CDK5RAP2 – Isolated Agenesis of the Corpus Callosum

Exome sequencing in a non-consanguineous family identified three siblings with isolated agenesis of the corpus callosum carrying compound heterozygous variants in CDK5RAP2: c.280G>C (p.Gly94Arg) and c.3695A>G (p.Asn1232Ser) (PMID:26197979). All affected individuals inherited one allele from each parent, consistent with an autosomal recessive mode of inheritance. No additional unrelated families or segregation beyond the three probands have been reported to date, limiting the genetic evidence supporting this association.

CDK5RAP2 encodes a centrosomal protein critical for mitotic spindle orientation in neuronal progenitors; loss‐of-function alleles impair neurogenic divisions and plausibly disrupt corpus callosum formation through defective neuronal migration and connectivity. Although functional studies in mouse and cell models establish a pathogenic mechanism for CDK5RAP2 in primary microcephaly, direct assays linking these specific ACC-associated alleles to callosal hypogenesis are lacking.

Overall, the evidence for CDK5RAP2 as a cause of isolated agenesis of the corpus callosum is classified as Limited. Additional unrelated cases, segregation data, and in vivo or in vitro functional assays of ACC-specific phenotypes are required to strengthen the clinical validity of this gene–disease relationship.

Key Take-home: CDK5RAP2 biallelic variants may underlie isolated ACC, but broader genetic and experimental validation is needed to support routine diagnostic use.

References

• European Journal of Human Genetics • 2016 • Exome sequencing identifies recessive CDK5RAP2 variants in patients with isolated agenesis of corpus callosum. PMID:26197979

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