stage [21][22][23]. Several mutations were found in addition to defects in the 129 genes of uncertain significance.…”