{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T17:05:06Z","timestamp":1790269506483,"version":"4.1.0"},"reference-count":45,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Hereditary autoinflammatory diseases have traditionally been defined as disorders caused by germline mutations in innate immune pathway genes transmitted through Mendelian inheritance, an assumption challenged by the discovery that postzygotic somatic mosaicism can reproduce similar autoinflammatory phenotypes. Aim of the review is to synthesize the mechanistic evidence for somatic and gonadal mosaicism across the major monogenic autoinflammatory diseases and to reassess the adequacy of \u201chereditary\u201d as a categorical descriptor for this disease class. A structured narrative review of PubMed\/MEDLINE was conducted (2002\u20132026), screening 241 records for evidence of somatic mosaicism in NLRP3, MEFV, TNFRSF1A, NOD2, NLRC4, UBA1, and MVK, of which 35 met inclusion criteria for qualitative synthesis; rather than proceeding disease-by-disease, evidence was organized around the underlying mechanisms by which a minority mutant-cell population produces disease. Four mechanistic categories were identified: (1) dominant effect without clonal expansion, most extensively documented in NLRP3-mediated cryopyrin-associated periodic disease; (2) clonal growth advantage, which introduces lineage-restricted diagnostic blind spots and, when gonadal tissue is involved, has implications for genetic counseling risk; (3) \u201cpassenger\u201d mechanism converging with age-related clonal hematopoiesis in late-onset disease; and (4) no germline counterpart at all for UBA1-driven VEXAS syndrome. The detection of variants depends heavily on sequencing depth and tissue\/lineage sampling, but variant allele fraction does not consistently predict clinical severity. Mevalonate kinase deficiency, a recessively inherited autoinflammatory disorder, has no reported mosaic cases, a pattern attributed to its biallelic genetic architecture rather than under-ascertainment. \u201cHereditary\u201d, which conflates transmission and cellular distribution, is no longer an adequate categorical descriptor for autoinflammatory diseases as a class, though it remains accurate for individual patients and specific variants.<\/jats:p>","DOI":"10.3390\/ijms27198554","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T16:29:53Z","timestamp":1790267393000},"page":"8554","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Mechanistic Framework for Somatic Mosaicism in Autoinflammatory Diseases Beyond Mendelian Inheritance"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-7667-6636","authenticated-orcid":false,"given":"Anoushka","family":"Krishnakumar","sequence":"first","affiliation":[{"name":"Department of Life Sciences and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli 8, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4707-2242","authenticated-orcid":false,"given":"Elisabetta","family":"Tabolacci","sequence":"additional","affiliation":[{"name":"UOC Genetica Medica, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy"},{"name":"Universit\u00e0 Cattolica Sacro Cuore, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7032-7779","authenticated-orcid":false,"given":"Donato","family":"Rigante","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli 8, 00168 Rome, Italy"},{"name":"Universit\u00e0 Cattolica Sacro Cuore, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/s41584-026-01390-6","article-title":"20 years of progress in the classification of immune mediated diseases","volume":"22","author":"McGonagle","year":"2026","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1016\/j.autrev.2011.10.008","article-title":"The fresco of autoinflammatory diseases from the pediatric perspective","volume":"11","author":"Rigante","year":"2012","journal-title":"Autoimmun. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"485103","DOI":"10.1155\/2013\/485103","article-title":"From the Mediterranean to the sea of Japan: The transcontinental odyssey of autoinflammatory diseases","volume":"2013","author":"Rigante","year":"2013","journal-title":"Biomed. Res. Int."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1007\/s10067-014-2722-z","article-title":"Key facts and hot spots on tumor necrosis factor receptor-associated periodic syndrome","volume":"33","author":"Rigante","year":"2014","journal-title":"Clin. Rheumatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.clim.2012.09.011","article-title":"Mevalonate kinase deficiency, a metabolic autoinflammatory disease","volume":"147","author":"Boes","year":"2013","journal-title":"Clin. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1177\/039463201102400402","article-title":"Bridging the gap between the clinician and the patient with cryopyrin-associated periodic syndromes","volume":"24","author":"Cantarini","year":"2011","journal-title":"Int. J. Immunopathol. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Dhar, A., Kitani, A., and Strober, W. (2026). Immunological analysis of Blau syndrome, a unique autoinflammatory state. Front. Immunol., 17.","DOI":"10.3389\/fimmu.2026.1793228"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1038\/s42003-026-10174-3","article-title":"Current understanding of the NLRC4 inflammasome in autoinflammation and enterocolitis","volume":"9","author":"Wang","year":"2026","journal-title":"Commun. