{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T16:09:44Z","timestamp":1761235784048},"reference-count":34,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2014,4,7]],"date-time":"2014-04-07T00:00:00Z","timestamp":1396828800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Birth Defects Research"],"published-print":{"date-parts":[[2014,6]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>The genes Gremlin\u20101 (GREM1) and Noggin (NOG) are components of the bone morphogenetic protein 4 pathway, which has been implicated in craniofacial development. Both genes map to recently identified susceptibility loci (chromosomal region 15q13, 17q22) for nonsyndromic cleft lip with or without cleft palate (nsCL\/P). The aim of the present study was to determine whether rare variants in either gene are implicated in nsCL\/P etiology.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The complete coding regions, untranslated regions, and splice sites of GREM1 and NOG were sequenced in 96 nsCL\/P patients and 96 controls of Central European ethnicity. Three burden and four nonburden tests were performed. Statistically significant results were followed up in a second case\u2010control sample (<jats:italic>n<\/jats:italic>\u2009=\u200996, respectively). For rare variants observed in cases, segregation analyses were performed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In NOG, four rare sequence variants (minor allele frequency\u2009&lt;\u20091%) were identified. Here, burden and nonburden analyses generated nonsignificant results. In<jats:italic>GREM1<\/jats:italic>, 33 variants were identified, 15 of which were rare. Of these, five were novel. Significant<jats:italic>p<\/jats:italic>\u2010values were generated in three nonburden analyses. Segregation analyses revealed incomplete penetrance for all variants investigated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our study did not provide support for NOG being the causal gene at 17q22. However, the observation of a significant excess of rare variants in<jats:italic>GREM1<\/jats:italic>supports the hypothesis that this is the causal gene at chr. 15q13. Because no single causal variant was identified, future sequencing analyses of<jats:italic>GREM1<\/jats:italic>should involve larger samples and the investigation of regulatory elements.<jats:italic>Birth Defects Research (Part A) 100:493\u2013498, 2014<\/jats:italic>. \u00a9 2014 Wiley Periodicals, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/bdra.23244","type":"journal-article","created":{"date-parts":[[2014,4,7]],"date-time":"2014-04-07T10:19:07Z","timestamp":1396865947000},"page":"493-498","source":"Crossref","is-referenced-by-count":23,"title":["Nonsyndromic cleft lip with or without cleft palate: Increased burden of rare variants within<i>Gremlin\u20101<\/i>, a component of the bone morphogenetic protein 4 pathway"],"prefix":"10.1002","volume":"100","author":[{"given":"Taofik","family":"Al Chawa","sequence":"first","affiliation":[{"name":"Institute of Human Genetics, University of Bonn Bonn Germany"},{"name":"Klinikverbund St. Antonius und St. Josef Wuppertal Germany"},{"name":"Department of Genomics Life and Brain Center University of Bonn Bonn Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kerstin U.","family":"Ludwig","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University of Bonn Bonn Germany"},{"name":"Department of Genomics Life and Brain Center University of Bonn Bonn Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heide","family":"Fier","sequence":"additional","affiliation":[{"name":"Institute for Genomic Mathematics, University of Bonn Bonn Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bernd","family":"P\u00f6tzsch","sequence":"additional","affiliation":[{"name":"Institute of Experimental Hematology and Transfusion Medicine, University of Bonn Bonn Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rudolf H.","family":"Reich","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillo\u2010Facial\u2010Plastic Surgery University of Bonn Bonn Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G\u00fcl","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Department of Cleft Lip and Cleft Palate Surgery Humboldt University of Berlin Berlin Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bert","family":"Braumann","sequence":"additional","affiliation":[{"name":"Department of Orthodontics University of Cologne Cologne Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nikolaos","family":"Daratsianos","sequence":"additional","affiliation":[{"name":"Department of Orthodontics University of Bonn Bonn Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne C.","family":"B\u00f6hmer","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University of Bonn Bonn Germany"},{"name":"Department of Genomics Life and Brain Center University of Bonn Bonn Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hannah","family":"Schuencke","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University of Bonn Bonn Germany"},{"name":"Department of Genomics Life and Brain Center University of Bonn Bonn Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margrieta","family":"Alblas","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University of Bonn Bonn Germany"},{"name":"Department of Genomics Life and Brain Center University of Bonn Bonn Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nadine","family":"Fricker","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University of Bonn Bonn Germany"},{"name":"Department of Genomics Life and Brain Center University of Bonn Bonn 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