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Original research
CDK5RAP2 primary microcephaly is associated with hypothalamic, retinal and cochlear developmental defects
  1. Hala Nasser1,2,
  2. Liza Vera3,
  3. Monique Elmaleh-Bergès4,
  4. Katharina Steindl5,
  5. Pascaline Letard1,6,7,8,
  6. Natacha Teissier6,9,
  7. Anais Ernault1,
  8. Fabien Guimiot6,10,
  9. Alexandra Afenjar11,
  10. Marie Laure Moutard12,
  11. Delphine Héron13,
  12. Yves Alembik14,
  13. Martha Momtchilova15,
  14. Paolo Milani16,
  15. Nathalie Kubis16,
  16. Nathalie Pouvreau1,
  17. Marcella Zollino17,18,
  18. Sophie Guilmin Crepon19,
  19. Florentia Kaguelidou20,
  20. Pierre Gressens6,21,
  21. Alain Verloes1,6,22,
  22. Anita Rauch5,
  23. Vincent El Ghouzzi6,
  24. Severine Drunat1,6,22,
  25. Sandrine Passemard1,6,22,23
  1. 1 Département de Génétique, APHP, Hopital Robert Debré, 75019 Paris, France
  2. 2 Service des Explorations Fonctionnelles, APHP, Hopital Robert Debré, 75019 Paris, France
  3. 3 Service d'Ophtalmologie, APHP, Hopital Robert Debré, 75019 Paris, France
  4. 4 Service de Radiologie Pédiatrique, APHP, Hopital Robert Debré, 75019 Paris, France
  5. 5 Institute of Medical Genetics, University of Zurich, Schlieren-Zurich, Switzerland
  6. 6 Université de Paris, NeuroDiderot, Inserm, F-75019 Paris, France
  7. 7 Service d'Anatomopathologie, Hopital Jean Verdier, APHP, Bondy, France
  8. 8 Université Paris 13, 93140 Bondy, France
  9. 9 Service d'ORL, APHP, Hopital Robert Debré, 75019 Paris, France
  10. 10 Service de Foetopathologie, APHP, Hopital Robert Debré, 75019 Paris, France
  11. 11 CRMR déficiences intellectuelles de causes rares, Département de génétique, Sorbonne Université, APHP, Hôpital Trousseau, 75012 Paris, France
  12. 12 Service de Neuropédiatrie, APHP, Hopital Trousseau, 75012 Paris, France
  13. 13 Département de Génétique, APHP, Hopital La Pitié-Salpetriere, 75013 Paris, France
  14. 14 Service de Génétique Médicale, CHU de Strasbourg, Hopital de Hautepierre, 67200 Strasbourg, France
  15. 15 Service d'Ophtalmologie, APHP, Hopital Trousseau, 75012 Paris, France
  16. 16 Service des Explorations Fonctionnelles, APHP, Hopital Lariboisière, 75010 Paris, France
  17. 17 Universita Cattolica Sacro Cuore Istituto di Medicina Genomica, Roma, Italy
  18. 18 Fondazione Policlinico A. Gemelli IRCCS, Roma, Italy
  19. 19 Unité d'Epidémiologie Clinique, APHP, Hopital Robert Debré, 75019 Paris, France
  20. 20 Université de Paris, Centre d'Investigation Clinique, CIC 1426, INSERM, APHP, Hopital Robert Debré, 75019 Paris, France
  21. 21 Center for Developing Brain, King's College, St. Thomas' Campus, London, United Kingdom
  22. 22 European Reference Network ERN ITHACA, 75019 Paris, France
  23. 23 Service de Neuropédiatrie, APHP, Hopital Robert Debré, 75019 Paris, France
  1. Correspondence to Dr Sandrine Passemard, Genetic Department, Hopital Robert Debré, APHP, Paris, France; sandrine.passemard{at}


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.

  • CDK5RAP2
  • MCPH
  • primary microcephaly
  • intellectual disability
  • retinal alteration
  • sensorineural hearing loss
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  • LV and ME-B contributed equally.

  • Contributors HN analysed and interpreted all clinical data. LV and NT analysed the ocular and ENT phenotypes, respectively for all patients with the help of MM. ME analysed brain MRI and temporal bone CT scan for all patients. HN, LV, NT and ME helped writing the manuscript. AE performed the neuropsychological assessment for all patients. KS, AA, MLM, DH, YA and MZ were involved in patient recruitment and clinical management. SGC and FK conducted the research protocol. PL and FG performed the immunostaining in human tissues. VEG, AV and PG revised and edited the manuscript. SD and AR analysed and interpreted NGS data and performed segregation analysis. SP conceived the study, interpreted the results and wrote the manuscript.

  • Funding This work was supported by the Délégation à la Recherche Clinique et à l’Innovation de l’Assistance Publique Hopitaux de Paris, the Institut National pour la Santé et la Recherche Médicale (Inserm), the Université Paris 7, the Centre National de la Recherche Scientifique (CNRS), the DHU PROTECT, the Programme Hospitalier de Recherche Clinique (PHRC, grant agreement n° P100128/IDRCB: 2010-A01481-38), by ERA-NET grant 'Euromicro' (ANR-13-RARE-0007-01, ANR-16-CE16-0024-01 to SP, AV, VE, SD and PG and SNF 31ER30_154238 to AR) and radiz–Rare Disease Initiative Zurich, clinical research priority programme, University of Zurich.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval The trial was approved by the National Ethics Committee (Comité de Protection des Personnes (CPP) Ile-de-France II).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available on reasonable request. Data used in the manuscript are available by request to the authors.

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