Identificatie en functionele karakterisatie van nieuwe genen oorzakelijk voor syndromatische microcephalie

Microcephalie (MC) in humans is a condition characterized by abnormal small head circumference for the respective age and sex. It can occur as isolated feature (non-syndromic forms) or in combination with other characteristics (syndromic forms). MC is genetically heterogeneous, but some of the non-syndromic forms were explained by mutations in genes implicated in cell division and cell cycle progression, including structural genes involved in orientation of the spindle pole and centrosomal stability. Moreover, an association between several conditions that exhibit syndromic MC and the dysregulation of pathways involved in the cell cycle checkpoint regulation, in the ATR-dependent DNA damage response, histone biosynthesis and neural cell migration was recently found. Enforced by these findings, we aim to identify novel genes involved in syndromic forms of MC. Building on our large resource of patients with MC and our successful implementation of genome wide array-CGH and exome sequencing in identifying genes involved in neurodevelopmental disorders, we propose a multidisciplinary genomic strategy for discovering and functionally characterize these novel candidate causative genes. The combinatorial approach(targeted and full exome sequencing, CNV region analysis by bioinformatic tools, functional studies on patients EBV and/or fibroblast cell lines and on mouse cerebral cortex) will enhance our fundamental understanding of how the cerebral cortex is formed and improve knowledge on the mechanisms which have driven in evolution the expansion of the brain.nrpages: 191status: publishe