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

Abstract

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: We sought to determine the genetic basis of disease in patients referred with Immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like (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 1 of the following 27 genes: 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 genes had not been previously associated with an IPEX-like diagnosis. For 42 of the 48 patients with genetic diagnoses, knowing the critical gene could have altered therapeutic management, including recommendations for targeted treatments and for or against hematopoietic cell transplantation.

Conclusions: 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.

Keywords: Immune dysregulation; autoimmunity; genetics; inborn errors of immunity; molecular diagnosis; pediatric; precision medicine; primary immunodeficiency disorders; sequencing.

Figure 1:

Genes responsible for childhood immune dysregulation, polyendocrinopathy, and enteropathy. Genes responsible for childhood IPE in 48 patients by principal biological function, based on literature review and Gene Ontogeny annotation. Genes may act primarily within the adaptive arm of the immune system (blue arc), the innate arm (maroon arc), or both.

Figure 2:

IPE disease management recommendations based on genetic diagnoses. Recommendations for therapy for each gene are presented in supplementary Table EII. Percentages add to more than 100%, because for some patients, more than one recommendation was available. HCT is hematopoietic cell transplant.