Method: Significant SNPs in NTN1 and NOG were genotyped in DNA from 275 Iowan NSCL/P case-parent-trios and 220 Filipino NSCL/P multiplex-families, and analyzed by the Transmission-Disequilibrium Test (TDT) using a family-based association test (FBAT). Direct sequencing was performed for the coding exons of both genes in 304 individuals from Iowa (217 cases, 84 controls) and 180 individuals from the Philippines (89 cases, 91 controls).
Results: Initial FBAT statistics replicated previous results. A p-value of 6 x 10-3 was obtained for rs9788972 (NTN1) for the Filipinos while the Iowan trios reached near-significance for this marker (p=0.073). In addition, rs227731 (NOG) also reached near-significance (p=0.094) for the Filipinos. Fourteen new mutations were found in NTN1 (5 missense, 2 synonymous, and 7 non-coding). Eight new mutations were found in NOG, all non-coding. Of the missense mutations in NTN1, Y162C and G440S are predicted to be probably damaging by PolyPhen-2 prediction algorithm.
Conclusion: Preliminary statistics replicated the GWAS results while more definitive results are still pending. The discovery of rare variants in these two genes within affected individuals, suggests their potential role in the etiology of NSCL/P, especially the two new missense mutations in NTN1 predicted to have damaging functional effects. Additional investigations are needed to further analyze these genes and the role of their variants.
Keywords: Cleft lip-palate and Genetics
See more of: Craniofacial Biology