Case Report: autosomal dominant distal motor neuropathy as a new phenotype of KIF21A-related disorders

Heterozygous missense variants in the <i>KIF21A</i> gene are best known to cause congenital fibrosis of the extraocular muscles. A recent report by Borja et al., 2025 suggested that the <i>KIF21A</i> gene may also be associated with syndromic phenotype, including peripheral neuropathy, brain malformations, and strabismus. We report the second case of early-onset distal motor neuropathy associated with the <i>KIF21A</i> gene. The proband was a 6-year-old female patient who had normal brain MRI, while neurophysiological examination and lower limb muscle MRI both suggested peripheral neuropathy. Quad whole-genome sequencing of the proband, her healthy sibling, and parents identified a <i>de novo</i> missense variant, c.1991T>C, p. (Leu664Pro), in the <i>KIF21A</i> gene and two compound-heterozygous missense variants, c.274C>T, p. (Pro92Ser) and c.512A>G, p. (Asn171Ser), in the <i>OXA1L</i> gene. Since the clinical features were not fully consistent with the known phenotypes associated with <i>KIF21A</i> or <i>OXA1L</i>-related disorders, initial genetic analysis prioritized <i>OXA1L</i>. However, functional studies, including exploratory Western blot analysis and high-resolution respirometry failed to support the pathogenicity of the identified variants. Following the publication of a similar <i>KIF21A</i>-associated case, the c.1991T>C, p. (Leu664Pro) variant was re-evaluated and re-classified as likely pathogenic. Our case supports expansion of the <i>KIF21A</i>-related phenotype to include distal motor neuropathy without brain malformations, in addition to multiple reports of other <i>KIF21</i>-associated syndromic phenotypes. This finding suggests that the <i>KIF21A</i> gene should be considered in the differential diagnosis for patients presenting with childhood-onset distal motor neuropathies.