In this study, we present the case of a first-cousin couple who had two children with severe malformation syndromes caused by homozygous variants in two different genes: KATNB1 and FAT1 We provide a comprehensive clinical case report of the two affected sibs, and provide new data expanding the clinical features associated with pathogenic variants in FAT1, a gene better known for the role of its somatic mutations in cancer than its germinal variants in Mendelian disorders. This evidence concerns the gene FAT1 and cancer.