| Popis: |
Mendelian disorders are classified as genetic diseases that follow a mongenic pattern of inheritance caused by mutations in a single gene, resulting in pathologic consequences. These disorders clinically and genetically heterogeneous and are often considered rare. Previously, genes causing Mendelian disorders have been identified through several strategies including physical mapping and candidate-gene sequencing. Over recent years, new high-throughput genotyping technologies have been introduced, including autozygosity mapping and next generation sequencing, using either targeted, whole exome or whole genome sequencing. These technologies are now widely used to investigate and identify Mendelian disorders at a significantly lower cost and with a shorter analysis time. This PhD project focuses on the potential of whole exome sequencing (WES) to lead to the discovery of novel disease-causing genes in patients with undiagnosed genetic disorders. The aims of this project are to identify the causative genes in patients with novel clinical disorders, and investigate the pathogenicity of the sequence variations by using appropriate functional studies. During the course of this PhD project, 50 DNA samples from 14 consanguineous and non-consanguineous families underwent WES. This led to the identification of: 1- Previously identified genetic variations in the known Mendelian disease genes (GPR172A, RPS19, KRAS, ELANE, FANCD2, PCYT1A and MYH9). 2- Novel genetic variations in the known Mendelian genes (PNPT1, TTC37 and TOR1A). 3- New disease gene (ACD). Specific molecular, biochemical and functional studies were performed, where relevant, to investigate the pathogenicity of the identified variations in each family. In summary, a number of novel and known variations have been identified among a number of patients with presumed Mendelian disorders. These findings demonstrate the power of WES and its utility in combination with developed bioinformatics tools and functional studies to rapidly identify rare causative disease variants. |
