TY - JOUR T1 - <em>CDK5RAP2</em> primary microcephaly is associated with hypothalamic, retinal and cochlear developmental defects JF - Journal of Medical Genetics JO - J Med Genet SP - 389 LP - 399 DO - 10.1136/jmedgenet-2019-106474 VL - 57 IS - 6 AU - Hala Nasser AU - Liza Vera AU - Monique Elmaleh-Bergès AU - Katharina Steindl AU - Pascaline Letard AU - Natacha Teissier AU - Anais Ernault AU - Fabien Guimiot AU - Alexandra Afenjar AU - Marie Laure Moutard AU - Delphine Héron AU - Yves Alembik AU - Martha Momtchilova AU - Paolo Milani AU - Nathalie Kubis AU - Nathalie Pouvreau AU - Marcella Zollino AU - Sophie Guilmin Crepon AU - Florentia Kaguelidou AU - Pierre Gressens AU - Alain Verloes AU - Anita Rauch AU - Vincent El Ghouzzi AU - Severine Drunat AU - Sandrine Passemard Y1 - 2020/06/01 UR - http://jmg.bmj.com/content/57/6/389.abstract N2 - 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 &gt;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. ER -