Nonsyndromic cleft lip with or without cleft palate: Increased burden of rare variants within Gremlin‐1, a component of the bone morphogenetic protein 4 pathway. Issue 6 (7th April 2014)

• Record Type: Journal Article
• Authors: Al Chawa, Taofik; Ludwig, Kerstin U.; Fier, Heide; Pötzsch, Bernd; Reich, Rudolf H.; Schmidt, Gül; Braumann, Bert; Daratsianos, Nikolaos; Böhmer, Anne C.; Schuencke, Hannah; Alblas, Margrieta; Fricker, Nadine; Hoffmann, Per; Knapp, Michael; Lange, Christoph; Nöthen, Markus M.; Mangold, Elisabeth
• Is Part Of: Birth defects research. Volume 100:Issue 6(2014:Jun.)
• Page Start: 493
• Page End: 498
• Publication Date: 2014-04-07
• Subjects: Teratology -- Periodicals; Abnormalities, Human -- Research -- Periodicals; Abnormalities, Human -- Periodicals; 616.043
• DOI: 10.1002/bdra.23244
• Languages: English
• ISSNs: 1542-0752

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bdra23244-sec-0001" sec-type="section"> <title>Background</title> <p>The genes Gremlin‐1 (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.</p> </sec> <sec id="bdra23244-sec-0002" sec-type="section"> <title>Methods</title> <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‐control sample (<italic>n</italic> = 96, respectively). For rare variants observed in cases, segregation analyses were performed.</p> </sec> <sec id="bdra23244-sec-0003" sec-type="section"> <title>Results</title> <p>In NOG, four rare sequence variants (minor allele frequency < 1%) were identified. Here, burden and nonburden analyses generated nonsignificant results. In <italic>GREM1</italic>, 33 variants were identified, 15 of which were rare. Of these, five were novel. Significant <italic>p</italic>‐values were generated in three nonburden analyses. Segregation analyses revealed incomplete penetrance for all variants investigated.</p> </sec> <sec id="bdra23244-sec-0004" sec-type="section"> <title>Conclusion</title> <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 <italic>GREM1</italic> supports the hypothesis that this is the causal gene at chr. 15q13. Because no single causal variant was identified, future sequencing analyses of <italic>GREM1</italic> should involve larger samples and the investigation of regulatory elements. <italic>Birth Defects Research (Part A) 100:493–498, 2014</italic>. © 2014 Wiley Periodicals, Inc.</p> </sec> </abstract>