A rare pLoF variant of ABCF1 disrupts cellular responses to IFN-α and multiple pathways in a family including multiple individuals with celiac disease. a. Pedigree of a family containing three patients (P1, P2, and P3) diagnosed with CeD in childhood. The three patients were found to be heterozygous for an ABCF1 mutation (E243X). The mother is also a carrier but has a mild phenotype. HLA-DQ genotype is indicated. b. Sanger sequencing electropherogram. c. A phenotype-association study was performed on 246 individuals heterozygous for an ABCF1 pLoF variant found in the UK Biobank, All of Us, and BioMe databases. Results of RNA sequencing on PBMCs from two wild-type healthy controls (HCs) and four patients (Pts) (d–h). d.ABCF1 mRNA level. e. Constitutive and IFN-α-stimulated mRNA levels for CXCL10, GBP1, RSAD2, and IFIT2. f. Heatmap of ISGs differentially expressed in the presence and absence of IFN-α stimulation. In the bubble plot on the right, circle size indicates the fold-change difference, and colors indicate the adjusted p-value. g. Volcano plot of genes displaying differential constitutive expression between patients and controls. h. Gene set enrichment analysis (GSEA) of genes displaying differential constitutive expression (at least a two-fold change and adjusted p value < 0.001). Unstim.: unstimulated; IFN-α: 40 ng/mL interferon-alpha; LPS: 1 μg/mL lipopolysaccharide. TPM: Transcripts per million. Log₂FC: log₂ fold-change, padj: p-values adjusted by the false discovery rate (FDR) procedure. P values were calculated in unpaired one-tailed Student’s t tests (d and e). ns, not significant; **p < 0.01; and ****p < 0.0001.