{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T23:51:54Z","timestamp":1791244314177,"version":"4.1.0"},"reference-count":31,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T00:00:00Z","timestamp":1757462400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union\u2013NextGenerationUE as part of PNRR MUR-M4C2-Investimento 1.3\u2014Public Call \u201cPartenariati Estesi\u201d\u2014D.D.","award":["341\/2022"],"award-info":[{"award-number":["341\/2022"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Factor XI (FXI) deficiency, or hemophilia C, is a rare bleeding disorder resulting from reduced levels or dysfunctional FXI protein due to mutations in the F11 gene. This study investigated the correlation between FXI activity levels, F11 genotype, and bleeding phenotypes. Clinical and genetic characteristics of 93 individuals from southern Italy diagnosed with congenital FXI deficiency, including 39 index cases and their relatives, were evaluated. FXI:C plasma levels were measured. Sanger sequencing of F11 was performed, and the pathogenicity of variants identified was assessed using in silico tools. FXI activity levels ranged widely (1\u201369%), with most cases being heterozygous and showing moderate deficiency. Only 12 individuals had severe FXI deficiency, typically associated with homozygosity or compound heterozygosity. Bleeding symptoms varied from mild to severe and occurred in 31% of subjects, though only a minority of those with severe deficiency experienced spontaneous or surgery-related bleeding. Sanger sequencing revealed 24 distinct F11 gene variants, predominantly missense mutations, with three novel variants (p.Val89*, p.Leu306Pro, and p.Trp515Gly). Common mutations included p.Glu135* and p.Glu315Lys. Variants were distributed across the gene, with no domain-specific clustering. No clear genotype\u2013phenotype correlation was observed. FXI levels alone did not reliably predict bleeding risk, highlighting the influence of additional factors such as age, gender, and clinical history. This study reinforces the allelic and clinical heterogeneity of FXI deficiency and the limited utility of FXI:C levels alone for predicting bleeding severity. Further research is needed to clarify the complex genotype\u2013phenotype relationships in FXI deficiency.<\/jats:p>","DOI":"10.3390\/ijms26188807","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T10:27:12Z","timestamp":1757500032000},"page":"8807","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Clinical and Genetic Heterogeneity of Factor XI Deficiency: Insights from a Southern Italian Cohort"],"prefix":"10.3390","volume":"26","author":[{"given":"Rosa","family":"Santacroce","sequence":"first","affiliation":[{"name":"Medical Genetics, Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna","family":"D\u2019Andrea","sequence":"additional","affiliation":[{"name":"Medical Genetics, Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5896-2024","authenticated-orcid":false,"given":"Giovanni Luca","family":"Tiscia","sequence":"additional","affiliation":[{"name":"Thrombosis and Haemostasis Unit, Fondazione IRCCS \u201cCasa Sollievo della Sofferenza\u201d, Viale Cappuccini, 71013 San Giovanni Rotondo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Lassandro","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Human Oncology, Pediatric Section, University of Bari \u201cA. Moro\u201d, 70126 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9170-4668","authenticated-orcid":false,"given":"Maria","family":"d\u2019Apolito","sequence":"additional","affiliation":[{"name":"Medical Genetics, Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0823-3357","authenticated-orcid":false,"given":"Doris","family":"Barcellona","sequence":"additional","affiliation":[{"name":"Department of Medical Science and Public Health, University of Cagliari, 09124 Cagliari, Italy"},{"name":"Departmental Unit of Thrombosis and Haemostasis, Azienda Ospedaliero-Universitaria di Cagliari, 09124 Cagliari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrizia","family":"De Bonis","sequence":"additional","affiliation":[{"name":"Thrombosis and Haemostasis Unit, Fondazione IRCCS \u201cCasa Sollievo della Sofferenza\u201d, Viale Cappuccini, 71013 San Giovanni Rotondo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Marongiu","sequence":"additional","affiliation":[{"name":"Department of Medical Science and Public Health, University of Cagliari, 09124 Cagliari, Italy"},{"name":"Departmental Unit of Thrombosis and Haemostasis, Azienda Ospedaliero-Universitaria di Cagliari, 09124 Cagliari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Giordano","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Human Oncology, Pediatric Section, University of Bari \u201cA. Moro\u201d, 70126 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8980-9783","authenticated-orcid":false,"given":"Elvira","family":"Grandone","sequence":"additional","affiliation":[{"name":"Thrombosis and Haemostasis Unit, Fondazione IRCCS \u201cCasa Sollievo della Sofferenza\u201d, Viale Cappuccini, 71013 San Giovanni Rotondo, Italy"},{"name":"Obstetrics and Gynecology Department, University of Foggia, 71122 Foggia, Italy"},{"name":"Department of Obstetrics, Gynaecology and Perinatal Medicine, First I.M. Sechenov Moscow State Medical University, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5627-9221","authenticated-orcid":false,"given":"Maurizio","family":"Margaglione","sequence":"additional","affiliation":[{"name":"Medical Genetics, Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1182\/blood.2023020721","article-title":"Factor XI deficiency: Phenotypic age-related considerations and clinical approach towards bleeding risk assessment","volume":"143","author":"Barg","year":"2024","journal-title":"Blood"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1056\/NEJM199107183250303","article-title":"Factor XI deficiency in Ashkenazi Jews in Israel","volume":"325","author":"Asakai","year":"1991","journal-title":"N. 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Haemost."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/18\/8807\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:43:09Z","timestamp":1760035389000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/18\/8807"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,10]]},"references-count":31,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["ijms26188807"],"URL":"https:\/\/doi.org\/10.3390\/ijms26188807","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,10]]}}}