Evidence of a sex-dependent association between the MSX1 locus and nonsyndromic cleft lip with or without cleft palate in the Chilean population

Prior studies have implicated an involvement of the Msxl homeobox gene in cleft palate in mice and its homolog in humans (called MSX1 in the HOX7 gene, located on chromosome 4). In this study we present evidence of a sex-dependent association between MSX1 and nonsyndromic cleft lip/palate (NSCLP) in the Chilean population. The sample included 73 NSCLP cases, 37 from multiplex families (Mx), 36 from simplex families (Sx), and 87 controls. Polymerase chain reaction amplification of the MSX1 intragenic microsatellite (CA)(n)-sequence shows significant (p = 0.035) differences in the allele frequencies between NSCLP-Mx males and control males. These differences are mainly due to frequency differences in allele *2 (173 base pairs) among cases (21.9%) and controls (13.2%). When the NSCLP cases are subdivided by sex and positive family history (Mx versus Sr), the Mr males (27.8%) as well as the total NSCLP-Mx cases (25.7%) showed significantly higher frequencies of allele *2, compared to controls (11.4% and 13.2%, respectively). Analysis of the genotype data indicates that the relative risk for NSCLP is greater for persons carrying allele *2 (i.e., odds ratio [OR] larger than 1), reaching significance for all Mr cases (OR = 2.67; 95% confidence interval [CI], 1.10 to 6.52) and even more pronounced for Mr males (OR = 3.33; 95% CI, 1.08 to 10.32). Taken together, these findings support the hypothesis that the genetic variation at the MSX1 locus is a predisposing gene involved in sex-dependent susceptibility to clefting and that it also differentiates simplex from multiplex families.