Orofacial clefts (OC), involving cleft lip with or without the palate (CL/P) and palate cleft only (PC) are the most common type of craniofacial malformations. Nonsyndromic OC (NS-OC) account for 70% of all cases reported, and its complex etiology remains poorly understood. The inheritance pattern is multifactorial with strong influence of genetic and environmental factors. Although linkage analysis and association studies have suggested several loci of susceptibility to NS-OC, the entire genetic component remains unclear. Advances in next generation sequencing technologies improved the detection rate of rare variants. Indeed, several studies suggested that rare variants might explain part of the missing heritability of many multifactorial diseases, including OC. Thus, the objective of this project is to identify the contribution of rare variants in the etiology of NS-OC. To this, 68 candidate genes will be sequenced in at least 200 patients with familial NS-OC using next generation sequencing. The rare variants will be validated by Sanger sequencing and compared with variants in public databases and in a sample of 609 Brazilian unaffected individuals.
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