1684: PATHOGENIC VARIATION ASSOCIATED WITH MONOGENIC DISORDERS IN A SEVERE PEDIATRIC SEPSIS COHORT

Abstract

Learning Objectives: Early work investigating the effect of genetic variation on sepsis outcome focused on identifying common polymorphisms. Recently, next generation sequencing technologies have enabled identification of rare variants associated with specific diseases or traits. Here, we report the findings of our single center experience with whole exome sequencing to identify pathogenic variants in 45 children, aged 28d to 18y of age with severe sepsis. Methods: Using defined analysis of 96 genes, we identified variants associated with monogenic inborn errors of inflammation, immunity and coagulation. Variant calling was restricted to those with 1.) minor allele frequency (MAF) <5% of the general population in ExAC, NHLBI and 1000 Genomes databases AND EITHER 2.) classified as pathogenic, likely pathogenic in the HGMD professional database, OR 3.) limited to start site, splice site, frameshifts or nonsense mutations, therefore likely non-functional, and classified as pathogenic or likely pathogenic according to ACMG guidelines. Results: The cohort was 53.3% male with a mean age of 8.40 years (SD 5.83). Fifty-three percent of children (N=24/45) had ≥1 pathogenic or likely pathogenic variant in a potentially diseasecausing inheritance pattern. Variants associated with autosomal dominant disorders were identified for: atypical hemolytic uremic syndrome 28.9% (N=13); autoimmune lymphoproliferative syndrome 17.7% (ALPS; N=8); cryopyrin-associated periodic syndromes 4.4% (N=2); combined variable immunodeficiency 4.4% (N=2) where the particular variant is reported to have phenotypic effect in heterozygous form; familial Mediterranean fever 2.2% (N=1); and PIK3R1 deficiency 2.2% (N=1). One case of compound heterozygosity for autosomal recessive hemophagocytic lymphohistiocytosis (HLH) and one case of X-linked recessive XIAP-related lymphoproliferative was also seen. Conclusions: Pathogenic variants associated with monogenic inborn errors of inflammation, immunity and coagulation are not uncommon in children with severe sepsis. A larger cohort is needed to corroborate these findings, however, this report highlights the importance of genetic testing in pediatric sepsis patients to identify possible monogenic disorders requiring specific management and follow-up.