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!
KIF22, encoding a kinesin‐like motor protein, is implicated in autosomal dominant spondyloepimetaphyseal dysplasia with multiple dislocations (MONDO:0011335). Affected individuals present postnatal short stature, midface hypoplasia, generalized joint laxity and progressive epimetaphyseal dysplasia. Radiographically, hallmark features include small and delayed epiphyses, metaphyseal striations and slender metacarpals. Genetic and experimental data converge to support a strong gene‐disease relationship, guiding diagnosis, management and genetic counselling.
Genetic evidence encompasses 32 unrelated probands with heterozygous KIF22 missense variants (20 familial cases from eight families segregating disease) and robust functional concordance. The number of sporadic and familial cases (32 probands) (PMID:22152678) and segregation in eight families (PMID:22152678) support a Strong classification.
Inheritance is autosomal dominant. Segregation analysis in eight multiplex families demonstrated co-segregation of KIF22 variants with disease in 20 additional affected relatives (PMID:22152678). Case reports include a de novo c.443C>T (p.Pro148Leu) variant in a child followed longitudinally from age 2 to 11 (PMID:25256152) and the same hotspot mutation in a 66-year-old man (PMID:37226647). Variant spectrum is dominated by adjacent missense changes at codons 148 and 149; recurrent alleles include c.443C>T (p.Pro148Leu), c.446G>A (p.Arg149Gln) and c.446G>T (p.Arg149Leu).
Homozygous variants (c.146G>A, p.Arg49Gln) identified in three unrelated families cause a recessive form with similar clinical features, implicating haploinsufficiency and altered ATP binding (PMID:38477767). Patient fibroblasts show decreased sulfated proteoglycan secretion and reduced chondroitin sulfate deposition, linking KIF22 dysfunction to proteoglycan biosynthesis defects (PMID:38477767). In vitro knockdown and expression of SEMDJL2 mutants in chondrocytes disrupt spindle formation and proliferation; KIF22 truncation mice recapitulate growth plate abnormalities and shortened bones (PMID:38989461).
No studies to date have refuted the association or described alternative phenotypes for KIF22 variants in SEMDJL2.
Combined genetic and functional data demonstrate that heterozygous missense variants in KIF22, particularly at codons 148–149, cause autosomal dominant spondyloepimetaphyseal dysplasia with multiple dislocations via dominant‐negative or haploinsufficient mechanisms affecting chondrocyte division and proteoglycan biosynthesis. Recessive variants expand the allelic spectrum and underscore critical roles in skeletal development. This evidence supports genetic testing for KIF22 in patients with compatible skeletal dysplasia and informs prognosis and family counseling.
Key Take-home: Pathogenic KIF22 missense variants (e.g., c.443C>T (p.Pro148Leu)) cause autosomal dominant SEMDJL2 with characteristic skeletal abnormalities and impaired proteoglycan synthesis, warranting inclusion in diagnostic gene panels.
Gene–Disease AssociationStrong32 probands ([PMID:22152678]), segregation in eight families ([PMID:22152678]), concordant functional data Genetic EvidenceStrong32 unrelated cases and familial segregation in eight families Functional EvidenceModerateProteoglycan biosynthesis impairment in patient cells and chondrocyte mitotic defects in models |