Genome scan, fine-mapping, and candidate gene analysis of non-syndromic cleft lip with or without cleft palate reveals phenotype-specific differences in linkage and association results.

OBJECTIVES: Non-syndromic orofacial clefts, i.e. cleft lip (CL) and cleft palate (CP), are among the most common birth defects. The goal of this study was to identify genomic regions and genes for CL with or without CP (CL/P). METHODS: We performed linkage analyses of a 10 cM genome scan in 820 multiplex CL/P families (6,565 individuals). Significant linkage results were followed by association analyses of 1,476 SNPs in candidate genes and regions, utilizing a weighted false discovery rate (wFDR) approach to control for multiple testing and incorporate the genome scan results. RESULTS: Significant (multipoint HLOD >or=3.2) or genome-wide-significant (HLOD >or=4.02) linkage results were found for regions 1q32, 2p13, 3q27-28, 9q21, 12p11, 14q21-24 and 16q24. SNPs in IRF6 (1q32) and in or near FOXE1 (9q21) reached formal genome-wide wFDR-adjusted significance. Further, results were phenotype dependent in that the IRF6 region results were most significant for families in which affected individuals have CL alone, and the FOXE1 region results were most significant in families in which some or all of the affected individuals have CL with CP. CONCLUSIONS: These results highlight the importance of careful phenotypic delineation in large samples of families for genetic analyses of complex, heterogeneous traits such as CL/P.

AXIS inhibition protein 2, orofacial clefts and a family history of cancer.

BACKGROUND: Cancer and congenital malformations occasionally may have a common etiology. The authors investigated whether families with one or more members affected by orofacial clefts (that is, families segregating orofacial clefts) had an increased cancer incidence when compared with control families. METHODS: The authors assessed 75 white families with nonsyndromic cleft lip with or without cleft palate (CL/P) and 93 white control families regarding a history of cancer. They used chi(2) and Fisher exact tests to determine significant differences. They then performed molecular studies with genes in which mutations have been independently associated with both cancer and craniofacial anomalies in a total of 111 families with CL/P. RESULTS: The families with CL/P reported a family history of cancer more often than did control families (P <.001), and they had higher rates of specific cancer types: colon (P <.001), brain (P = .003), leukemia (P = .005), breast (P = .009), prostate (P = .01), skin (P = .01), lung (P = .02) and liver (P = .02). The authors detected overtransmission of AXIS inhibition protein 2 (AXIN2) in CL/P probands (P = .003). CONCLUSION: Families segregating CL/P may have an increased susceptibility to cancer, notably colon cancer. Furthermore, AXIN2, a gene that when mutated increases susceptibility to colon cancer, also is associated with CL/P. CLINICAL IMPLICATIONS: People who are at a higher risk of developing disease need to adopt a healthier lifestyle, including avoiding exposure to risk factors that may interact with their genotypes.