Human genetics can play a key role in determining susceptibility, severity, and outcome of infectious diseases resulting from otherwise common infections. Inborn errors of immunity (IEI) in invasive bacterial and viral infections, including Neisseria meningitidis, Staphylococcal aureus, Streptococcus pneumoniae, Group A Streptococcus and SARS-CoV-2, have been recognised to contribute to disease pathogenesis but do not explain all cases, highlighting the need for discovery of novel genetic aetiologies. This thesis aimed to use large existing well-defined disease cohorts, as well as patients recruited into a specialised paediatric IEI clinic, to discover novel causative variants associated with infectious disease. This was accomplished by employing whole exome sequencing to statistically identify significant and promising candidates that were subsequently characterised by functional validation assays. Firstly, gain-of-function JAK2 variants were discovered in severe invasive meningococcal disease cases and were shown to constitutively activate the JAK/STAT signalling pathway. Secondly, heterozygous KRT10 variants were enriched in an invasive bacterial disease cohort, including Neisseria meningitidis, Staphylococcal aureus, Streptococcus pneumoniae, and Group A Streptococcus, and hypothesised to confer predisposition of invasive bacterial infection by enhancing bacterial adherence and thereby, colonisation. Thirdly, TICAM1 loss-of-function variants were characterised to impair type I IFN signalling resulting in severe COVID-19 pneumonia. Finally, genetic analysis and functional immunological techniques developed during this project was applied to a new specialist paediatric clinic. This facilitated novel genomic discoveries, in real time, and improved understanding of disease pathogenesis in children with severe or unusual infections which allowed for improved and more accurate patient care and clinical follow up. In this work, efforts were made to understand the impact of novel genetic aetiologies in susceptibility to and severity of infectious disease, discovered by whole exome sequencing and functionally validated.