Genetics in inborn errors of immunity: pediatric autoinflammatory phenotypes and the underlying genetic causes in 125 families

Monogenic autoinflammatory diseases (AID) encompass a growing group of inborn errors in the innate immune system causing unprovoked or exaggerated systemic inflammation. Diagnosis of monogenic AID requires an accurate description of the patients´ phenotype and the identification of highly penetrant genetic variants in single genes is pivotal. In a routine genetic diagnostic setting, we performed whole exome sequencing (WES) of 125 pediatric patients with suspected monogenic AID. Datasets were analyzed in a step-wise approach to identify the most feasible diagnostic strategy: First, we analyzed a virtual gene panel including 13 genes associated with known AID and, if no genetic diagnosis could be established, followed by the analysis of a virtual panel including 420 genes published by the International Union of Immunological Societies associated with all known inborn error of immunity (IEI). Subsequently WES data were analyzed without pre-filtering for known AID/IEI genes. Analyzing 13 genes yielded a definite diagnosis in 16.0% (n=20). The diagnostic yield was increased by analyzing 420 genes to 21.8% (n=26). Importantly, expanding the analysis to WES data did not increase the diagnostic yield in our cohort, neither in single WES analysis nor in trio-WES analysis. The study highlights that analyzing virtual gene panels based on WES that include the majority of known genes causing AID or differential diagnosis can rapidly confirm the diagnosis for a large number of pediatric patients. WES data or trio-WES data analysis as a first-tier diagnostic analysis in patients with suspected monogenic AID is of minor use.