Detailed, standardized and systematic phenotyping for the interpretation of genetic variation

Contains fulltext : 132628.pdf (Publisher’s version ) (Open Access) The identification of the underlying genetic causes for neurodevelopmental disorders and/or congenital anomalies is complicated due to the high genetic heterogeneity of these disorders and the large amount of genetic variation in each individual. Therefore, the aim of this thesis is to improve the interpretation of genetic variation by using detailed, standardized and systematic phenotyping. The first part of this thesis describes the results of a large-scale genotype-phenotype study in a cohort of over 5,000 patients who have been tested for copy number variations . The second part reports a broadening of the phenotypic spectrum associated with two previously described disease genes, MED12 and CUL4B. The third part describes the identification and characterization of two novel causes for neurodevelopmental disorders, ADNP and DEAF1. These results show that the identification of multiple patients with variants affecting the same gene and an overlapping phenotype in combination with information from model systems and biological networks is essential to conclude that a mutation is the underlying cause. The systematic collection of standardized and detailed genotype and phenotype information will allow for systematic analyses, which will result in novel genetic causes for various phenotypes and further understanding of phenotypic variability. Knowledge about the underlying genetic causes will directly improve the care for individuals with neurodevelopmental disorders and/or congenital anomalies through targeted management, genetic counseling, and tailor-made therapy. Radboud Universiteit Nijmegen, 16 december 2014 Promotor : Brunner, H.G. Co-promotores : Vries, L.B.A. de, Brouwer, A.P.M. de