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Torreggiani, S., and Aksentijevich, I. (2026). Somatic variants in immune dysregulation: An ongoing challenge. Arthritis Rheumatol., Epub ahead of print.","DOI":"10.1002\/art.70179"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1146\/annurev-immunol-090222-105848","article-title":"Genetic regulation of cell death: Insights from autoinflammatory diseases","volume":"43","author":"Oda","year":"2025","journal-title":"Annu. Rev. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"The French FMF Consortium (1997). A candidate gene for familial Mediterranean fever. Nat. Genet., 17, 25\u201331.","DOI":"10.1038\/ng0997-25"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"The International FMF Consortium (1997). Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell, 90, 797\u2013807.","DOI":"10.1016\/S0092-8674(00)80539-5"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1038\/ng756","article-title":"Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome","volume":"29","author":"Hoffman","year":"2001","journal-title":"Nat. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1080\/10408363.2018.1488805","article-title":"Mosaicism in autoinflammatory diseases: Cryopyrin-associated periodic syndromes (CAPS) and beyond. A systematic review","volume":"55","author":"Labrousse","year":"2018","journal-title":"Crit. Rev. Clin. Lab. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2482","DOI":"10.1002\/art.39190","article-title":"Cryopyrin-associated periodic syndrome caused by a myeloid-restricted somatic NLRP3 mutation","volume":"67","author":"Zhou","year":"2015","journal-title":"Arthritis Rheumatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1002\/art.41999","article-title":"First description of late-onset autoinflammatory disease due to somatic NLRC4 mosaicism","volume":"74","author":"Ionescu","year":"2022","journal-title":"Arthritis Rheumatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2044","DOI":"10.1002\/art.39683","article-title":"Brief report: Association of tumor necrosis factor receptor\u2013associated periodic syndrome with gonosomal mosaicism of a novel 24-nucleotide TNFRSF1A deletion","volume":"68","author":"Rowczenio","year":"2016","journal-title":"Arthritis Rheumatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1016\/j.jaci.2019.11.035","article-title":"NLRP3-associated autoinflammatory diseases: Phenotypic and molecular characteristics of germline versus somatic mutations","volume":"145","author":"Louvrier","year":"2020","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2628","DOI":"10.1056\/NEJMoa2026834","article-title":"Somatic mutations in UBA1 and severe adult-onset autoinflammatory disease","volume":"383","author":"Beck","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.ajhg.2007.09.009","article-title":"Rare missense and synonymous variants in UBE1 are associated with X-linked infantile spinal muscular atrophy","volume":"82","author":"Ramser","year":"2008","journal-title":"Am. J. Hum. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1038\/nrg3424","article-title":"A genomic view of mosaicism and human disease","volume":"14","author":"Biesecker","year":"2013","journal-title":"Nat. Rev. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1093\/intimm\/dxz047","article-title":"Low-frequency mosaicism in cryopyrin-associated periodic fever syndrome: Mosaicism in systemic autoinflammatory diseases","volume":"31","author":"Nishikomori","year":"2019","journal-title":"Int. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/j.jaci.2018.09.009","article-title":"Unexpected relevant role of gene mosaicism in patients with primary immunodeficiency diseases","volume":"143","author":"Fuster","year":"2019","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.ajhg.2015.05.008","article-title":"Post-zygotic point mutations are an underrecognized source of de novo genomic variation","volume":"97","author":"Bo","year":"2015","journal-title":"Am. J. Hum. Genet."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Jaiswal, S., and Ebert, B.L. (2019). Clonal hematopoiesis in human aging and disease. Science, 366.","DOI":"10.1126\/science.aan4673"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1038\/nrg906","article-title":"Mechanisms and consequences of somatic mosaicism in humans","volume":"3","author":"Youssoufian","year":"2002","journal-title":"Nat. Rev. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.cell.2020.06.024","article-title":"Pathogenic mechanisms of somatic mutation and genome mosaicism in aging","volume":"182","author":"Vijg","year":"2020","journal-title":"Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1007\/s10875-025-01907-w","article-title":"Somatic mosaic NLRC4 variants in autoinflammatory diseases: Functional characterization and correlation of mosaicism levels with disease age of onset and severity","volume":"45","author":"Diab","year":"2025","journal-title":"J. Clin. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.ejim.2024.01.028","article-title":"Diagnosis traps for patients with acquired NLRP3 mutation","volume":"125","author":"Cescato","year":"2024","journal-title":"Eur. J. Intern. Med."