{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T19:05:19Z","timestamp":1791313519911,"version":"4.3.1"},"reference-count":18,"publisher":"BMJ","issue":"11","funder":[{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2013\/08028-1"],"award-info":[{"award-number":["2013\/08028-1"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2018\/18007-5"],"award-info":[{"award-number":["2018\/18007-5"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2019\/06039-2"],"award-info":[{"award-number":["2019\/06039-2"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["303375\/2019"],"award-info":[{"award-number":["303375\/2019"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2023,3,27]]},"published-print":{"date-parts":[[2023,11]]},"abstract":"<jats:p>Rothmund-Thomson syndrome (RTS) is a rare, heterogeneous autosomal recessive genodermatosis, with poikiloderma as its hallmark. It is classified into two types: type I, with biallelic variants in <jats:italic>ANAPC1<\/jats:italic> and juvenile cataracts, and type II, with biallelic variants in <jats:italic>RECQL4<\/jats:italic>, increased cancer risk and no cataracts. We report on six Brazilian probands and two siblings of Swiss\/Portuguese ancestry presenting with severe short stature, widespread poikiloderma and congenital ocular anomalies. Genomic and functional analysis revealed compound heterozygosis for a deep intronic splicing variant in trans with loss of function variants in <jats:italic>DNA2<\/jats:italic>, with reduction of the protein levels and impaired DNA double-strand break repair. The intronic variant is shared by all patients, as well as the Portuguese father of the European siblings, indicating a probable founder effect. Biallelic variants in <jats:italic>DNA2<\/jats:italic> were previously associated with microcephalic osteodysplastic primordial dwarfism. Although the individuals reported here present a similar growth pattern, the presence of poikiloderma and ocular anomalies is unique. Thus, we have broadened the phenotypical spectrum of <jats:italic>DNA2<\/jats:italic> mutations, incorporating clinical characteristics of RTS. Although a clear genotype\u2013phenotype correlation cannot be definitively established at this moment, we speculate that the residual activity of the splicing variant allele could be responsible for the distinct manifestations of <jats:italic>DNA2<\/jats:italic>-related syndromes.<\/jats:p>","DOI":"10.1136\/jmg-2022-109119","type":"journal-article","created":{"date-parts":[[2023,4,13]],"date-time":"2023-04-13T13:40:28Z","timestamp":1681393228000},"page":"1127-1132","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":19,"title":["Biallelic variants in <i>DNA2<\/i> cause poikiloderma with congenital cataracts and severe growth failure reminiscent of Rothmund-Thomson syndrome"],"prefix":"10.1136","volume":"60","author":[{"given":"Ricardo","family":"Di Lazzaro Filho","sequence":"first","affiliation":[{"name":"Departamento de Gen\u00e9tica e Biologia Evolutiva do Instituto de Bioci\u00eancias, Universidade de S\u00e3o Paulo, Sao Paulo, Brazil"},{"name":"Gen\u00f4mica\/Genera, Diagn\u00f3sticos da Am\u00e9rica SA, Barueri, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guilherme Lopes","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Gen\u00f4mica\/Genera, Diagn\u00f3sticos da Am\u00e9rica SA, Barueri, Brazil"},{"name":"Departamento de Pediatria do Hospital das Cl\u00ednicas da Faculdade de Medicina, Universidade de S\u00e3o Paulo, Sao Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiago J","family":"Silva","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica do Instituto de Qu\u00edmica, Universidade de Sao Paulo, Sao Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leticia A","family":"Rocha","sequence":"additional","affiliation":[{"name":"Departamento de Gen\u00e9tica e Biologia Evolutiva do Instituto de Bioci\u00eancias, Universidade de S\u00e3o Paulo, Sao Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca D W","family":"Linnenkamp","sequence":"additional","affiliation":[{"name":"Departamento de Pediatria do Hospital das Cl\u00ednicas da Faculdade de Medicina, Universidade de S\u00e3o Paulo, Sao Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0335-8799","authenticated-orcid":false,"given":"Matheus Augusto Ara\u00fajo","family":"Castro","sequence":"additional","affiliation":[{"name":"Departamento de Pediatria do Hospital das Cl\u00ednicas da Faculdade de Medicina, Universidade de S\u00e3o Paulo, Sao Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah","family":"Bartholdi","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, University of Bern, Bern, 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Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos E","family":"Steiner","sequence":"additional","affiliation":[{"name":"Hospital das Cl\u00ednicas, UNICAMP, Campinas, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leandra","family":"Steinmetz","sequence":"additional","affiliation":[{"name":"Departamento de Pediatria do Hospital das Cl\u00ednicas da Faculdade de Medicina, Universidade de S\u00e3o Paulo, Sao Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel Sayuri","family":"Honjo","sequence":"additional","affiliation":[{"name":"Departamento de Pediatria do Hospital das Cl\u00ednicas da Faculdade de Medicina, Universidade de S\u00e3o Paulo, Sao Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chong Ae","family":"Kim","sequence":"additional","affiliation":[{"name":"Departamento de Pediatria do Hospital das Cl\u00ednicas da Faculdade de Medicina, Universidade de S\u00e3o 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