Elliot L. James

Primary atopic disorders (PADs), a subset of inborn errors of immunity, are a growing group of more than 50 monogenic diseases characterized by severe, early-onset allergic inflammation, often coexisting with immune deficiency or dysregulation. Once considered clinical curiosities, PADs have emerged as powerful human models for understanding immune homeostasis. Advances in next-generation sequencing have accelerated gene discovery, revealing that allergic disease can arise from disruption of interconnected regulatory systems rather than immune hyperactivity alone. Here, we synthesize insights from genetically defined PADs to illustrate how defects across epithelial barrier function, immune signaling, cytoskeletal organization, antigen receptor pathways, lymphocyte repertoire, and regulatory networks converge on impaired tolerance and persistent type 2 inflammation. Beyond mechanistic insights, PADs provide a framework for precision therapy enabling targeted use of cytokine inhibitors, JAK inhibitors, biologics, hematopoietic stem cell transplantation, and emerging gene therapies. These insights bridge rare and common disease, informing the pathophysiology and treatment of polygenic atopy.

Inborn errors of immunity (IEIs) are caused by deleterious variants in immune-related genes. ASXL1 is an epigenetic modifier not previously linked to an IEI. Clonal hematopoiesis and hematologic neoplasms often feature somatic ASXL1 variants, and Bohring–Opitz syndrome, a neurodevelopmental disorder, is caused by heterozygous truncating ASXL1 variants. We present an IEI caused by biallelic germline missense variants in ASXL1. The patient had a history of hematologic abnormalities and viral-associated complications, including chronic macrocytosis, persistent vaccine-strain rubella granulomas, and EBV-associated Hodgkin lymphoma. Immunophenotyping revealed loss of B cells, hypogammaglobulinemia, and impairments in cytotoxic T and NK cell populations. T cells exhibited skewing toward an exhausted memory phenotype, global DNA methylation loss, and increased epigenetic aging. These aberrations were ameliorated by wild-type ASXL1 transduction, confirming the patient variants’ pathogenicity. This study defines a novel human IEI caused by ASXL1 deficiency, a diagnosis that should be considered in individuals with chronic viral infections, viral-associated malignancies, and combined immune deficiency.