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Cook, C.B., Armstrong, L., Boerkoel, C.F., Clarke, L.A., du Souich, C., Demos, M.K., Gibson, W.T., Gill, H., Lopez, E., and Patel, M.S. (2021). Somatic mosaicism detected by genome-wide sequencing in 500 parent\u2013child trios with suspected genetic disease: Clinical and genetic counseling implications. Cold Spring Harb. Mol. Case Stud., 7.","DOI":"10.1101\/mcs.a006125"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1007\/978-1-4939-7778-9_11","article-title":"Detection and quantification of mosaic genomic DNA variation in primary somatic tissues using ddPCR: Analysis of mosaic transposable-element insertions, copy-number variants, and single-nucleotide variants","volume":"Volume 1768","author":"Zhou","year":"2018","journal-title":"Methods in Molecular Biology"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Melo Gomes, S., Ar\u00f3stegui, J.I., Mensa-Vilaro, A., Omoyinmi, E., Hong, Y., McCreary, D., Rowczenio, D., Hawkins, P., and Brogan, P. (2025). Somatic NLRP3 mosaicism in patients with \u201cmutation-negative\u201d CAPS: Insights from a single centre UK cohort. Front. Pediatr., 13.","DOI":"10.3389\/fped.2025.1598748"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1016\/j.jaci.2024.11.038","article-title":"Somatic mosaicism in genetic errors of immunity","volume":"155","author":"Cooper","year":"2025","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1186\/s13023-015-0298-6","article-title":"Acquired familial Mediterranean fever associated with a somatic MEFV mutation in a patient with JAK2-associated post-polycythemia myelofibrosis","volume":"10","author":"Shinar","year":"2015","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1016\/j.jaci.2014.07.050","article-title":"Myeloid lineage-restricted somatic mosaicism of NLRP3 mutations in patients with variant Schnitzler syndrome","volume":"135","author":"Stoffels","year":"2015","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3435","DOI":"10.1111\/all.15411","article-title":"Absence of NLRP3 somatic mutations and VEXAS-related UBA1 mutations in a large cohort of patients with Schnitzler syndrome","volume":"77","author":"Louvrier","year":"2022","journal-title":"Allergy"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Kontzias, A., Zarabi, S.K., Calabrese, C., Wang, Y., Judis, L., Yao, Q., and Cheng, Y.W. (2019). Somatic mosaicism in adult-onset TNF receptor-associated periodic syndrome (TRAPS). Mol. Genet. Genom. Med., 7.","DOI":"10.1002\/mgg3.791"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1002\/art.39519","article-title":"Brief report: First identification of intrafamilial recurrence of Blau syndrome due to gonosomal NOD2 mosaicism","volume":"68","author":"Cham","year":"2016","journal-title":"Arthritis Rheumatol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1626","DOI":"10.1056\/NEJMc2212928","article-title":"TET2-driver and NLRC4-passenger variants in adult-onset autoinflammation","volume":"388","author":"Metzemaekers","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1002\/art.43329","article-title":"Longitudinal analysis of somatic mosaicism and clonal hematopoiesis in cryopyrin-associated periodic syndrome","volume":"78","author":"Kato","year":"2026","journal-title":"Arthritis Rheumatol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1001\/jama.2022.24836","article-title":"Estimated prevalence and clinical manifestations of UBA1 variants associated with VEXAS syndrome in a clinical population","volume":"329","author":"Beck","year":"2023","journal-title":"JAMA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2694","DOI":"10.1093\/rheumatology\/keae123","article-title":"Comparing clinical features between males and females with VEXAS syndrome: Data from literature analysis of patient reports","volume":"63","author":"Echerbault","year":"2024","journal-title":"Rheumatology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1038\/9691","article-title":"Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome","volume":"22","author":"Houten","year":"1999","journal-title":"Nat. Genet."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1016\/j.gendis.2021.05.002","article-title":"Twists and turns of the genetic story of mevalonate kinase-associated diseases: A review","volume":"9","author":"Touitou","year":"2022","journal-title":"Genes Dis."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Shinar, Y., Hashkes, P.J., Cohen, R., Kessel, A., Tirosh, I., Padeh, S., Ar\u00f3stegui, J.I., and Livneh, A. (2015). Mevalonate kinase somatic mosaicism and bigenic genotypes may explain heterogeneity in mevalonate kinase deficiency. Pediatr. Rheumatol., 13.","DOI":"10.1186\/1546-0096-13-S1-P48"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/19\/8554\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T16:31:14Z","timestamp":1790267474000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/19\/8554"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,24]]},"references-count":45,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["ijms27198554"],"URL":"https:\/\/doi.org\/10.3390\/ijms27198554","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,24]]}}}