Unravelling the genetic basis of hereditary disorders by high-throughput exome sequencing strategies

The research presented in this thesis focuses on using Whole Exome Sequencing (WES) to unravel the genetic basis of human hereditary disorders with different inheritance patterns. We set out to apply WES as a diagnostic approach for establishing a molecular diagnosis in a highly heterogeneous group of patients with microcephaly and varied intellectual disability. Additionally, a family with familial glucocorticoid deficiency (FGD) and a cohort of patients with L1 syndrome were studied.
In our microcephaly project, we achieved a diagnostic yield of 29% and found mutations in known disease-genes. Our results confirmed that many microcephaly cases are explained by autosomal recessive inheritance. For FGD, trio-exome sequencing revealed a novel homozygous mutation in the NNT gene. We also reviewed the literature for all reported NNT mutations and their clinical presentation. By application of X-exome sequencing in a cohort of 58 patients with L1 syndrome, an X-linked disorder, we identified 5 possible novel candidate genes, among which three independent mutations in DACH2 suggest this gene as the most promising candidate gene for L1 syndrome. Finally, using an in silico composite biological network analysis, we identified molecular pathomechanisms underlying congenital microcephaly (CM) and predicted further CM-candidate genes. Next to known processes, our analysis suggested, telomere biology and tRNA metabolic process as biological functions underlying CM. Supportive evidence for several selected candidate genes demonstrated the potential of our network approach to facilitate gene discovery in genetically heterogeneous disease.