Background
Invasive meningococcal disease (IMD) is a rare condition affecting
children and young adults due to infection with Neisseria meningitidis, resulting in meningitis or sepsis. Although the majority of the
general population is colonized by N. meningitidis, only a small minority go on to develop IMD, suggesting that those that succumb to
invasive disease may possess an underlying genetic susceptibility.
The notion of a genetic contribution to disease manifestation is supported by the finding that patients with congenital complement deficiencies are susceptible to recurrent IMD, yet these conditions are
rare. With the aim of identifying other genetic factors underlying IMD, we carried out whole exome sequencing (WES) of approximately 300 IMD patients from an extensive and well characterized
cohort of >2,000 childhood IMD patients.
Materials and Methods
The WES analysis focused on rare variants (MAF<0.01) predicted to
have a detrimental effect on protein function. We undertook analysis
of seven multiplex families identifying IBD variants. The rest of the
index cases were analysed as a cohort and put through gene and
pathway burden tests to identify any genes/pathways that were
enriched in the collection of patients.
Results
These analyses revealed a number of patients harbouring mutations
in known primary immunodeficiency genes (approx. 10%) as well as
a novel configuration of mutations underlying the complement
genes. Furthermore, novel mutations in the coagulation pathway and
mucosal immunity genes were identified and functionally confirmed.
Conclusions
The identification of genes involved in IMD through WES has demonstrated the complex genetic architecture of meningococcal immunity
revealed some novel and unexpected genes/pathways that modulate
disease susceptibility and severity. The results from this study
provide us with a more comprehensive understanding of IMD
pathogenesis.