Identification of microdeletions in candidate genes for cleft lip and/or palate.
BACKGROUND
Genome-wide association studies are now used routinely to identify genes implicated in complex traits. The panels used for such analyses can detect single nucleotide polymorphisms and copy number variants, both of which may help to identify small deleted regions of the genome that may contribute to a particular disease.


METHODS
We performed a candidate gene analysis involving 1,221 SNPs in 333 candidate genes for orofacial clefting, using 2,823 samples from 725 two- and three-generation families with a proband having cleft lip with or without cleft palate. We used SNP genotyping, DNA sequencing, high-resolution DNA microarray analysis, and long-range PCR to confirm and characterize the deletion events.


RESULTS
This dataset had a high duplicate reproducibility rate (99.98%), high Mendelian consistency rate (99.93%), and low missing data rate (0.55%), which provided a powerful opportunity for deletion detection. Apparent Mendelian inconsistencies between parents and children suggested deletion events in 15 individuals in 11 genomic regions. We confirmed deletions involving CYP1B1, FGF10, SP8, SUMO1, TBX1, TFAP2A, and UGT7A1, including both de novo and familial cases. Deletions of SUMO1, TBX1, and TFAP2A are likely to be etiologic.


CONCLUSIONS
These deletions suggest the potential roles of genes or regulatory elements contained within deleted regions in the etiology of clefting. Our analysis took advantage of genotypes from a candidate-gene-based SNP survey and proved to be an efficient analytical approach to interrogate genes potentially involved in clefting. This can serve as a model to find genes playing a role in complex traits in general.
Shi
Min
M
Biostatistics Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.
Mostowska
Adrianna
A
Jugessur
Astanand
A
Johnson
Marla K
MK
Mansilla
Maria Adela
MA
Christensen
Kaare
K
Lie
Rolv T
RT
Wilcox
Allen J
AJ
Murray
Jeffrey C
JC
D002872:Chromosome Deletion; D002971:Cleft Lip / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics*; D003718:Denmark; D005192:Family Health; D005838:Genotype; D006801:Humans; D009664:Norway; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D025842:SUMO-1 Protein / Q000235:genetics; D017422:Sequence Analysis, DNA
D025842:SUMO-1 Protein; C495501:SUMO1 protein, human