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Updated: Jan 19, 2026
Detection of Rare Mutations in CtDNA Using Next Generation Sequencing
Published on: August 24, 2017
A Rare Mutation in SPLUNC1 Affects Bacterial Adherence and Invasion in Meningococcal Disease
Bayarchimeg Mashbat1, Evangelos Bellos1, Stephanie Hodeib1
1Department of Paediatric Infectious Diseases, Division of Medicine, Imperial College London, Norfolk Place, United Kingdom.
Background:
Neisseria meningitidis (Nm) is a nasopharyngeal commensal carried by healthy individuals. However, invasive infections occurs in a minority of individuals, with devastating consequences. There is evidence that common polymorphisms are associated with invasive meningococcal disease (IMD), but the contributions of rare variants other than those in the complement system have not been determined.
Methods:
We identified familial cases of IMD in the UK meningococcal disease study and the European Union Life-Threatening Infectious Disease Study. Candidate genetic variants were identified by whole-exome sequencing of 2 patients with familial IMD. Candidate variants were further validated by in vitro assays.
Results:
Exomes of 2 siblings with IMD identified a novel heterozygous missense mutation in BPIFA1/SPLUNC1. Sequencing of 186 other nonfamilial cases identified another unrelated IMD patient with the same mutation. SPLUNC1 is an innate immune defense protein expressed in the nasopharyngeal epithelia; however, its role in invasive infections is unknown. In vitro assays demonstrated that recombinant SPLUNC1 protein inhibits biofilm formation by Nm, and impedes Nm adhesion and invasion of human airway cells. The dominant negative mutant recombinant SPLUNC1 (p.G22E) showed reduced antibiofilm activity, increased meningococcal adhesion, and increased invasion of cells, compared with wild-type SPLUNC1.
Conclusions:
A mutation in SPLUNC1 affecting mucosal attachment, biofilm formation, and invasion of mucosal epithelial cells is a new genetic cause of meningococcal disease.
Insights
A rare mutation in the SPLUNC1 gene is a newly identified genetic cause of invasive meningococcal disease (IMD). This finding impacts our understanding of IMD pathogenesis and potential genetic risk factors.
Area of Science:
- Genetics
- Immunology
- Microbiology
Background:
- Neisseria meningitidis (Nm) is a common nasopharyngeal bacterium.
- Invasive meningococcal disease (IMD) has severe consequences, with genetic factors playing a role.
- The contribution of rare genetic variants, beyond complement system genes, to IMD risk is largely unknown.
Purpose of the Study:
- To investigate the role of rare genetic variants in invasive meningococcal disease (IMD).
- To identify novel genetic factors contributing to IMD susceptibility.
Main Methods:
- Whole-exome sequencing was performed on patients with familial IMD.
- Candidate variants were identified and validated using in vitro assays.
- Genetic analysis included familial and non-familial IMD cases.
Main Results:
- A novel heterozygous missense mutation in BPIFA1/SPLUNC1 was identified in siblings with IMD.
- The same SPLUNC1 mutation was found in another unrelated IMD patient.
- In vitro studies showed recombinant SPLUNC1 inhibits Nm biofilm formation, adhesion, and invasion; a dominant-negative mutant impaired these functions.
Conclusions:
- A mutation in SPLUNC1 represents a new genetic cause of meningococcal disease.
- The identified SPLUNC1 mutation affects bacterial mucosal attachment, biofilm formation, and invasion of epithelial cells.
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