This study describes the results of whole exome sequencing in the etiological investigation and genetic counseling of families presenting with non-syndromic oral clefts with vertical transmission recorded in the Brazilian Database on Craniofacial Anomalies. Whole exome sequencing was performed in 18 families presenting with non-syndromic oral clefts with vertical transmission, and variant filtering was used to identify rare, and also possibly pathogenic variants in genes associated with oral clefts. Overall, our study identified seven families (38.88%) presented with segregating variants possibly related to oral clefts in our cohort: SETX, NOTCH1, FRAS1, ARHGAP29, KMT2D, ANKRD11, SIX1, BMP6, LRP2 and TFAP2A. In another family, all affected members (5.55%) presented a rare variant in FAM193A, which has no recognized function yet, but has prediction of deleterious effect. Our study highlights oral clefts clinical and etiological heterogeneity and shows the complexity of using whole exome sequencing for genetic counseling in non-syndromic oral clefts with vertical transmission.