Association of IFT88 gene variants with nonsyndromic cleft lip with or without cleft palate

Background: Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common birth defect with multifactorial etiology. Genetic studies have identified numerous gene variants in association with NSCLP. IFT88 (intraflagellar transport 88) has been suggested to play a major role in craniofacial development, as Ift88 mutant mice exhibit cleft palate and mutations in IFT88 were identified in individuals with NSCLP. Objective: To investigate the association of IFT88 single nucleotide gene variants (SNVs) with NSCLP in a large family data set consisting of non-Hispanic white (NHW) and Hispanic families. Methods: Nine SNVs in/nearby IFT88 were genotyped in 482 NHW families and 301 Hispanic NSCLP families. Genotyping was performed using TaqMan® chemistry. Single- and pairwise-SNV association analyses were performed for all families stratified by ethnicity and family history of NSCLP using the family-based association test (FBAT), and association in the presence of linkage (APL). Bonferroni correction was used to adjust for multiple testing and p values ≤.0055 were considered statistically significant. Results: Significant association was found between IFT88 rs9509311 and rs2497490 and NSCLP in NHW all families (p =.004 and.005, respectively), while nominal associations were found for rs7998361 and rs9509307 (p <.05). Pairwise association analyses also showed nominal associations between NSCLP in both NHW and Hispanic data sets (p <.05). No association was found between individual variants in IFT88 and NSCLP in Hispanics. Conclusions: Our results suggest that variation in IFT88 may contribute to NSCLP risk, particularly in multiplex families from a non-Hispanic white population.