Abstract
Cleft lip with or without palate (CL/P) is a common congenital anomaly with a high birth prevalence in China. Based on a previous linkage signal of nonsyndromic CL/P (NSCL/P) on the chromosomal region 4q31–q32 from the Chinese populations, we screened the 4q31–q32 region for susceptibility genes in 214 trios of Han Chinese. PDGF-C, an important developmental factor, resides in the region and has been implicated in NSCL/P. However, in our family-based association test (transmission disequilibrium test; TDT), we could not conclude an association between PDGF-C and NSCL/P as previously suggested. Instead, we found strong evidence for parent-of-origin effect at a PDGF-C SNP, rs17035464, by a likelihood ratio test (unadjusted p-value = 0.0018; Im = 2.46). The location of rs17035464 is 13 kb downstream of a previously reported, NSCL/P-associated SNP, rs28999109. Furthermore, a patient from our sample trios was observed with a maternal segmental uniparental isodisomy (UPD) in a region containing rs17035464. Our findings support the involvement of PDGF-C in the development of oral clefts; moreover, the UPD case report contributes to the collective knowledge of rare variants in the human genome.
Highlights
Cleft lip with or without palate (CL/P) is one of the most common birth defects, affecting 0.5–1% of newborns worldwide [1,2]
transmission disequilibrium test (TDT) and Parent-of-Origin Effects Our first step genotyping with 10 STR markers was on a 30-Mb region encompassing the linkage peak reported by Marazita at 4q31-q32 [9]
With our complete Nonsyndromic CL/P (NSCL/P) sample set of 214 trios, we found most-significant association between the D4S413 marker and the disease by TDT
Summary
Cleft lip with or without palate (CL/P) is one of the most common birth defects, affecting 0.5–1% of newborns worldwide [1,2]. Several susceptibility loci of NSCL/P have been located to the regions of MTHFR, TGFA, 4q28 (D4S175), F13A1, TGFB3, 17q12 (D17S250) and APOC2. The first genome-wide linkage scan of NSCL/P in Chinese families found the most significant signal to be at chromosome 4q31–q32 [9]. Other NSCL/P studies reported linkage signals involving 4q31–q32 in Filipino and Syrian families [10,11]. The involvement of chromosome 4q31–q32 in human CL/P was suggested by both cytogenetic deletion and association studies [12,13,14,15,16]. The rs28999109 SNP found to associate with NSCL/P in Chinese families was mapped to the regulatory region of platelet derived growth factor C (PDGF-C, [MIM:608452]) at 4q32 [17]. The role of PDGF-C in palatogenesis was supported by a mouse knockout study in which the Pdgfc (2/2) embryos had a phenotype of cleft face [18]
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