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KIF14 – Autosomal Recessive Primary Microcephaly

Autosomal recessive primary microcephaly (MCPH; MONDO:0016660) is characterized by a markedly reduced cerebral cortex leading to intellectual disability and often short stature. The kinesin motor protein KIF14 (HGNC:19181) has been implicated in MCPH through defects in cytokinesis.

Linkage analysis and whole-exome sequencing in three consanguineous families and one nonconsanguineous patient revealed biallelic KIF14 variants segregating with MCPH (PMID:28892560). Inheritance is autosomal recessive, with homozygous truncating and in-frame deletion alleles in three families and compound heterozygous missense alleles in a fourth patient.

Overall, four unrelated probands were reported with five distinct variants: c.263T>A (p.Leu88Ter), c.2480_2482del (p.Val827del), c.4071G>A (p.Gln1357=), c.2545C>G (p.His849Asp) and c.3662G>T (p.Gly1221Val) (PMID:28892560). The variant c.263T>A (p.Leu88Ter) is a recurring truncating allele that abolishes motor function.

Functional studies in patient-derived fibroblasts demonstrated mislocalization of KIF14 and its partner CRIK at the midbody, increased binucleation and apoptosis indicative of failed cytokinesis (PMID:28892560). KIF14 loss-of-function was further supported by Kif14 knockout mouse models showing primary microcephaly (PMID:23308235).

Additional evidence from a zebrafish kif14 mutant and human fetal tissue analyses confirmed a conserved requirement for KIF14 in brain and kidney development, with midbody remnant accumulation mimicking ciliopathy-like phenotypes (PMID:30388224). These data substantiate haploinsufficiency of KIF14 as a mechanism for MCPH.

Integration of genetic and experimental findings supports a Moderate clinical validity. KIF14 variants provide diagnostic utility in MCPH, guiding genetic testing and potential therapeutic targeting of cytokinesis pathways.

References

  • Ann Neurol • 2017 • Mutations of KIF14 cause primary microcephaly by impairing cytokinesis. PMID:28892560
  • PLoS One • 2013 • Kif14 mutation causes severe brain malformation and hypomyelination. PMID:23308235
  • Hum Mol Genet • 2019 • Loss-of-function mutations in KIF14 cause severe microcephaly and kidney development defects in humans and zebrafish. PMID:30388224

Evidence Based Scoring (AI generated)

Gene–Disease Association

Moderate

4 probands in 4 unrelated families with recessive inheritance and concordant functional and animal model data

Genetic Evidence

Moderate

Biallelic truncating, in-frame deletion and missense variants in 4 probands across 4 families ([PMID:28892560])

Functional Evidence

Strong

Patient fibroblast cytokinesis assays, Kif14 knockout mouse and zebrafish models recapitulate microcephaly