Expanding the Oro-Dental and Mutational Spectra of Kabuki Syndrome and Expression of <i>KMT2D</i> and<i> KDM6A</i> in Human Tooth Germs

Abstract

Kabuki syndrome is a rare genetic disorder characterized by distinct dysmorphic facial features, intellectual disability, and multiple developmental abnormalities. Despite more than 350 documented cases, the oro-dental spectrum associated with kabuki syndrome and expression of <i>KMT2D</i> (histone-lysine N-methyltransferase 2D) or <i>KDM6A</i> (lysine-specific demethylase 6A) genes in tooth development have not been well defined. Here, we report seven unrelated Thai patients with Kabuki syndrome having congenital absence of teeth, malocclusion, high-arched palate, micrognathia, and deviated tooth shape and size. Exome sequencing successfully identified that six patients were heterozygous for mutations in <i>KMT2D</i>, and one in <i>KDM6A</i>. Six were novel mutations, of which five were in <i>KMT2D</i> and one in <i>KDM6A</i>. They were truncating mutations including four frameshift deletions and two nonsense mutations. The predicted non-functional KMT2D and KDM6A proteins are expected to cause disease by haploinsufficiency. Our study expands oro-dental, medical, and mutational spectra associated with Kabuki syndrome. We also demonstrate for the first time that <i>KMT2D</i> and <i>KDM6A</i> are expressed in the dental epithelium of human tooth germs.