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KIF2A – Complex Cortical Dysplasia with Other Brain Malformations 3

KIF2A, encoding a kinesin-13 microtubule-depolymerase, is associated with a rare autosomal dominant cortical dysplasia syndrome (CDCBM3). A single unrelated 8-year-old boy presented with posterior dominant agyria/pachygyria and motor dysfunction and harbored a de novo heterozygous NM_001098511.2:c.1298C>A (p.Ser433Tyr) variant, located distal to the nucleotide-binding domain in line with CDCBM3 mutation spectrum (PMID:33506645). No additional familial segregation has been reported.

Multiple functional studies reinforce a dominant-negative mechanism: de novo motor domain substitutions c.950G>A (p.Ser317Asn) and c.962A>C (p.His321Pro) disrupt ATP hydrolysis and microtubule depolymerization, causing lissencephaly and microcephaly (PMID:27747449). Cell models show impaired progenitor proliferation, neuron migration, and ciliogenesis–cell cycle coupling (PMID:29077851). Conditional KIF2A p.His321Asp knock-in mice recapitulate microcephaly, cortical malformation, increased apoptosis, and neuronal differentiation defects (PMID:31919497). Although clinical data are limited to one proband, the concordant functional evidence supports pathogenicity. Key take-home: consider KIF2A testing in patients with agyria/pachygyria and motor deficits.

References

  • American journal of medical genetics. Part A • 2021 • Variants in KIF2A cause broad clinical presentation; the computational structural analysis of a novel variant in a patient with a cortical dysplasia, complex, with other brain malformations 3. PMID:33506645
  • Neurogenetics • 2017 • Recurrent KIF2A mutations are responsible for classic lissencephaly. PMID:27747449
  • Human molecular genetics • 2018 • Ciliogenesis and cell cycle alterations contribute to KIF2A-related malformations of cortical development. PMID:29077851
  • Human molecular genetics • 2020 • Conditional switching of KIF2A mutation provides new insights into cortical malformation pathogeny. PMID:31919497

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Single unrelated proband with de novo heterozygous variant and no segregation evidence

Genetic Evidence

Limited

One proband with de novo c.1298C>A (p.Ser433Tyr) variant in KIF2A with no additional familial segregation ([PMID:33506645])

Functional Evidence

Moderate

Multiple functional studies, including patient-derived cell assays and knock-in mouse models, demonstrate KIF2A variant-induced microtubule depolymerization defects and cortical malformations ([PMID:27747449], [PMID:29077851], [PMID:31919497])