Universität zu Köln

Mangold, Elisabeth, Boehmer, Anne C., Ishorst, Nina, Hoebel, Ann-Kathrin, Gueltepe, Pinar, Schuenke, Hannah, Klamt, Johanna, Hofmann, Andrea, Goelz, Lina, Raff, Ruth, Tessmann, Peter, Nowak, Stefanie, Reutter, Heiko, Hemprich, Alexander, Kreusch, Thomas, Kramer, Franz-Josef, Braumann, Bert, Reich, Rudolf, Schmidt, Guel, Jaeger, Andreas, Reiter, Rudolf, Brosch, Sibylle, Stavusis, Janis, Ishida, Miho, Seselgyte, Rimante, Moore, Gudrun E., Noethen, Markus M., Borck, Guntram, Aldhorae, Khalid A., Lace, Baiba ORCID: 0000-0001-5371-6756, Stanier, Philip ORCID: 0000-0001-9340-8117, Knapp, Michael and Ludwig, Kerstin U. (2016). Sequencing the GRHL3 Coding Region Reveals Rare Truncating Mutations and a Common Susceptibility Variant for Nonsyndromic Cleft Palate. Am. J. Hum. Genet., 98 (4). S. 755 - 763. CAMBRIDGE: CELL PRESS. ISSN 1537-6605

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Abstract

Nonsyndromic cleft lip with/without cleft palate (nsCL/P) and nonsyndromic cleft palate only (nsCPO) are the most frequent subphenotypes of orofacial clefts. A common syndromic form of orofacial clefting is Van der Woude syndrome (VWS) where individuals have CL/P or CPO, often but not always associated with lower lip pits. Recently, similar to 5% of VWS-affected individuals were identified with mutations in the grainy head-like 3 gene (GRHL3). To investigate GRHL3 in nonsyndromic clefting, we sequenced its coding region in 576 Europeans with nsCL/P and 96 with nsCPO. Most strikingly, nsCPO-affected individuals had a higher minor allele frequency for rs41268753 (0.099) than control subjects (0.049; p = 1.24 x 10(-2)). This association was replicated in nsCPO/control cohorts from Latvia, Yemen, and the UK (p(combined) = 2.63 x 10(-5); ORallelic = 2.46 [95% CI 1.6-3.7]) and reached genome-wide significance in combination with imputed data from a GWAS in nsCPO triads (p = 2.73 x 10(-9)). Notably, rs41268753 is not associated with nsCL/P (p = 0.45). rs41268753 encodes the highly conserved p.Thr454Met (c.1361C>T) (GERP = 5.3), which prediction programs denote as deleterious, has a CADD score of 29.6, and increases protein binding capacity in silico. Sequencing also revealed four novel truncating GRHL3 mutations including two that were de novo in four families, where all nine individuals harboring mutations had nsCPO. This is important for genetic counseling: given that VWS is rare compared to nsCPO, our data suggest that dominant GRHL3 mutations are more likely to cause nonsyndromic than syndromic CPO. Thus, with rare dominant mutations and a common risk variant in the coding region, we have identified an important contribution for GRHL3 in nsCPO.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Mangold, Elisabeth UNSPECIFIED UNSPECIFIED UNSPECIFIED Boehmer, Anne C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ishorst, Nina UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoebel, Ann-Kathrin UNSPECIFIED UNSPECIFIED UNSPECIFIED Gueltepe, Pinar UNSPECIFIED UNSPECIFIED UNSPECIFIED Schuenke, Hannah UNSPECIFIED UNSPECIFIED UNSPECIFIED Klamt, Johanna UNSPECIFIED UNSPECIFIED UNSPECIFIED Hofmann, Andrea UNSPECIFIED UNSPECIFIED UNSPECIFIED Goelz, Lina UNSPECIFIED UNSPECIFIED UNSPECIFIED Raff, Ruth UNSPECIFIED UNSPECIFIED UNSPECIFIED Tessmann, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Nowak, Stefanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Reutter, Heiko UNSPECIFIED UNSPECIFIED UNSPECIFIED Hemprich, Alexander UNSPECIFIED UNSPECIFIED UNSPECIFIED Kreusch, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Kramer, Franz-Josef UNSPECIFIED UNSPECIFIED UNSPECIFIED Braumann, Bert UNSPECIFIED UNSPECIFIED UNSPECIFIED Reich, Rudolf UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmidt, Guel UNSPECIFIED UNSPECIFIED UNSPECIFIED Jaeger, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Reiter, Rudolf UNSPECIFIED UNSPECIFIED UNSPECIFIED Brosch, Sibylle UNSPECIFIED UNSPECIFIED UNSPECIFIED Stavusis, Janis UNSPECIFIED UNSPECIFIED UNSPECIFIED Ishida, Miho UNSPECIFIED UNSPECIFIED UNSPECIFIED Seselgyte, Rimante UNSPECIFIED UNSPECIFIED UNSPECIFIED Moore, Gudrun E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Noethen, Markus M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Borck, Guntram UNSPECIFIED UNSPECIFIED UNSPECIFIED Aldhorae, Khalid A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lace, Baiba UNSPECIFIED orcid.org/0000-0001-5371-6756 UNSPECIFIED Stanier, Philip UNSPECIFIED orcid.org/0000-0001-9340-8117 UNSPECIFIED Knapp, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Ludwig, Kerstin U. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-278795
DOI:	10.1016/j.ajhg.2016.02.013
Journal or Publication Title:	Am. J. Hum. Genet.
Volume:	98
Number:	4
Page Range:	S. 755 - 763
Date:	2016
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	1537-6605
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GENOME-WIDE ASSOCIATION; RISK LOCI; LIP; GENE; SCAN; METAANALYSIS; POPULATIONS; INHERITANCE; EFFICIENT; HISTORY Multiple languages Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/27879