Kabuki syndrome is a disorder that can affect many parts of the body. It is characterized by distinctive facial features including arched eyebrows; long eyelashes; long openings of the eyelids (long palpebral fissures) with the lower lids turned out (everted) at the outside edges; a flat, broadened tip of the nose; and large protruding earlobes. The name of this disorder comes from the resemblance of its characteristic facial appearance to stage makeup used in traditional Japanese Kabuki theater.

People with Kabuki syndrome may have mild to severe developmental delay and intellectual disability. Affected individuals may also have seizures, an unusually small head size (microcephaly), or weak muscle tone (hypotonia). Some have eye problems such as rapid, involuntary eye movements (nystagmus) or eyes that do not look in the same direction (strabismus).

Other characteristic features of Kabuki syndrome include short stature and skeletal abnormalities such as abnormal side-to-side curvature of the spine (scoliosis), short fifth (pinky) fingers, or problems with the hip and knee joints. The roof of the mouth may have an abnormal opening (cleft palate) or be high and arched, and dental problems are common in affected individuals. People with Kabuki syndrome may also have fingerprints with unusual features and fleshy pads at the tips of the fingers. These prominent finger pads are called fetal finger pads because they normally occur in human fetuses; in most people they disappear before birth.

A wide variety of other health problems occur in some people with Kabuki syndrome. Among the most commonly reported are heart abnormalities, frequent ear infections (otitis media), hearing loss, and early puberty.

Kabuki syndrome is caused by variants (also known as mutations) in the KMT2D gene (also known as MLL2) or the KDM6A gene.

Between 55 and 80 percent of cases of Kabuki syndrome are caused by variants in the KMT2D gene. This gene provides instructions for making an enzyme, called lysine-specific methyltransferase 2D, that is found in many organs and tissues of the body. Lysine-specific methyltransferase 2D functions as a histone methyltransferase. Histone methyltransferases are enzymes that modify proteins called histones. Histones are structural proteins that attach (bind) to DNA and give chromosomes their shape. By adding a molecule called a methyl group to histones (a process called methylation), histone methyltransferases control (regulate) the activity of certain genes. Lysine-specific methyltransferase 2D appears to activate certain genes that are important for development.

Between 2 and 6 percent of cases of Kabuki syndrome are caused by variants in the KDM6A gene. This gene provides instructions for making an enzyme called lysine-specific demethylase 6A. This enzyme is a histone demethylase, which means that it helps to remove methyl groups from certain histones. Like lysine-specific methyltransferase 2D, lysine-specific demethylase 6A regulates the activity of certain genes, and research suggests that the two enzymes work together to control certain developmental processes.

The KMT2D and KDM6A gene variants associated with Kabuki syndrome lead to the absence of the corresponding functional enzyme. A lack of either of the enzymes produced from these genes disrupts normal histone methylation and impairs proper activation of certain genes in many of the body's organs and tissues, resulting in the abnormalities of development and function characteristic of Kabuki syndrome.

Some people with Kabuki syndrome have no identified KMT2D or KDM6A gene variant. These individuals are diagnosed based on the presence of characteristic features of the condition. The cause of Kabuki syndrome in these individuals is unknown.

Normal Function

The KMT2D gene, also known as MLL2, provides instructions for making an enzyme called lysine-specific methyltransferase 2D that is found in many organs and tissues of the body. Lysine-specific methyltransferase 2D functions as a histone methyltransferase. Histone methyltransferases are enzymes that modify proteins called histones. Histones are structural proteins that attach (bind) to DNA and give chromosomes their shape. By adding a molecule called a methyl group to histones (a process called methylation), histone methyltransferases control (regulate) the activity of certain genes. Lysine-specific methyltransferase 2D appears to activate certain genes that are important for development.

Lysine-specific methyltransferase 2D is also believed to act as a tumor suppressor, which means it normally helps prevent cells from growing and dividing in an uncontrolled way.

