Genetics of Brain Malformations: Towards the Identification of New Genes Involved in Brain Development

Genetics of Brain Malformations: Towards the Identification of New Genes Involved in Brain DevelopmentCongenital brain malformations (CBM) are important causes of neurologic morbidity in children because they are often associated with developmental delay, motor disturbances and epilepsy. To date, tremendous advances have been made in brain imaging techniques, microscopic imaging methods and during the last decade, progress in genomic technologies enabled a breakthrough in whole genome analysis. In this study, we aimed to identify novel genes involved in brain and cognitive development to contribute in the understanding of human embryonic development and the mechanisms of multiple congenital anomalies (MCA). In addition, we intended to evaluate the outcome of array-comparative genomic hybridisation (aCGH) in the clinical setting of paediatric neurology to try improving its yield in the diagnostic workup of patients with CBM and genetic counselling of their families.In the first part of this study, we applied the novel cytogenetic techniques to investigate a selected group of patients with CBM and MCA. We were able to show evidence for simultaneous occurrence of neo-telomere formation and telomere capture in the healing of broken chromosomes (chapter 1). The latter mechanism was thought to be specific for cancer-cells. We found, also, novel mutational mechanisms in diseases illustrated by microdeletions involving the ZIC2 gene in holoprosencephaly, with evidence for specific dysmorphic and epidemiological features (chapter3), the LIS1 gene in isolated lissencephaly (ILS) (chapter4), and also the duplication of the chromosome 3p25 encompassing the VHL gene in overgrowth with epilepsy (chapter 5). Furthermore, we mapped novel loci for CBM (13q34 for the agenesis of corpus callosum, 3q27q29 for the oculocerebral hypopigmentation syndrome). In addition, we described the smallest deletion of the newly reported 2p15p16.1 microdeletion syndrome.In the second part of this work, we evaluated prospectively the outcome of aCGH for the diagnostic workup of 120 patients with CBM (chapter 8). We detected pathogenic copy number variations (CNVs) in 20.8% of the patients with 11 CNVs mapping to novel loci for CBM and we suggested strategies based on technical, clinical, and epidemiological parameters to optimise the yield of aCGH for a better clinical work-up and improvement of the genetic counselling in the paediatric neurology clinic.In the last part (chapter 9) we discovered by homozygosity mapping 2 genes, COLEC11 and MASP, mutated in the 3MC syndrome. We showed that these genes from the lectin-accessory-complement-activating pathway act as guidance clues for the neural crest cell migration during early vertebrate embryogenesis. This represents an unprecedented evidence in human disease mechanisms that the complement pathway has core function during embryogenesis and a novel paradigm in developmental genetics.status: publishe