{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T00:31:59Z","timestamp":1777249919756,"version":"3.51.4"},"reference-count":55,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2019,10,1]],"date-time":"2019-10-01T00:00:00Z","timestamp":1569888000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010801","name":"Ernst G\u00f6hner Stiftung","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010801","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008473","name":"Gebauer Stiftung","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008473","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008449","name":"Dr. Med. 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Furthermore, focusing on the fibrillinopathies Marfan syndrome (MFS) and congenital contractural arachnodactyly (CCA), we screened 500 genomes of our patients for co\u2010occurring variants in\n                    <jats:italic>FBN1<\/jats:italic>\n                    and\n                    <jats:italic>FBN2<\/jats:italic>\n                    . In gnomAD, we detected 2653 (likely) pathogenic variants in 253 genes associated with autosomal\u2010dominant disorders, enabling the estimation of variant\u2010filtering thresholds and disease predisposition\/prevalence rates. In our database, we discovered two families with hitherto unreported co\u2010occurrence of\n                    <jats:italic>FBN1<\/jats:italic>\n                    \/\n                    <jats:italic>FBN2<\/jats:italic>\n                    variants causing phenotypes with mixed or modified MFS\/CCA clinical features. We show that (likely) pathogenic gnomAD variants may be more frequent than expected and are challenging to classify according to the ACMG\/AMP guidelines as well as that fibrillinopathies are likely underdiagnosed and may co\u2010occur. Consequently, selection of appropriate frequency cutoffs, recognition of digenic variants, and variant classification represent considerable challenges in variant interpretation. Neglecting these challenges may lead to incomplete or missed diagnoses.\n                  <\/jats:p>","DOI":"10.1111\/cge.13640","type":"journal-article","created":{"date-parts":[[2019,9,11]],"date-time":"2019-09-11T03:13:36Z","timestamp":1568171616000},"page":"235-245","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Variant filtering, digenic variants, and other challenges in clinical sequencing: a lesson from fibrillinopathies"],"prefix":"10.1111","volume":"97","author":[{"given":"Arash","family":"Najafi","sequence":"first","affiliation":[{"name":"Center for Cardiovascular Genetics and Gene Diagnostics Foundation for People with Rare Diseases  Schlieren\u2010Zurich Switzerland"},{"name":"Cantonal Hospital Winterthur Institute of Radiology and Nuclear Medicine  Winterthur Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sylvan M.","family":"Caspar","sequence":"additional","affiliation":[{"name":"Center for Cardiovascular Genetics and Gene Diagnostics Foundation for People with Rare Diseases  Schlieren\u2010Zurich Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janine","family":"Meienberg","sequence":"additional","affiliation":[{"name":"Center for Cardiovascular Genetics and Gene Diagnostics Foundation for People with Rare Diseases  Schlieren\u2010Zurich Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marianne","family":"Rohrbach","sequence":"additional","affiliation":[{"name":"Division of Metabolism and Children's Research Center University Children's Hospital Zurich Eleonore Foundation  Zurich Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beat","family":"Steinmann","sequence":"additional","affiliation":[{"name":"Division of Metabolism and Children's Research Center University Children's Hospital Zurich Eleonore 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