{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:27:50Z","timestamp":1786976870429,"version":"build-2736575974"},"reference-count":13,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2021,7,13]],"date-time":"2021-07-13T00:00:00Z","timestamp":1626134400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2021,12]]},"abstract":"Abstract<\/jats:title>\n \n Terminal osseous dysplasia with pigmentary defects (TODPD), also known as digitocutaneous dysplasia, is one of the X\u2010linked filaminopathies caused by a variety of\n FLNA<\/jats:italic>\n \u2010variants. TODPD is characterized by skeletal defects, skin fibromata and dysmorphic facial features. So far, only a single recurrent variant (c.5217G>A;p.Val1724_Thr1739del) in\n FLNA<\/jats:italic>\n has found to be responsible for TODPD. We identified a novel c.5217+5G>C variant in\n FLNA<\/jats:italic>\n in a female proband with skeletal defects, skin fibromata, interstitial lung disease, epilepsy, and restrictive cardiomyopathy. This variant causes mis\u2010splicing of exon 31 predicting the production of a FLNA\u2010protein with an in\u2010frame\u2010deletion of 16 residues identical to the miss\u2010splicing\u2010effect of the recurrent TODPD c.5217G>A variant. This mis\u2010spliced transcript was explicitly detected in heart tissue, but was absent from blood, skin, and lung. X\u2010inactivation analyses showed extreme skewing with almost complete inactivation of the mutated allele (>90%) in these tissues, except for heart. The mother of the proband, who also has fibromata and skeletal abnormalities, is also carrier of the\n FLNA<\/jats:italic>\n \u2010variant and was diagnosed with noncompaction cardiomyopathy after cardiac screening. No other relevant variants in cardiomyopathy\u2010related genes were found. Here we describe a novel variant in\n FLNA<\/jats:italic>\n (c.5217+5G>C) as the second pathogenic variant responsible for TODPD. Cardiomyopathy has not been described as a phenotypic feature of TODPD before.\n <\/jats:p>","DOI":"10.1002\/ajmg.a.62417","type":"journal-article","created":{"date-parts":[[2021,7,13]],"date-time":"2021-07-13T05:55:42Z","timestamp":1626155742000},"page":"3814-3820","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Terminal osseous dysplasia with pigmentary defects and cardiomyopathy caused by a novel\n \n FLNA<\/i>\n <\/scp>\n variant"],"prefix":"10.1002","volume":"185","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6427-5033","authenticated-orcid":false,"given":"Lynne","family":"Rumping","sequence":"first","affiliation":[{"name":"Department of Clinical Genetics Amsterdam UMC, University of Amsterdam Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marja W.","family":"Wessels","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Erasmus Medical Centre Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex V.","family":"Postma","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Amsterdam UMC, University of Amsterdam Amsterdam The Netherlands"},{"name":"Department of Medical Biology Amsterdam UMC, University of Amsterdam Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joost","family":"van Schuppen","sequence":"additional","affiliation":[{"name":"Department of Radiology and Nuclear Medicine Amsterdam UMC, University of Amsterdam Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marjon A.","family":"van Slegtenhorst","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Erasmus Medical Centre Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasper J.","family":"Saris","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Erasmus Medical Centre Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Peter","family":"van Tintelen","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Amsterdam UMC, University of Amsterdam Amsterdam The Netherlands"},{"name":"Department of Genetics University Medical Center Utrecht Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5181-7809","authenticated-orcid":false,"given":"Stephen P.","family":"Robertson","sequence":"additional","affiliation":[{"name":"Department of Women's and Children's Health University of Otago Dunedin New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mari\u00eblle","family":"Alders","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Amsterdam UMC, University of Amsterdam Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saskia M.","family":"Maas","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Amsterdam UMC, University of Amsterdam Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald H. Lekanne","family":"Deprez","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Amsterdam UMC, University of Amsterdam Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,7,13]]},"reference":[{"issue":"6","key":"e_1_2_9_2_1","first-page":"1229","article-title":"Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen\u2010receptor gene correlates with X chromosome inactivation","volume":"51","author":"Allen R. C.","year":"1992","journal-title":"American Journal of Human Genetics"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/ajd.12367"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/1096-8628(20000911)94:2<91::AID-AJMG1>3.0.CO;2-D"},{"issue":"7","key":"e_1_2_9_5_1","first-page":"1825","article-title":"Terminal osseous dysplasia with pigmentary defects (TODPD): Follow\u2010up of the first reported family, characterization of the radiological phenotype, and refinement of the linkage region","volume":"152","author":"Brunetti\u2010Pierri N.","year":"2010","journal-title":"American Journal of Human Genetics"},{"issue":"1","key":"e_1_2_9_6_1","first-page":"1","article-title":"A syndrome of digital fibromas, facial pigmentary dysplasia, and metacarpal and metatarsal disorganization","volume":"80","author":"Horii E.","year":"1998","journal-title":"American Journal of Human Genetics"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx1153"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1086\/301651"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature19057"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1437"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gde.2005.04.001"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00431-018-3301-0"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2010.06.008"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.24002"}],"container-title":["American Journal of Medical Genetics Part A"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.62417","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ajmg.a.62417","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.62417","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T06:19:46Z","timestamp":1692944386000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ajmg.a.62417"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,13]]},"references-count":13,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["10.1002\/ajmg.a.62417"],"URL":"https:\/\/doi.org\/10.1002\/ajmg.a.62417","archive":["Portico"],"relation":{},"ISSN":["1552-4825","1552-4833"],"issn-type":[{"value":"1552-4825","type":"print"},{"value":"1552-4833","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,13]]},"assertion":[{"value":"2021-02-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-06-25","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-07-13","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}