IDENTIFICAZIONE DI VARIANTI GENETICHE ASSOCIATE A RISCHIO DI LABIO/PALATOSCHISI O PALATOSCHISI NON-SINDROMICHE E DI INTERAZIONI GENE-AMBIENTE IN UNA AMPIA CASISTICA DI TRIADI EUROPEE

Orofacial clefts (OFCs) are common birth defects affecting approximately 1/700 live births worldwide. OFCs may occur in the context of malformation syndromes or, more often, as isolated anomalies (non-syndromic). Epidemiological and embryological data suggest that cleft lip with or without cleft palate (CL/P) and cleft palate only (CP) may represent etiologically distinct condition. Non-syndromic OFCs (nsCL/P and nsCP) have a complex multifactorial etiology, determined by the interaction of multiple genetic factors and specific environmental conditions affecting the intrauterine environment during early pregnancy, such as nutritional deficiency (hyperhomocysteinemia/folate deficiency), alcohol intake, maternal smoking. The molecular pathways and the identification of genetic elements involved in the developmental malformations of OFC are crucial to improve prevention strategies and recurrence genetic risks counseling. Different approaches such as linkage analysis, gene-candidate association studies, cytogenetic analysis and, more recently, genome-wide association studies (GWAS), led to the identification of several susceptibility loci for OFC development. The present study investigates specific genetic variants within susceptibility loci, in order to identify genetic risks factors for nsCP and/or nsCL/P. Family-based association studies were carried out in a large case-parent trios cohort (EUROCRAN and ITALCLEFT). The studies have focused on functional candidate genes and genetic region identified by GWAS. Genetic polymorphism were investigated in CBS gene (homocysteine metabolism), HLA-G gene (maternal-fetal immune tolerance), IRF6 gene (Wan der Woude syndrome, the most common cleft syndrome) and GREM1 gene (antangonist of Bone Morphogenetic Protein). Analyses were performed considering the cleft phenotype and gene-environment interaction (folic acid intake and maternal smoking in early pregnancy period). A new nsOFC risk variant were identified, in close proximity to IRF6 gene; moreover, significant results were obtain underling interactions between HLA-G genotype and pregnancy specific parameters. The study on nsCP etiology, conducted in collaboration with the De Duve Institute, Leuven University (Belgium), was focused on FAF1, SOX9, MTRR, SFSWAP and MMP17 candidate genes. The study has highlighted an association between polymorphic variants of FAF1 and SOX9 genes in nsCP risk indicating a strong relation with maternal smoking during early pregnancy.