Clinical relevance of somatic mosaic variants detected from exome sequencing data

Abstract

Several recent reports have implicated somatic mosaic variants as phenocopies of germline defects of inborn errors of immunity (IEI). Somatic variants can also result from clonal hematopoiesis (CH), which has been associated with increased risk of hematological malignancies and cardiovascular disorders. The extent of clinical relevance of somatic variants remain uncertain.We developed a workflow to detect and interpret somatic mosaic variants from exome data obtained from blood-extracted DNA of 2841 patients, a subset of whom had a genetic diagnoses in genes implicated in IEI. These somatic variants had variant allele fraction (VAF) between 0.05 and 0.31 and were called using LoFreq2, an algorithm that detects variants with low VAF that may be missed by standard germline variant calling pipelines. We highlight three examples of characterization of this somatic variant data from 2841 exomes.1) We identified 39 somatic variants as potential clinical diagnoses in our cohort. These variants were previously associated with disorders overlapping with the clinical features of the respective patients. Ten of these variants were not detected by a standard pipeline for calling germline variants.2) We detected 16 predicted loss of function and missense somatic variants in 12 published IEI genes that were consistent with disease pathogenesis. The clinical relevance of these findings is under investigation.3) Clustering analysis of somatic variants in genes known to be recurrently mutated in CH identified groups of patients harboring distinct patterns of somatic variants. For example, patients with germline defects in GATA2 were enriched in predicted loss of function variants in a subset of genes implicated in CH namely ASXL1, STAG2, and DNMT3A. These results were independently replicated in a formal case control analysis. We plan to extend this analysis to cohorts with germline defects in other IEI genes. Here we report a pipeline for calling and interpreting somatic variants that resulted in clinical diagnoses and allowed characterization of clonal hematopoiesis. Further investigation of the identified somatic variants will contribute to new diagnoses and methods for prognostication and potentially uncover new genes underlying inborn errors of immunity.