These results are important for understanding the phenotypic consequences of MLL2 mutations for individuals and their families as well as for providing a basis for the identification of additional genes for Kabuki syndrome.
An intriguing example is the identification of de novo dominant mutations in MLL2 as a cause of Kabuki syndrome, a well-known congenital syndrome that is associated with a very recognizable facial gestalt.
Recently, KMT2D has emerged as one of the most frequently mutated genes in a variety of cancers and in other human diseases, including lymphoma, medulloblastoma, gastric cancer, and Kabuki syndrome.
We report a 34-year-old male patient with a novel variant in KMT2D gene, which finally ended a quest for a diagnosis that was clinically suspected in the past, prior the molecular basis of Kabuki Syndrome (KS) was known.
Here, we report a patient with features of Kabuki syndrome who carries two rare heterozygous variants in KMT2D: c.12935C>T, p.(Ser4312Phe) and c.15785-10T>G.
Following knockdown of kmt2d and the two zebrafish paralogs kdm6a and kdm6al, we analyzed morphants for developmental abnormalities in tissues that are affected in individuals with KS, including craniofacial structures, heart and brain.
We analysed 1920 distinct KMT2D MVs that included 1535 germline MVs in controls (Control-MVs), 584 somatic MVs in cancers (Cancer-MVs) and 201 MV in individuals with KS (KS-MVs).
Kabuki syndrome (KS), is a infrequent inherited malformation syndrome caused by mutations in a H3 lysine 4 methylase (KMT2D) or an X-linked histone H3 lysine 27 demethylase (UTX/KDM6A).
To elucidate further the molecular characteristics of Korean patients with KS, we screened a cohort of patients with clinically defined KS for mutations in KMT2D and KDM6A.
The facial features of patients in the MLL2 truncating-type mutation group were typical based on those of the 10 originally reported patients with Kabuki syndrome; those of the other groups were less typical.
Diagnosis of KS was established after whole exome sequencing (WES) and detection of de novo frameshift 1bp deletion in histone-lysine N-methyltransferase 2D gene (KMT2D).
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.
Our results indicate that MLL2 is the major gene for Kabuki syndrome with a wide spectrum of de novo mutations and strongly suggest further genetic heterogeneity.
We propose that the mutated KMT2D gene contributes to the development of both KS and BL observed in our patient and we suggest that strict surveillance must be performed in KS patients.
Kabuki syndrome (KS) is a disorder of epigenetic dysregulation due to heterozygous mutations in KMT2D or KDM6A, genes encoding a lysine-specific methyltransferase or demethylase, respectively.