POLYMORPHISM OF MSX1, TGFβ3, IRF6 AND OFCC1 GENES AND GENOME-WIDE LINKAGE ANALYSIS OF FAMILIES WITH NONSYNDROMIC CLEFT LIP WITH OR WITHOUT CLEFT PALATE
| dc.contributor.author | IMAN, SALAHSHOURIFAR | |
| dc.date.accessioned | 2017-10-31T01:49:57Z | |
| dc.date.available | 2017-10-31T01:49:57Z | |
| dc.date.issued | 2012-03 | |
| dc.description.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. | en_US |
| dc.identifier.uri | http://hdl.handle.net/123456789/5179 | |
| dc.language.iso | en | en_US |
| dc.publisher | Pusat Pengajian Sains Perubatan Universiti Sains Malaysia | en_US |
| dc.subject | PLASTIC SURGERY | en_US |
| dc.title | POLYMORPHISM OF MSX1, TGFβ3, IRF6 AND OFCC1 GENES AND GENOME-WIDE LINKAGE ANALYSIS OF FAMILIES WITH NONSYNDROMIC CLEFT LIP WITH OR WITHOUT CLEFT PALATE | en_US |
| dc.type | Thesis | en_US |
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