{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T20:41:23Z","timestamp":1789072883738,"version":"build-2803163510"},"reference-count":50,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,3,3]],"date-time":"2025-03-03T00:00:00Z","timestamp":1740960000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Jeffrey Modell Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Cytotoxic-T-lymphocyte-antigen-4 (CTLA-4), a member of the immunoglobulin superfamily, is an essential negative regulator of immune responses that is constitutively expressed on both regulatory (Treg) and activated T cells. To date, heterozygous germline variants in CTLA4, leading to haploinsufficiency, have been associated with several immunological disorders, including hypogammaglobulinemia, multi-organ autoimmunity, lymphoproliferative disorders, and enlarged lymphoid organs. Indeed, CTLA4 carriers display highly heterogeneous clinical manifestations with a phenotypic spectrum ranging from asymptomatic carrier status to fatal autoimmunity. Here, we describe a family with autoimmune phenotypes (Hashimoto thyroiditis, psoriasiform dermatitis, celiac disease\/inflammatory bowel disease, and rheumatoid arthritis), segregating across three different generations due to a recurrent missense variant [c.436G&gt;A, p.(Gly146Arg)] in the CTLA4 gene. Interestingly, the proband showed prominent neurological manifestations, including seizures, hydrocephalus, and demyelination, which are less frequently reported in individuals with pathogenic variants in CTLA4. A detailed literature review of neurologic features that have been reported so far in CTLA4 carriers is also provided.<\/jats:p>","DOI":"10.3390\/genes16030306","type":"journal-article","created":{"date-parts":[[2025,3,3]],"date-time":"2025-03-03T09:04:49Z","timestamp":1740992689000},"page":"306","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["CTLA4 Alteration and Neurologic Manifestations: A New Family with Large Phenotypic Variability and Literature Review"],"prefix":"10.3390","volume":"16","author":[{"given":"Edoardo","family":"Genio","sequence":"first","affiliation":[{"name":"Unit of Medical Genetics, Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0577-5259","authenticated-orcid":false,"given":"Mauro","family":"Lecca","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics, Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6297-7576","authenticated-orcid":false,"given":"Rachele","family":"Ciccocioppo","sequence":"additional","affiliation":[{"name":"Gastroenterology and Endoscopic Unit, Department of Medicine and Ageing, University Gabriele D\u2019Annunzio of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6346-1988","authenticated-orcid":false,"given":"Edoardo","family":"Errichiello","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics, Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy"},{"name":"IRCCS Mondino Foundation, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2004973","DOI":"10.1002\/advs.202004973","article-title":"In Vivo Induction of Regulatory T Cells Via CTLA-4 Signaling Peptide to Control Autoimmune Encephalomyelitis and Prevent Disease Relapse","volume":"8","author":"Kim","year":"2021","journal-title":"Adv. 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