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A common feature of infectious diseases, including an infection with Neisseria meningitidis (Nm), is that only a small proportion of the individuals exposed to the same strain of the bacteria suffer from the clinical disease. Host genetics has long been considered to be an important determinant of both predisposition to and severity of outcome from invasive meningococcal disease (IMD). The human complement system is central to protection against IMD. It is well established that individuals with terminal or alternative complement deficiencies are predisposed to invasive, often recurrent meningococcal infections. However, the occurrence of these putative genetic deficiencies is rare, such that complement deficiencies account for less than 3 % of the disease cases. The current study sought to uncover novel genetic aetiologies of IMD, by employing WES and GWAS, in conjunction with molecular functional characterisation assays. Firstly, genetic analysis of six familial IMD exomes revealed a novel mutation in the SPLUNC1 gene. The encoding protein has been shown to play an important role in innate immune defence against a number of Gram-negative bacterial infections. The characterisation assays undertaken in this work suggest that the protein encoded by SPLUNC1 is also implicated with host innate immune defence against Nm infection, by providing protection against nasopharyngeal colonisation of a pathogenic Nm strain. The results further suggest that harbouring rare pathogenic mutations that impact the function of the encoding protein is associated with reduced host defence activities in the resulting protein, which in turn may possibly lead to increased susceptibility to IMD in the carriers. Furthermore, a large-scale GWAS was performed to define common polymorphisms underlying host susceptibility and severity of IMD, using 1236 individuals with confirmed disease and over 5000 controls. In this work, efforts were made to understand the biological plausibility of the genetic associations identified through the GWAS analysis. Open Access

Galactokinase catalyses the first committed step in galactose metabolism, the conversion of galactose to galactose-1-phosphate. Galactokinase deficiency is an extremely rare form of galactosaemia, and the most frequent complication reported is cataracts. Congenital hyperinsulinism (CHI) is a cause of severe hypoglycaemia in the newborn period. Galactosaemia has not previously been reported in a neonate with concomitant CHI.To report the first case of a patient with CHI and galactokinase deficiency, and to describe the diagnostic pitfalls with bedside blood glucose testing in a neonate with combined galactokinase deficiency and CHI.A 3-day-old baby girl from consanguineous parents presented with poor feeding, irritability and seizures. Capillary blood glucose testing using bedside test strips and glucometer showed a glucose level of 18 mmol/L, but the actual laboratory blood glucose level was only 1.8 mmol/L. After discontinuation of oral feeding (stopping provision of dietary galactose), the bedside capillary blood glucose correlated with laboratory glucose concentrations.Biochemically the patient had CHI (blood glucose level 2.3 mmol/L with simultaneous serum insulin level of 30 mU/L) and galactokinase deficiency (elevated serum galactose level 0.62 μmol/L). Homozygous loss of function mutations in ABCC8 and GALK1 were found, which explained the patient's CHI and galactokinase deficiency, respectively.This is the first reported case of CHI and galactokinase deficiency occurring in the same patient. Severe hypoglycaemia in neonates with CHI may go undetected with bedside blood glucose meters in patients with galactokinase deficiency.