Maternal transmission effect of a PDGF-C SNP on nonsyndromic cleft lip with or without palate from a Chinese population

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; I(m) = 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.

Figure 1. Linkage disequilibrium (LD) pattern of the 80 SNPs in step 2.

Linkage disequilibrium derived from the parents of our sample set as measured in r ². White, r ² = 0; Shades of gray, 0<r ²<1; Black, r ² = 1.

Figure 2. Scatter diagram of the p-values of FBAT and PLORT tests.

Scatter diagram of the p-values (−log₁₀ (p-value)) of FBAT and POLRT tests. The p-value of rs17035464 exceeds the corrected threshold of multiple testing.

Figure 3. Schematic diagram of two-step mapping strategy.

The genotyping was first conducted with 10 STR markers covering a 30-Mb region on 4q31–q32 and followed by 80 SNPs spanning the region from D4S1498 to D4S413. Lastly, the minimal UPD region was estimated to be from rs17035464 to D4S1498 in a physical distance of 14 Kb.