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.
- 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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