Our findings suggest that the CR inserted at the topologically associating domain (TAD) containing the two potassium channel genes KCNJ2 and KCNJ16 cause the severe skeletal Class II malocclusion with gingival hyperplasia in the family, and that the most probable pathogenic mechanism underlying the abnormal phenotype involves KCNJ2/KCNJ16 misregulation induced by neo-TAD formation and adopted craniofacial enhancers. This evidence concerns the gene KCNJ16 and gingival disorder.