1. CDK5RAP2 primary microcephaly is associated with hypothalamic, retinal and cochlear developmental defects
- Author
-
Anita Rauch, Nathalie Pouvreau, Séverine Drunat, Yves Alembik, Anais Ernault, Liza Vera, Hala Nasser, Katharina Steindl, Fabien Guimiot, Pierre Gressens, Vincent El Ghouzzi, Sophie Guilmin Crepon, Delphine Héron, Nathalie Kubis, Alain Verloes, Natacha Teissier, Marie Laure Moutard, Sandrine Passemard, Florentia Kaguelidou, Alexandra Afenjar, Paolo Milani, Marcella Zollino, Pascaline Letard, Martha Momtchilova, Monique Elmaleh-Bergès, University of Zurich, Passemard, Sandrine, Service d'imagerie pédiatrique, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP Hôpital universitaire Robert-Debré [Paris], Hôpital Robert Debré, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Department of Medical Genetics, Hôpitaux Universitaires de Strasbourg, Service de Neurologie Pédiatrique, HFME, Bron, France, Hôpital Lariboisière, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 (UPD7), Unité fonctionnelle de génétique clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Istituto di Genetica Medica, Epidémiologie Clinique et Evaluation Economique Appliquées aux Populations Vulnérables (ECEVE (U1123 / UMR_S_1123)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Institute of Medical Genetics, University of Zürich [Zürich] (UZH), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), and Universität Zürich [Zürich] = University of Zurich (UZH)
- Subjects
Microcephaly ,Pathology ,medicine.medical_specialty ,2716 Genetics (clinical) ,10039 Institute of Medical Genetics ,[SDV]Life Sciences [q-bio] ,CDK5RAP2 ,intellectual disability ,MCPH ,primary microcephaly ,retinal alteration ,sensorineural hearing loss ,610 Medicine & health ,Settore MED/03 - GENETICA MEDICA ,Microphthalmia ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Holoprosencephaly ,1311 Genetics ,Genetics ,medicine ,[SDV.BDD]Life Sciences [q-bio]/Development Biology ,Genetics (clinical) ,Cochlea ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,0303 health sciences ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,business.industry ,Retinal ,medicine.disease ,chemistry ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,Brain size ,570 Life sciences ,biology ,Sensorineural hearing loss ,business ,030217 neurology & neurosurgery - Abstract
BackgroundPrimary 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.Methods7 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.ResultsAll 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.ConclusionThis 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 numberNCT01565005.
- Published
- 2020