Hereditary neuropathy or pain disorder

Gene: KIF21A

Green List (high evidence)

Comment on list classification: There are 3 unrelated individuals with progressive peripheral neuropathy reported with de novo heterozygous missense variants localised in the second coiled‑coil domain of KIF21A. Variants in other KIF21A domains are not known to cause neuropathy. Based on available evidence, KIF21A should be promoted to Green for Hereditary neuropathy or pain disorder.

Created: 19 Dec 2025, 10:43 a.m. | Last Modified: 19 Dec 2025, 10:43 a.m.

Panel Version: 7.29

PMID: 32141982 Soliani et al., 2021
13yo male patient, Caucasian, with CFEOM, intellectual disability, brain malformations, and peripheral sensory-motor neuropathy. Cyclic vomiting not present. Multiple brain malformations noted on MRI. He harboured a de novo KIF21A variant c.2015T>C, p.Leu672Pro (NM_001173464.2 KIF21A:c.2054T>C, p.Leu685Pro).

PMID: 39643435 Borja et al., 2025
Proband: 7yo White, non-Hispanic female; presented with developmental delay (not speaking or crawling at 15 months), hypotonia, abnormal corpus callosum, peripheral neuropathy, comitant strabismus, frequent vomiting, and other systemic features. Het for a de novo KIF21A variant (NM_001173464.2: c.1991T>C, NP_001166935.1: p.Leu664Pro).

PMID: 41282472 Subbotin et al., 2025
6yo Russian female patient with peripheral neuropathy, normal MRI; had delayed motor development, she began walking independently at 18 months, no speech delay; frequent vomiting until age 5; intermittent exotropia; pes cavus and ankle contractures; dysarthria. She harboured a de novo variant c.1991T>C, p. (Leu664Pro) in KIF21A, as well as 2 compound het variants in OXA1L. KIF21A p.Leu664Pro (same variant as in PMID: 39643435) was selected as causal.

Other heterozygous variants in KIF21A do not cause neuropathy e.g.:
PMID: 22699964 Di Fabio et al., 2013: Family with adult onset autosomal dominant CFEOM1 (Congenital bilateral ptosis and non-progressive restrictive ophthalmoparesis) with a heterozygous p.R954W variant segregating with disease.
PMID: 37921537 Bhola et al., 2024: Reported a case with heterozygous KIF21A variant:c.836A>G, p.Glu279Gly. 10yo female patient (deceased). Presented with DD, microcephaly, axial hypotonia, hyporeflexia, muscle atrophy.

It appears that phenotypic variability may be tied to KIF21A domains; missense variants in the second coiled‑coil domain of KIF21A (p.Leu644Pro and p.Leu685Pro) are reported to cause a consistent phenotype of progressive peripheral neuropathy.

KIF21A is linked to AD Fibrosis of extraocular muscles, congenital, 1 and Fibrosis of extraocular muscles, congenital, 3B, MIM:135700 (OMIM accessed 19th Dec 2025).

Created: 19 Dec 2025, 10:39 a.m. | Last Modified: 19 Dec 2025, 10:39 a.m.

Panel Version: 7.29

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
CFEOM; agenesis of the corpus callosum; peripheral neuropathy

Publications

• 22699964
• 32141982
• 37921537
• 39643435
• 41282472

I don't know

Currently only two unrelated individuals reported with peripheral neuropathy
Sources: Expert list

Created: 7 Dec 2025, 4:35 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
CFEOM; agenesis of the corpus callosum; peripheral neuropathy

Publications

• 39643435
• 41282472

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments