Identification of susceptibility loci for nonsyndromic cleft lip with or without cleft palate in a two stage genome scan of affected sib-pairs .
Nonsyndromic cleft lip with or without cleft palate ( CL/P ) is a complex disorder of multigenic origin involving between two and ten loci .
Linkage and association studies of CL/P have implicated a number of candidate genes and regions but have often proved difficult to replicate .
Here , we report the findings from a two-stage genome-wide scan of 92 affected sib-pairs to identify susceptibility loci to CL/P .
An initial set of 400 microsatellite markers was used , with an average spacing of 10 cM throughout the genome .
Eleven regions on eight chromosomes were found to have a P-value smaller than 0.05 .
These eight chromosomes were then further mapped with a second set of markers to increase the average map density to 5 cM .
In seven out of eleven areas densely mapped , significance was markedly increased by decreasing the marker interval .
Excessive allele sharing was found at 1p ( NPL=2.35 , P=0.009 , MLS=1.51 ) , 2p ( NPL=1.77 , P= 0.04 , MLS=0.66 ) , 6p ( NPL=2.35 , P=0.009 , MLS=1.34 ) , 8q ( NPL=2.15 , P=0.015 , MLS= 1.51 ) 11 cen ( NPL=2.70 , P=0.003 , MLS=2.10 ) , 12q ( NPL=2.08 , P=0.02 , MLS= 1.5 ) , 16p ( NPL=2.1 , P=0.018 , MLS=0.97 ) and Xcen-q ( NPL=2.40 , P=0.008 , MLS=2.68 ) .
Although none reached the level required for significant susceptibility loci , two of these areas have previously been implicated in CL/P , viz. 2p13 , an area harbouring the TGFA gene , and 6p23-24 .
We also demonstrate highly suggestive linkage to a susceptibility locus for nonsyndromic clefting on the X chromosome .
Further studies are currently underway to replicate these findings in a larger cohort of affected sib-pairs .