Background: Invasive group A streptococcal (IGAS) disease is a severe manifestation of Streptococcus pyogenes infection with high mortality. It remains unclear why IGAS sometimes develops in individuals without comorbidity or other risk factors suggesting underlying host genetic predisposition.
Methods: We undertook whole-exome sequencing of two cohorts of children and adults with microbiological confirmed IGAS comprising 25 with necrotising fasciitis recruited in the UK, and 26 with necrotising fasciitis, 40 with streptococcal toxic shock syndrome and 23 with both syndromes recruited in the USA. We utilised a recently developed statistical framework of gene burden analysis (“burdenMC”) to identify enrichment for rare predicted deleterious variants based on comparison with existing large-scale population sequencing databases that capture the breadth of human genomic variation across different populations.
Results: Across the two cohorts we identified 326 genes enriched with an empirical burden P-value < 10-5 based on variants with allele frequency < 0.001 predicted to be among the 1% most deleterious of variants (i.e. CADD score > 20). Four were genes previously associated with inborn errors of immunity. One of these four and an additional gene demonstrating enrichment in both cohorts (variants in 11% individuals) belong to the NOD-like receptor (NLR) gene family, key regulators of inflammation. Further there was preliminary evidence for enrichment in a pathway previously implicated by genome-wide genotyping.
Conclusion: Identification of rare deleterious variants in genes that were not previously linked to IGAS susceptibility offer new insights into pathogenesis, potentially providing targets for future development of host-directed therapies.