CDK5RAP2 primary microcephaly is associated with hypothalamic, retinal and cochlear developmental defects

J Med Genet. 2020 Jun;57(6):389-399. doi: 10.1136/jmedgenet-2019-106474. Epub 2020 Feb 3.


Background: Primary hereditary microcephaly (MCPH) comprises a large group of autosomal recessive disorders mainly affecting cortical development and resulting in a congenital impairment of brain growth. Despite the identification of >25 causal genes so far, it remains a challenge to distinguish between different MCPH forms at the clinical level.

Methods: 7 patients with newly identified mutations in CDK5RAP2 (MCPH3) were investigated by performing prospective, extensive and systematic clinical, MRI, psychomotor, neurosensory and cognitive examinations under similar conditions.

Results: All patients displayed neurosensory defects in addition to microcephaly. Small cochlea with incomplete partition type II was found in all cases and was associated with progressive deafness in 4 of them. Furthermore, the CDK5RAP2 protein was specifically identified in the developing cochlea from human fetal tissues. Microphthalmia was also present in all patients along with retinal pigmentation changes and lipofuscin deposits. Finally, hypothalamic anomalies consisting of interhypothalamic adhesions, a congenital midline defect usually associated with holoprosencephaly, was detected in 5 cases.

Conclusion: This is the first report indicating that CDK5RAP2 not only governs brain size but also plays a role in ocular and cochlear development and is necessary for hypothalamic nuclear separation at the midline. Our data indicate that CDK5RAP2 should be considered as a potential gene associated with deafness and forme fruste of holoprosencephaly. These children should be given neurosensory follow-up to prevent additional comorbidities and allow them reaching their full educational potential.

Trial registration number: NCT01565005.

Keywords: CDK5RAP2; MCPH; intellectual disability; primary microcephaly; retinal alteration; sensorineural hearing loss.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Proteins / genetics*
  • Child
  • Child, Preschool
  • Cochlea / diagnostic imaging
  • Cochlea / metabolism
  • Cochlea / pathology
  • Cochlear Diseases / diagnostic imaging
  • Cochlear Diseases / genetics*
  • Cochlear Diseases / pathology
  • Fanconi Anemia / genetics
  • Fanconi Anemia / pathology
  • Female
  • Humans
  • Hypothalamus / diagnostic imaging
  • Hypothalamus / pathology
  • Infant
  • Magnetic Resonance Imaging
  • Male
  • Microcephaly / diagnostic imaging
  • Microcephaly / genetics*
  • Microcephaly / pathology
  • Mutation
  • Nerve Tissue Proteins / genetics*
  • Neurogenesis / genetics
  • Pedigree
  • Retina / diagnostic imaging
  • Retina / pathology


  • CDK5RAP2 protein, human
  • Cell Cycle Proteins
  • Nerve Tissue Proteins

Supplementary concepts

  • Microcephaly, Primary Autosomal Recessive, 3

Associated data