Abstract
Nonsyndromic cleft lip with or without cleft palate (NSCL/P) are common birth defects with a complex etiology. Multiple interacting loci and possible environmental factors influence the risk of NSCL/P. 12 single nucleotide polymorphisms (SNPs) in 7 candidate genes were tested using an allele-specific primer extension for case-control and case-parent analyses in northeast China in 236 unrelated patients, 185 mothers and 154 fathers, including 128 complete trios, and 400 control individuals. TGFA and IRF6 genes showed a significant association with NSCL/P. In IRF6, statistical evidence of an association between rs2235371 (p = 0.003), rs2013162 (p<0.0001) and NSCL/P was observed in case-control analyses. Family based association tests (FBATs) showed over-transmission of the C allele at the rs2235371 polymorphism (p = 0.007). In TGFA, associations between rs3771494, rs3771523 (G3822A), rs11466285 (T3851C) and NSCL/P were observed in case-control and FBAT analyses. Associations between other genes (BCL3, TGFB3, MTHFR, PVRL1 and SUMO1) and NSCL/P were not detected.
Highlights
Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common birth defects, affecting 1 in 500 to 1000 births worldwide [1]
Single nucleotide polymorphism (SNP) genotyping using competitive allele-specific PCR were conducted in 12 candidate genes, including CLPTM1, CRISPLD2, FGFR2, GABRB3, GLI2, PTCH1, RARA, RYK, SATB2, SUMO1, Transforming growth factor alpha (TGFA), and interferon regulatory factor 6 (IRF6), and reported that PTCH1, SUMO1, and TGFA contribute to nonsyndromic oral clefts [5]
Due to NSCL/P genetic heterogeneity in different populations, we investigated the contribution of previously reported candidate genes TGFA, IRF6, BCL3, TGFB3, MTHFR, PVRL1, and SUMO1 for NSCL/P in northeast China (Table 1)
Summary
Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common birth defects, affecting 1 in 500 to 1000 births worldwide [1]. Progress has been made toward defining genetic variations involved in oral-facial cleft by utilizing gene discovery techniques, including genome wide linkage, association mapping and candidate gene approaches. Positive associations between 14 interacting genes and NSCL/P have been reported [3]. Carinci et al reviewed genes and available loci in the literature and suggested that 6p24, 2p13, 19q13.2, 4q, Msx, IRF6, PVRL1, TP73L, 13q33, 1q34 and SUMO1 are related to oral clefts [4]. Single nucleotide polymorphism (SNP) genotyping using competitive allele-specific PCR were conducted in 12 candidate genes, including CLPTM1, CRISPLD2, FGFR2, GABRB3, GLI2, PTCH1, RARA, RYK, SATB2, SUMO1, TGFA, and IRF6, and reported that PTCH1, SUMO1, and TGFA contribute to nonsyndromic oral clefts [5]. Through multiple stages involving positional cloning, candidate gene sequencing and developmental gene expression analysis, FOXE1 had been identified as a major disease gene for NSCL/P [6]
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