Likely Pathogenic Variants in One Third of Non-Syndromic Discontinuous Cleft Lip and Palate Patients

Oral clefts are composed of cleft of the lip, cleft of the lip and palate, or cleft of the palate, and they are associated with a wide range of expression and severity. When cleft of the palateis associated with cleft of the lip with preservation of the primary palate, it defines an atypical phenotype called discontinuouscleft. Although this phenotype may represent 5% of clefts of the lip and/or palate(CLP), it is rarely specifically referred to and its pathophysiology is unknown. We conducted whole exome sequencing(WES) and apply a candidate gene approach to non-syndromic discontinuousCLP individuals in order to identify genes and deleterious variants that could underlie this phenotype. We discovered loss-of-function variants in two out of the seven individuals, implicating FGFR1 and DLG1genes, which represents almost one third of this cohort. Whole exome sequencingof clinically well-defined subgroups of CLP, such as discontinuouscleft, is a relevant approach to study CLP etiopathogenesis. It could facilitate more accurate clinical, epidemiological and fundamental research, ultimately resulting in better diagnosis and care of CLP patients. Non-syndromic discontinuouscleft lip and palateseems to have a strong genetic basis.