Overlap of Genomic and Transcriptomic Genes Identified in Familial Eosinophilic Esophagitis

Evidence for a genetic contribution to eosinophilic esophagitis (EoE) exists from family and genome-wide association studies. Extensive investigation into rare variants contributing to EoE has not been performed. The study's aim was to evaluate families with multiple cases of EoE by genomic and transcriptomic sequencing to identify genes predisposing to EoE.

Distant relative pairs (eg, cousins) in extended EoE families and other affected relatives were whole exome sequenced to identify rare, shared, potentially pathologic variants. RNA sequencing was performed in nuclear families with multiple EoE cases. We compared the overlap of genes from DNA and RNA sequencing for relevance to disease manifestations.

Whole exome sequencing was performed in 50 familial cases in 21 EoE extended pedigrees. We observed 189 rare candidate predisposition variants in 181 genes with complete sharing among all affected family members within each pedigree. RNA sequencing was performed for 43 EoE cases in 18 nuclear families, including 6 relatives without EoE. We observed 698 total differentially expressed genes compared with controls. We identified 3 genes (MUC16, ADGRE1, and TENM3) with evidence of rare variant sharing among all affected family members and differential gene expression. We identified 36 other genes with partial sharing of rare variants among some affected family members and with differential gene expression. Several genes identified as prominent in EoE were also differentially expressed in unaffected relatives.

Genes related to immune response, barrier dysfunction, and cell adhesion were identified in familial EoE cases and unaffected family members, supporting a genetic familial predisposition and a possible multihit background to disease pathophysiology.