POLYMORPHISM OF MSX1, TGFβ3, IRF6 AND OFCC1 GENES AND GENOME-WIDE LINKAGE ANALYSIS OF FAMILIES WITH NONSYNDROMIC CLEFT LIP WITH OR WITHOUT CLEFT PALATE
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Date
2012-03
Authors
IMAN, SALAHSHOURIFAR
Journal Title
Journal ISSN
Volume Title
Publisher
Pusat Pengajian Sains Perubatan Universiti Sains Malaysia
Abstract
Non-syndromic cleft lip with or without cleft palate (CL±P) is a common congenital
anomaly. Both genetic and environmental factors contribute to the condition. Familybased
transmission disequilibrium test (TDT) and genome-wide linkage analysis was
conducted on Malay families with non-syndromic CL±P. A strong transmission
distortion for multiple haplotypes was found for variants in and near to the IRF6.
Haplotypes carrying the 243bp allele of D1S2136 and the T allele of rs861019 and the
V allele of rs2235371 were usually found to be over-transmitted to patients. In
contrast, haplotypes consisting of the 251bp allele of D1S2136 and the I allele of
rs2235371 were more frequently under-transmitted. Despite preferential maternal
transmission for multiple haplotypes, it appeared that fetal genotype could be the
major contributor to the non-syndromic CL±P than maternal genotype. Hence, having
a single or double copy of the V allele of rs2235371 and the T allele of rs861019
showed approximately three-fold increase in the risk of developing cleft. Despite
strong association, seven non-causative variants including five known (-4A>G, -
73T>C, 459G>T, 820G>A, and +37C>T) and two novel (-23G>C and 1380G>T),
were found the sequencing of IRF6. However, a patient with bilateral cleft lip showed
a 2.98 Mb microdeletion at the 1q32.2-1q32.3 including entire IRF6 deletion.
However, no transmission distortion was fouxnxdv ifi or MSX1 and TFGβ3 variants but
101-bp allele of D6S470 showed over-transmission to patients. This marker is located
in the OFCC1 gene, and carrying two copies of the 101-bp allele showed a 2.5 fold
increased risk of oral clefts. Five variants were found, including three known (A34G,
G110G and P147Q) and two novel (M37L and G267A) in the sequencing of MSX1
gene. In silico analysis showed these variants may not be damaging.
Four linkage intervals attained the statistical threshold of NPL genome-wide linkage
analysis including 2q33.1-q35 (NPL = 3.25 at 205 cM), 4q22.1-q25 (NPL = 2.7 at 102
cM), 7q22.3-q33 (NPL = 2.24 at 128 cM) and 14q12 (NPL = 2.88 at 26 cM). Of
these, 2q33.1-q35 that harbors SABT2 and SUMO1 cleft candidate genes showed the
most suggestive linkage. In addition, this region showed a suggestive HLOD score
under autosomal recessive mode of inheritance (HLOD = 2.63, α = 0.124).
The present study suggests that IRF6 gene contributes significantly to the etiology of
non-syndromic CL±P rather than MSX1, TGFβ3 and OFCC1 in the current
population. However, MSX1 contributes to a subset of families, which is in consistent
with the signals from genome-wide linkage analysis. Consistent with others, nonsyndromic
CL±P is genetically heterogeneous in this population.
Description
Keywords
PLASTIC SURGERY