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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.<\/jats:p>","DOI":"10.70962\/jhi.20260006","type":"journal-article","created":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T06:21:56Z","timestamp":1776320516000},"update-policy":"https:\/\/doi.org\/10.70962\/jhi.crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Primary atopic disorders: Monogenic insights into immunity"],"prefix":"10.70962","volume":"2","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1510-5916","authenticated-orcid":true,"given":"Bhavi P.","family":"Modi","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04n901w50","id-type":"ROR","asserted-by":"publisher"}],"name":"BC Children\u2019s Hospital, University of British Columbia 1 Department of Pediatrics, , Vancouver,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5559-2494","authenticated-orcid":true,"given":"Cassandra","family":"McDonald","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04n901w50","id-type":"ROR","asserted-by":"publisher"}],"name":"BC Children\u2019s Hospital, University of British Columbia 1 Department of Pediatrics, , Vancouver,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8851-8052","authenticated-orcid":true,"given":"Liam","family":"Golding","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04n901w50","id-type":"ROR","asserted-by":"publisher"}],"name":"BC Children\u2019s Hospital, University of British Columbia 1 Department of Pediatrics, , Vancouver,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6545-5725","authenticated-orcid":true,"given":"Leandro B.R.","family":"Da Silva","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04n901w50","id-type":"ROR","asserted-by":"publisher"}],"name":"BC Children\u2019s Hospital, University of British Columbia 1 Department of Pediatrics, , Vancouver,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4363-2660","authenticated-orcid":true,"given":"Catherine M.","family":"Biggs","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04n901w50","id-type":"ROR","asserted-by":"publisher"}],"name":"BC Children\u2019s Hospital, University of British Columbia 1 Department of Pediatrics, , Vancouver,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6313-4434","authenticated-orcid":true,"given":"Julia","family":"K\u00f6rholz","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04za5zm41","id-type":"ROR","asserted-by":"publisher"}],"name":"Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universit\u00e4t Dresden 2 Department of Pediatrics, , Dresden,","place":["Germany"]},{"name":"German Center for Child and Adolescent Health, Partner site Leipzig\/Dresden 3 , Dresden,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5249-857X","authenticated-orcid":true,"given":"Elliot L.","family":"James","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04n901w50","id-type":"ROR","asserted-by":"publisher"}],"name":"BC Children\u2019s Hospital, University of British Columbia 1 Department of Pediatrics, , Vancouver,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1599-1065","authenticated-orcid":true,"given":"Stuart E.","family":"Turvey","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04n901w50","id-type":"ROR","asserted-by":"publisher"}],"name":"BC Children\u2019s Hospital, University of British Columbia 1 Department of Pediatrics, , Vancouver,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2026,5,7]]},"reference":[{"key":"2026051110364676600_bib1","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1016\/S2213-2600(25)00003-7","article-title":"Global, regional, and national burden of asthma and atopic dermatitis, 1990-2021, and projections to 2050: A systematic analysis of the global burden of disease study 2021","volume":"13","author":"GBD 2021 Asthma and Allergic Diseases Collaborators","year":"2025","journal-title":"Lancet Respir. 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