Idiopathic hypereosinophilic syndrome: Potential pathologic somatic gene variants identified by exome sequencing

Hypereosinophilic syndrome (HES) is a rare group of disorders characterized by eosinophilia in blood and/or tissues. The etiology of HES is largely unknown. Characterizing the molecular pathophysiology of HES may improve diagnostic and therapeutic methodology.

We sought to identify somatic gene variants associated with idiopathic HES using exome sequencing.

Exome sequencing (SureSelect capture kit, 80× average depth) was performed using either PBMCs or bone marrow cytogenetic pellets from 31 patients with idiopathic HES. We used Mutect2 in tumor-only mode with gnomAD as the germline resource and FilterMutectCalls for confident somatic variant calling. Variants selected had at least 20 supporting reads, variant allele frequency below 35%, high Clinical Annotation of Variants impact, and minor allele frequency of <1% in gnomAD and Mayo Clinic Biobank.

A total of 332 unique variants in 310 genes were identified at least in 1 patient. Of these, 5 genes were found recurrently mutated (present in at least 10% of samples): PRTFDC1 (16%), TYRO3 (16%), TDG (12.9%), TYW1B (12.9%), and ZNF880 (12.9%). Pathway enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology databases utilizing all variants identified in the cohort found significant enrichment in pathways related to cell cycle and PI3K-Akt signaling (Kyoto Encyclopedia of Genes and Genomes) and RAS signal transduction (Gene Ontology).

Several somatic mutations were identified in our cohort of patients with idiopathic HES. Increasing the number of patients through collaborative efforts and pursuing functional testing of these variants will help elucidate the importance of these genes in idiopathic HES.