Genetic evidence for the role of loci at 19q13 in cleft lip and palate.
BACKGROUND
Clefts of the lip and palate are common birth defects, affecting approximately 1 in 700 births worldwide. The aetiology of clefting is complex, with multiple genetic and environmental influences.


METHODS
Genotype based linkage disequilibrium analysis was conducted using the family based association test (FBAT) and the likelihood ratio test (LRT). We also carried out direct sequencing of the PVR and PVRL2 candidate genes based on their homology to PVRL1, a gene shown previously to cause Margarita Island clefting. Participants included 434 patients with cleft lip with or without cleft palate or cleft palate only and their mothers from eight countries in South America, 205 nuclear triads (father-mother-affected child) from Iowa, 541 nuclear triads from Denmark, and 100 patients with cleft lip and palate from the Philippines.


RESULTS
An allelic variant in the PVR gene showed statistically significant association with both South American and Iowa populations (p = 0.0007 and p = 0.0009, respectively). Direct sequencing of PVR and PVRL2 yielded 26 variants, including two rare amino acid changes, one in each gene, which were not seen in controls.


CONCLUSIONS
We found an association between a common variant in a gene at 19q and isolated clefting in two heterogeneous populations. However, it is unclear from our data if rare variants in PVR and PVRL2 are sufficient to cause clefting in isolation.
Warrington
A
A
Vieira
A R
AR
Christensen
K
K
Orioli
I M
IM
Castilla
E E
EE
Romitti
P A
PA
Murray
J C
JC
D000483:Alleles; D000595:Amino Acid Sequence; D015815:Cell Adhesion Molecules; D002874:Chromosome Mapping; D002888:Chromosomes, Human, Pair 19; D002971:Cleft Lip / Q000175:diagnosis / Q000235:genetics*; D002972:Cleft Palate / Q000175:diagnosis / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D006801:Humans; D007484:Iowa / Q000208:ethnology; D015810:Linkage Disequilibrium; D008297:Male; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D000075983:Nectins; D011991:Receptors, Virus / Q000235:genetics; D016415:Sequence Alignment; D013020:South America / Q000208:ethnology
D015815:Cell Adhesion Molecules; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C000619010:NECTIN1 protein, human; D000075983:Nectins; D011991:Receptors, Virus; C066100:poliovirus receptor