Universität zu Köln

Al Chawa, Taofik, Ludwig, Kerstin U., Fier, Heide, Poetzsch, Bernd, Reich, Rudolf H., Schmidt, Guel, Braumann, Bert, Daratsianos, Nikolaos ORCID: 0000-0003-2098-0379, Boehmer, Anne C., Schuencke, Hannah, Alblas, Margrieta, Fricker, Nadine, Hoffmann, Per, Knapp, Michael, Lange, Christoph, Noethen, Markus M. and Mangold, Elisabeth (2014). 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. Birth Defects Res. Part A-Clin. Mol. Teratol., 100 (6). S. 493 - 499. HOBOKEN: WILEY-BLACKWELL. ISSN 1542-0760

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Abstract

Background: 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. Methods: 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 (n=96, respectively). For rare variants observed in cases, segregation analyses were performed. Results: In NOG, four rare sequence variants (minor allele frequency <1%) were identified. Here, burden and nonburden analyses generated nonsignificant results. In GREM1, 33 variants were identified, 15 of which were rare. Of these, five were novel. Significant p-values were generated in three nonburden analyses. Segregation analyses revealed incomplete penetrance for all variants investigated. Conclusion: 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 GREM1 supports the hypothesis that this is the causal gene at chr. 15q13. Because no single causal variant was identified, future sequencing analyses of GREM1 should involve larger samples and the investigation of regulatory elements. (C) 2014 Wiley Periodicals, Inc.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Al Chawa, Taofik UNSPECIFIED UNSPECIFIED UNSPECIFIED Ludwig, Kerstin U. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fier, Heide UNSPECIFIED UNSPECIFIED UNSPECIFIED Poetzsch, Bernd UNSPECIFIED UNSPECIFIED UNSPECIFIED Reich, Rudolf H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmidt, Guel UNSPECIFIED UNSPECIFIED UNSPECIFIED Braumann, Bert UNSPECIFIED UNSPECIFIED UNSPECIFIED Daratsianos, Nikolaos UNSPECIFIED orcid.org/0000-0003-2098-0379 UNSPECIFIED Boehmer, Anne C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schuencke, Hannah UNSPECIFIED UNSPECIFIED UNSPECIFIED Alblas, Margrieta UNSPECIFIED UNSPECIFIED UNSPECIFIED Fricker, Nadine UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoffmann, Per UNSPECIFIED UNSPECIFIED UNSPECIFIED Knapp, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Lange, Christoph UNSPECIFIED UNSPECIFIED UNSPECIFIED Noethen, Markus M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mangold, Elisabeth UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-436602
DOI:	10.1002/bdra.23244
Journal or Publication Title:	Birth Defects Res. Part A-Clin. Mol. Teratol.
Volume:	100
Number:	6
Page Range:	S. 493 - 499
Date:	2014
Publisher:	WILEY-BLACKWELL
Place of Publication:	HOBOKEN
ISSN:	1542-0760
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GENOME-WIDE ASSOCIATION; RISK; LOCUS; GENETICS; COMMON; VAX1; 8Q24; BMP Multiple languages Developmental Biology; Toxicology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/43660