Why Epigenetics Matter to Us

To identify new treatment pathways, we must first understand Kabuki syndrome as an epigenetic disorder.

To date, researchers have identified two genes that can cause Kabuki syndrome when variants in the gene cause a dysfunction – known as pathogenic variants. Pathogenic variants in the KMT2D gene (formerly known as MLL2) account for 75% of cases.8 Pathogenic variants in the KDM6A gene account for ~10% of cases.1 Pathogenic changes in these genes can cause epigenetic changes.

Understanding these changes may be key to identifying therapeutic targets and developing treatments.9

How Epigenetic Mechanisms Influence Symptoms

DNA is the language of life, and how the cells in our bodies know what to do. The entirety of our DNA is the human genome, or the “book of life.” If the genome is a book, the genes are the words. Even though researchers have had the entire human genome “book” for over 20 years, they are still learning how to read it. Each gene (“word”) can have hundreds of different meanings. One way to read a book in different ways is to highlight the words that you need, and maybe you even have a different color highlighter for different types of words. Your genome’s highlighting system, or how your DNA is read, is your epigenetics.

Epigenetics are reversible and affected by your environment, including diet and drugs. Epigenetic marks (like highlights) change how the DNA is read, but not the DNA itself. Note that your DNA is not floating around in long lines; it is often tightly packed into chromatin – a mixture of DNA wrapped around histone proteins that provide structural support. Epigenetic “highlights” in the form of histone marks can be added (highlighted) or removed (erased), changing which information in the DNA is read. Your genes and epigenetics normally complete these jobs of highlighting and erasing in a balanced way.

KMT2D and KDM6A enable DNA to be read and ultimately influence gene expression – how your body looks and functions. Mutations, or variants, in these genes can prevent your body from reading your DNA instructions.

KMT2D Should Open Chromatin

KMT2D is one such highlighter that enables DNA to be read. This gene is located on chromosome 12. KMT2D marks histones to open chromatin, which enables the DNA to be read, and ultimately influences gene expression (how your body looks and functions). Variants in KMT2D that cause Kabuki syndrome result in too much closed chromatin, and the instructions in DNA cannot be read.

Without these instructions, gene expression is changed during development and throughout life, and this leads to the symptoms of Kabuki syndrome. Researchers are exploring different ways to restore the balance between open and closed chromatin to treat symptoms of Kabuki syndrome.9

Mutations in KMT2D and KDM6A result in too much closed chromatin.

This leads to the symptoms of Kabuki syndrome throughout the body.

In people without Kabuki syndrome, chromatin is kept in balance between open and closed states. Closed chromatin prevents DNA instructions from being read.

KDM6A Should Prevent Too Much Closed Chromatin

Pathogenic variants in KDM6A also result in too much closed chromatin but in a different way. This gene is located on the X chromosome, a sex-linked chromosome. Males, such as in the photo, have an X and Y chromosome. Females have two X chromosomes.

KDM6A “erases” or removes a close chromatin mark. If the marks to close the chromatin are not appropriately erased, too much chromatin is closed and an imbalance occurs. Researchers are exploring ways to restore the balance between open and closed chromatin to treat symptoms in people with a KDM6A mutation.9

Clincally Diagnosed Kabuki Syndrome

Some individuals are clinically diagnosed with Kabuki syndrome.10 This means that no pathogenic variant was found on either gene, or that genetic testing was not completed or did not include these genes. In the future, additional genes and gene mutations that cause Kabuki syndrome may also be discovered.