Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
Kinesin family member 21A (KIF21A) is an anterograde motor protein essential for axonal outgrowth and cranial nerve innervation. Heterozygous missense variants in KIF21A cause congenital fibrosis of the extraocular muscles type 1 (CFEOM1; [MONDO:0021083]), an autosomal dominant disorder characterized by restrictive ophthalmoplegia, ptosis, and sometimes Marcus Gunn jaw-winking phenomenon. The clinical validity of the KIF21A–CFEOM1 association is rated Definitive based on extensive case reports, recurrent hotspot variants, segregation in multiple families, and concordant functional studies.
Genetic evidence supports autosomal dominant inheritance, with de novo and inherited heterozygous variants clustering in coiled-coil and motor domains. A novel de novo c.2840T>C (p.Met947Thr) was identified in a simplex case (PMID:16157808), and the recurrent hotspot c.2860C>T (p.Arg954Trp) was observed in eight Chinese families and in maternal germline mosaicism segregating in three affected siblings (PMID:36138147; PMID:24426772). Over 25 unrelated probands across ≥26 families have been reported, confirming variant pathogenicity and recurrence.
The variant spectrum in CFEOM1 includes missense changes at Arg954 (c.2860C>T, p.Arg954Trp; c.2861G>A, p.Arg954Gln) and novel mutations outside the hotspot (c.84C>G, p.Cys28Trp). Recurrent CpG mutations at exon 21 implicate methylation-induced mutability (PMID:15621877). Penetrance is high, and germline mosaicism can result in multiple affected offspring despite unaffected parents.
Clinically, patients present with bilateral non-progressive ptosis, restricted horizontal gaze, infraduction of both eyes, compensatory chin-up posture, and dysinnervation signs such as Marcus Gunn jaw-winking. MRI often reveals hypoplastic oculomotor nerves and absence of specific extraocular muscles. Phenotypic variability is minimal but may include CFEOM3 expression in some families.
Functional assays demonstrate that CFEOM-associated KIF21A variants alter motor activity and microtubule interactions. Mutant kinesin exhibits enhanced processivity and plus-end dwell on microtubules (PMID:38170592), while CFEOM1 mutants (p.Met947Thr, p.Arg954Trp) increase Kank1 membrane translocation in neuronal models (PMID:19559006). These findings support a gain-of-function mechanism leading to dysregulated axonal guidance.
No significant conflicting evidence has been reported. The cumulative genetic and experimental data meet ClinGen criteria for a Definitive gene–disease relationship and support clinical genetic testing in suspected CFEOM1 cases.
Key Take-home: KIF21A heterozygous missense variants definitively cause autosomal dominant CFEOM1; targeted hotspot screening expedites diagnosis and informs genetic counseling.
Gene–Disease AssociationDefinitiveOver 25 probands across ≥26 families (16 Chinese families [PMID:36138147], 5 families [PMID:18332320]), recurrent hotspot variants, multi-family segregation, and concordant functional data Genetic EvidenceStrongMultiple unrelated probands with recurrent heterozygous missense variants (c.2860C>T, c.2840T>C), de novo cases, and segregation in three siblings from germline mosaicism Functional EvidenceModerateIn vitro assays demonstrate altered motor activity and enhanced microtubule transport ([PMID:38170592]), and CFEOM1 mutants show increased Kank1 membrane translocation ([PMID:19559006]) |