Nasser, Entessar, Mangold, Elisabeth, Tradowsky, Daniela C., Fier, Heide, Becker, Jessica, Boehmer, Anne C., Herberz, Ruth, Fricker, Nadine, Barth, Sandra, Wahle, Philipp ORCID: 0000-0002-4728-806X, Nowak, Stefanie, Reutter, Heiko, Reich, Rudolf H., Lauster, Carola, Braumann, Bert, Kreusch, Thomas, Hemprich, Alexander, Poetzsch, Bernd, Hoffmann, Per ORCID: 0000-0002-6573-983X, Kramer, Franz-Josef, Knapp, Michael, Lange, Christoph, Noethen, Markus M. and Ludwig, Kerstin U. (2012). Resequencing of VAX1 in patients with nonsyndromic cleft lip with or without cleft palate. Birth Defects Res. Part A-Clin. Mol. Teratol., 94 (11). S. 925 - 934. HOBOKEN: WILEY. ISSN 1542-0760

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Abstract

BACKGROUND: Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common of all congenital anomalies, and has a multifactorial etiology involving both environmental and genetic factors. Recent genome-wide association studies (GWAS) identified strong association between a locus on chromosome 10q25.3 and NSCL/P in European samples. One gene at 10q25.3, the ventral anterior homeobox 1 (VAX1) gene, is considered a strong candidate gene for craniofacial malformations. The purpose of the present study was to provide further evidence that VAX1 is the causal gene at the 10q25.3 locus through identification of an excess of rare mutations in patients with NSCL/P. METHODS: The 5'UTR, complete coding regions, and adjacent splice sites of the two known VAX1 isoforms were sequenced in 384 patients with NSCL/P and 384 controls of Central European descent. Observed variants were investigated with respect to familial cosegregation or de novo occurrence, and in silico analyses were performed to identify putative effects on the transcript or protein level. RESULTS: Eighteen single-base variants were found, 15 of them rare and previously unreported. In the long VAX1 isoform, predicted functionally relevant variants were observed more often in NSCL/P cases, although this difference was not significant (p = 0.17). Analysis of family members demonstrated incomplete cosegregation in most pedigrees. CONCLUSION: Our data do not support the hypothesis that highly penetrant rare variants in VAX1 are a cause of NSCL/P. To determine whether VAX1 is the causative gene at 10q25.3 further research, in particular into the biologic function of its long isoform, is warranted. Birth Defects Research (Part A), 2012. (c) 2012 Wiley Periodicals, Inc.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Nasser, EntessarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mangold, ElisabethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tradowsky, Daniela C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fier, HeideUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Becker, JessicaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boehmer, Anne C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herberz, RuthUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fricker, NadineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barth, SandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wahle, PhilippUNSPECIFIEDorcid.org/0000-0002-4728-806XUNSPECIFIED
Nowak, StefanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reutter, HeikoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reich, Rudolf H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lauster, CarolaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Braumann, BertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kreusch, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hemprich, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Poetzsch, BerndUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoffmann, PerUNSPECIFIEDorcid.org/0000-0002-6573-983XUNSPECIFIED
Kramer, Franz-JosefUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Knapp, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lange, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Noethen, Markus M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ludwig, Kerstin U.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-480361
DOI: 10.1002/bdra.23078
Journal or Publication Title: Birth Defects Res. Part A-Clin. Mol. Teratol.
Volume: 94
Number: 11
Page Range: S. 925 - 934
Date: 2012
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1542-0760
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCUS; SYNONYMOUS MUTATIONS; OROFACIAL CLEFTS; HOMEOBOX GENES; VARIANTS; RISK; IRF6; GENETICS; SHOOTIN1Multiple languages
Developmental Biology; ToxicologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/48036

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