Molecular diagnosis of childhood immune dysregulation, polyendocrinopathy and enteropathy, and implications for clinical management

Background Most patients with childhood-onset immune dysregulation, polyendocrinopathy and enteropathy have no genetic diagnosis for their illness. These patients may undergo empirical immunosuppressive treatment with highly variable outcomes. Objective To determine the genetic basis of disease in patients referred with “IPEX-like” disease, but with no mutation in FOXP3; then to assess consequences of genetic diagnoses for clinical management. Methods Genomic DNA was sequenced using a panel of 462 genes implicated in inborn errors of immunity. Candidate mutations were characterized by genomic, transcriptional, and (for some) protein analysis. Results Of 123 patients with FOXP3-negative IPEX-like disease, 48 (39%) carried damaging germline mutations in one of 27 genes including AIRE, BACH2, BCL11B, CARD11, CARD14, CTLA4, IRF2BP2, ITCH, JAK1, KMT2D, LRBA, MYO5B, NFKB1, NLRC4, POLA1, POMP, RAG1, SH2D1A, SKIV2L, STAT1, STAT3, TNFAIP3, TNFRSF6/FAS, TNRSF13B/TACI, TOM1, TTC37, and XIAP. Many of these had not been previously associated with an IPEX-like diagnosis. For 42 of the 48 patients with genetic diagnoses, knowing the critical gene may have altered therapeutic management, including recommendations for targeted treatments and for or against hematopoietic cell transplantation. Conclusion Many childhood disorders now bundled as “IPEX-like” disease are caused by individually rare, severe mutations in immune regulation genes. Most genetic diagnoses of these conditions yield clinically actionable findings. Barriers are lack of testing or lack of repeat testing if older technologies failed to provide a diagnosis. Clinical Implication Pediatric immune dysregulation would benefit from a genetics-first approach to diagnosis: for >80% of these patients with genetic diagnoses, the genetic information offers critical guidance to clinical management.