{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T01:39:35Z","timestamp":1776044375876,"version":"3.50.1"},"reference-count":12,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2024,8,29]],"date-time":"2024-08-29T00:00:00Z","timestamp":1724889600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Genetic variants in the zone of polarizing activity regulatory sequence (ZRS) that induce ectopic expression of the SHH gene have been associated with different ZRS-related phenotypes. We report the first patient with a de novo variant, c.423+4916 T&gt;C, in ZRS (previously classified as a variant of uncertain significance) that causes tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome (THPTTS). A two-month-old male patient presented with bilateral preaxial polydactyly, triphalangeal thumb, and tibial agenesis and was heterozygous for the variant c.423+4916T&gt;C (neither of his parents was a carrier). The findings obtained from the family study were sufficient to reclassify the variant from \u201cuncertain significance\u201d to \u201clikely pathogenic\u201d according to three criteria from the American College of Medical Genetics and Genomics guidelines, as follows: (1) absence of gnomAD, (2) confirmation of paternity and maternity, and (3) strong phenotype\u2013genotype association. In ZRS-associated syndromes, a wide clinical spectrum has been observed, ranging from polydactyly to THPTTS; our patient has the most severe and rare phenotype. We did not perform functional assays. However, the c.423+4916T&gt;C variant is flanked by three variants, which have been proven not only to cause the phenotype but also to increase the expression of SHH. Through all this data gathering, we consider the c.423+4916T&gt;C variant to be causative of THPTTS.<\/jats:p>","DOI":"10.3390\/ijms25179348","type":"journal-article","created":{"date-parts":[[2024,8,29]],"date-time":"2024-08-29T03:40:39Z","timestamp":1724902839000},"page":"9348","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The First Patient with Tibial Hemimelia-Polysyndactyly-Triphalangeal Thumb Syndrome Caused by De Novo c.423+4916 T&gt;C ZRS Variant: A Case Report"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5452-821X","authenticated-orcid":false,"given":"Paola Montserrat","family":"Zepeda-Olmos","sequence":"first","affiliation":[{"name":"Divisi\u00f3n de Gen\u00e9tica, Centro de Investigaci\u00f3n Biom\u00e9dica de Occidente, Instituto Mexicano del Seguro Social, Sierra Mojada 800, Independencia Oriente, Guadalajara 44340, Jalisco, Mexico"},{"name":"Doctorado en Gen\u00e9tica Humana, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Sierra Mojada 950, Independencia Oriente, Guadalajara 44340, Jalisco, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1036-3249","authenticated-orcid":false,"given":"Kiabeth","family":"Robles-Espinoza","sequence":"additional","affiliation":[{"name":"Divisi\u00f3n de Gen\u00e9tica, Centro de Investigaci\u00f3n Biom\u00e9dica de Occidente, Instituto Mexicano del Seguro Social, Sierra Mojada 800, Independencia Oriente, Guadalajara 44340, Jalisco, Mexico"},{"name":"Doctorado en Gen\u00e9tica Humana, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Sierra Mojada 950, Independencia Oriente, Guadalajara 44340, Jalisco, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6451-0366","authenticated-orcid":false,"given":"Eduardo","family":"Esparza-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Unidad M\u00e9dica de Alta Especialidad, Hospital de Pediatr\u00eda del Centro M\u00e9dico Nacional de Occidente, Instituto Mexicano del Seguro Social, Belisario Dom\u00ednguez 735, La Perla, Guadalajara 44360, Jalisco, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda Teresa","family":"Maga\u00f1a-Torres","sequence":"additional","affiliation":[{"name":"Divisi\u00f3n de Gen\u00e9tica, Centro de Investigaci\u00f3n Biom\u00e9dica de Occidente, Instituto Mexicano del Seguro Social, Sierra Mojada 800, Independencia Oriente, Guadalajara 44340, Jalisco, Mexico"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1002\/ajmg.a.63132","article-title":"Nosology of Genetic Skeletal Disorders: 2023 Revision","volume":"191","author":"Unger","year":"2023","journal-title":"Am. 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