Resequencing of VAX1 in patients with nonsyndromic cleft lip with or without cleft palate.
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.


CONCLUSIONS
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.
Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.
Entessar
E
Nasser
Elisabeth
E
Mangold
Daniela C
DC
Tradowsky
Heide
H
Fier
Jessica
J
Becker
Anne C
AC
Boehmer
Ruth
R
Herberz
Nadine
N
Fricker
Sandra
S
Barth
Philipp
P
Wahle
Stefanie
S
Nowak
Heiko
H
Reutter
Rudolf H
RH
Reich
Carola
C
Lauster
Bert
B
Braumann
Thomas
T
Kreusch
Alexander
A
Hemprich
Bernd
B
Pötzsch
Per
P
Hoffmann
Franz-Josef
FJ
Kramer
Michael
M
Knapp
Christoph
C
Lange
Markus M
MM
Nöthen
Kerstin U
KU
Ludwig
D000483:Alleles; D000595:Amino Acid Sequence; D016022:Case-Control Studies; D002879:Chromosomes, Human, Pair 10; D002971:Cleft Lip / Q000235:genetics* / Q000473:pathology; D002972:Cleft Palate / Q000235:genetics* / Q000473:pathology; D005260:Female; D056426:Genetic Loci; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000235:genetics; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics*; D044465:White People
D018398:Homeodomain Proteins; D020033:Protein Isoforms; D014157:Transcription Factors; C572055:VAX1 protein, human