{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T10:39:51Z","timestamp":1791110391243,"version":"4.1.0"},"reference-count":16,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2011,7,13]],"date-time":"2011-07-13T00:00:00Z","timestamp":1310515200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2012,8]]},"abstract":"<jats:p>Eyries M, Coulet F, Girerd B, Montani D, Humbert M, Lacombe P, Chinet T, Gouya L, Roume J, Axford MM, Pearson CE, Soubrier F. <jats:italic>ACVRL1<\/jats:italic> germinal mosaic with two mutant alleles in hereditary hemorrhagic telangiectasia associated with pulmonary arterial hypertension.<\/jats:p><jats:p>Germline mutations in genes encoding members of the transforming growth factor\u2010<jats:italic>\u03b2<\/jats:italic> (TGF\u2010<jats:italic>\u03b2<\/jats:italic>)\/bone morphogenetic protein (BMP) superfamily are causal for two hereditary vascular disorders, hereditary hemorrhagic telangiectasia (HHT) and heritable pulmonary arterial hypertension (PAH). When the two diseases coexist, activin A receptor type II\u2010like kinase\u20101 (<jats:italic>ACVRL1<\/jats:italic>) gene mutations are usually identified. We report a remarkable <jats:italic>ACVRL1<\/jats:italic> germinal and somatic mosaicism characterized by the presence of two distinct mutant alleles and a non\u2010mutant <jats:italic>ACVRL1<\/jats:italic> allele in a woman diagnosed with PAH at the age 40. She also met the Cura\u00e7ao diagnostic criteria for HHT based on additional findings of telangiectases, epistaxis and arteriovenous malformations. Mutation analysis of <jats:italic>ACVRL1<\/jats:italic> identified two adjacent heterozygous deleterious mutations within exon 10: c.1388del (p.Gly463fsX2) and c.1390del (p.Leu464X) in a region enriched by mutation\u2010associated DNA motifs. The mother transmitted the c.1388del to one child and the c.1390del to two children confirming germinal mosaicism. Allele\u2010specific polymerase chain reaction analysis showed that c.1388del is the predominant mutation in lymphocytes of the index case. Haplotype analysis revealed that both mutant alleles have a common chromosomal origin which is distinct from that of the mother's non\u2010mutant <jats:italic>ACVRL1<\/jats:italic> allele. These distinct mutant alleles in tissues and germline could have arisen by DNA structure\u2010mediated events occurring in the early stages of the mother's embryogenesis, prior to the segregation of her germline, which ultimately led to the independent transmission of each allele. These highlight the complexity of genomic events occurring during early embryogenesis and the consequences of mutational mosaicism upon pathogenic variability.<\/jats:p>","DOI":"10.1111\/j.1399-0004.2011.01727.x","type":"journal-article","created":{"date-parts":[[2011,6,8]],"date-time":"2011-06-08T19:38:03Z","timestamp":1307561883000},"page":"173-179","source":"Crossref","is-referenced-by-count":31,"title":["<i>ACVRL1<\/i> germinal mosaic with two mutant alleles in hereditary hemorrhagic telangiectasia associated with pulmonary arterial hypertension"],"prefix":"10.1111","volume":"82","author":[{"given":"M","family":"Eyries","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F","family":"Coulet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B","family":"Girerd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D","family":"Montani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Humbert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P","family":"Lacombe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T","family":"Chinet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L","family":"Gouya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Roume","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"MM","family":"Axford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"CE","family":"Pearson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F","family":"Soubrier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2011,7,13]]},"reference":[{"key":"e_1_2_7_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.blre.2010.07.001"},{"key":"e_1_2_7_3_2","doi-asserted-by":"publisher","DOI":"10.1055\/s-0029-1233307"},{"key":"e_1_2_7_4_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200108023450503"},{"key":"e_1_2_7_5_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200908-1284OC"},{"key":"e_1_2_7_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0027-5107(99)00147-5"},{"key":"e_1_2_7_7_2","doi-asserted-by":"publisher","DOI":"10.1006\/meth.2001.1262"},{"key":"e_1_2_7_8_2","volume-title":"The Criteria Committee of the New York Heart Association Nomenclature and criteria for diagnosis of diseases of the heart and blood vessels.","year":"1964"},{"key":"e_1_2_7_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2003.09.006"},{"key":"e_1_2_7_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddr099"},{"key":"e_1_2_7_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20212"},{"key":"e_1_2_7_12_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20352"},{"key":"e_1_2_7_13_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-005-0037-5"},{"key":"e_1_2_7_14_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20017"},{"key":"e_1_2_7_15_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2006.042606"},{"key":"e_1_2_7_16_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.2010.01418.x"},{"key":"e_1_2_7_17_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2010.088286"}],"container-title":["Clinical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fj.1399-0004.2011.01727.x","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/j.1399-0004.2011.01727.x","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,15]],"date-time":"2023-10-15T18:04:08Z","timestamp":1697393048000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/j.1399-0004.2011.01727.x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,7,13]]},"references-count":16,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2012,8]]}},"alternative-id":["10.1111\/j.1399-0004.2011.01727.x"],"URL":"https:\/\/doi.org\/10.1111\/j.1399-0004.2011.01727.x","archive":["Portico"],"relation":{},"ISSN":["0009-9163","1399-0004"],"issn-type":[{"value":"0009-9163","type":"print"},{"value":"1399-0004","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,7,13]]}}}