{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T09:03:36Z","timestamp":1789376616737,"version":"build-2803163510"},"reference-count":23,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T00:00:00Z","timestamp":1789257600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant vascular disorder primarily caused by pathogenic variants in the ENG and ACVRL1 genes. Although genotype\u2013phenotype correlations are well established at the population level, the degree of phenotypic similarity among relatives sharing the same variant is poorly characterized. Objective: to explore differences in expressivity and quantify the degree of phenotypic variability among individuals with HHT carrying the same pathogenic variant. Methods: We evaluated 60 patients from a reference center with recurrent ENG and ACVRL1 variants, to quantify intra-familial phenotypic heterogeneity using Shannon entropy indices, Jaccard distances, and a latent variable liability-threshold approach. Results: There was substantial phenotypic variability among individuals and families, with cutaneous telangiectasia being the most frequent manifestation. Shannon entropy and Jaccard analyses indicated broadly high variability. The shared variant accounted for only 3.3% of total variance. Age was significantly associated with disease manifestations (\u03b2 = 0.027, p = 0.002; OR = 1.028, 95% CI 1.010\u20131.045), with each additional year increasing the odds of severe symptoms by 2.7%, particularly bleeding severity and skin telangiectasias. Conclusions: These findings suggest that the variable expressivity in HHT is predominantly driven by individual-level factors other than the specific pathogenic variant carried by each patient.<\/jats:p>","DOI":"10.3390\/genes17091112","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T08:10:23Z","timestamp":1789373423000},"page":"1112","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Phenotypic Heterogeneity Among Carriers of the Same Pathogenic Variant in Hereditary Hemorrhagic Telangiectasia"],"prefix":"10.3390","volume":"17","author":[{"given":"Elena","family":"Ur\u00edzar","sequence":"first","affiliation":[{"name":"Servicio de Medicina Interna, Hospital Universitario Marqu\u00e9s deValdecilla, 39008 Santander, Spain"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4957-4219","authenticated-orcid":false,"given":"Pablo","family":"Solis","sequence":"additional","affiliation":[{"name":"Servicio de Medicina Interna, Hospital Universitario Marqu\u00e9s deValdecilla, 39008 Santander, Spain"},{"name":"Instituto de Investigaci\u00f3n Marqu\u00e9s de Valdecilla (IDIVAL), 39011 Santander, Spain"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Nuria","family":"Puente","sequence":"additional","affiliation":[{"name":"Servicio de Medicina Interna, Hospital Universitario Marqu\u00e9s deValdecilla, 39008 Santander, Spain"},{"name":"Instituto de Investigaci\u00f3n Marqu\u00e9s de Valdecilla (IDIVAL), 39011 Santander, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Ana","family":"Fontalba","sequence":"additional","affiliation":[{"name":"Unidad de Gen\u00e9tica, Hospital Universitario Marqu\u00e9s de Valdecilla, 39008 Santander, Spain"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Roberto","family":"Zarrabeitia","sequence":"additional","affiliation":[{"name":"Servicio de Medicina Interna, Hospital Sierrallana, 39300 Torrelavega, Spain"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0691-8755","authenticated-orcid":false,"given":"Jos\u00e9 A.","family":"Riancho","sequence":"additional","affiliation":[{"name":"Servicio de Medicina Interna, Hospital Universitario Marqu\u00e9s deValdecilla, 39008 Santander, Spain"},{"name":"Instituto de Investigaci\u00f3n Marqu\u00e9s de Valdecilla (IDIVAL), 39011 Santander, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain"},{"name":"Departamento de Medicina y Psiquiatr\u00eda, Universidad de Cantabria, 39008 Santander, Spain"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41572-024-00585-z","article-title":"Hereditary haemorrhagic telangiectasia","volume":"11","author":"Hermann","year":"2025","journal-title":"Nat. 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