Health Conditions Related to Genetic Changes

Kabuki syndrome

Hundreds of variants (also known as mutations) in the KMT2D gene have been identified in people with Kabuki syndrome, a disorder characterized by distinctive facial features, intellectual disability, and abnormalities affecting other parts of the body.

The KMT2D gene variants associated with Kabuki syndrome change one building block (amino acid) in the lysine-specific methyltransferase 2D enzyme, delete genetic material in the KMT2D gene sequence, or result in a premature stop signal that leads to an abnormally short enzyme. As a result of these changes, the enzyme is nonfunctional. A lack of functional lysine-specific methyltransferase 2D enzyme disrupts its role in histone methylation and impairs proper activation of certain genes in many of the body's organs and tissues, resulting in the abnormalities of development and function characteristic of Kabuki syndrome.

Although lysine-specific methyltransferase 2D is believed to be a tumor suppressor, a loss of this enzyme's function does not seem to increase cancer risk in people with Kabuki syndrome.

Bladder cancer

MedlinePlus Genetics provides information about Bladder cancer

Coloboma

MedlinePlus Genetics provides information about Coloboma

Cancers

Some gene variants occur during a person's lifetime. Such changes, which are called somatic variants, are present only in certain cells. Somatic variants in the KMT2D gene have been identified in certain cancers. These include medulloblastomas, which are cancerous brain tumors that occur in childhood, and blood-related cancers called lymphomas. Most of these variants result in an abnormally short, nonfunctional lysine-specific methyltransferase 2D enzyme that cannot perform its role as a tumor suppressor, resulting in the development of cancer.

Increased amounts of lysine-specific methyltransferase 2D and altered distribution of the enzyme within cells have been identified in cancerous tumors of the breast and colon. It is unknown whether these changes result primarily from increased activity (overexpression) of the KMT2D gene, extra copies of the gene in tumor cells, altered stability or processing of the enzyme, or other mechanisms. Excess amounts of lysine-specific methyltransferase 2D may disrupt the regulation of other genes. As a result, cells may grow and divide too quickly or in an uncontrolled way, leading to cancer.

Other Names for This Gene

• AAD10
• ALL1-related protein
• ALR
• CAGL114
• histone-lysine N-methyltransferase MLL2
• KMT2B
• lysine (K)-specific methyltransferase 2D
• lysine N-methyltransferase 2B
• MLL2
• MLL2_HUMAN
• MLL4
• myeloid/lymphoid or mixed-lineage leukemia 2
• TNRC21
• trinucleotide repeat containing 21

Genomic Location

Normal Function

The KDM6A gene provides instructions for making an enzyme called lysine-specific demethylase 6A that is found in many organs and tissues of the body. Lysine-specific demethylase 6A functions as a histone demethylase. Histone demethylases are enzymes that modify proteins called histones. Histones are structural proteins that attach (bind) to DNA and give chromosomes their shape. By removing a molecule called a methyl group from histones (a process called demethylation), histone demethylases control (regulate) the activity of certain genes. Lysine-specific demethylase 6A appears to regulate certain genes that are important for development.

Lysine-specific demethylase 6A is also believed to act as a tumor suppressor, which means it normally helps prevent cells from growing and dividing in an uncontrolled way.

Health Conditions Related to Genetic Changes

Kabuki syndrome

Many variants (also known as mutations) in the KDM6A gene have been identified in people with Kabuki syndrome, a disorder characterized by distinctive facial features, intellectual disability, and abnormalities affecting other parts of the body.

Most of the KDM6A gene variants associated with Kabuki syndrome remove (delete) genetic material in the KDM6A gene sequence or result in a premature stop signal that leads to an abnormally short lysine-specific demethylase 6A enzyme. As a result of these changes, the enzyme is nonfunctional. A lack of functional lysine-specific demethylase 6A enzyme disrupts its role in histone demethylation and impairs proper regulation of certain genes in many of the body's organs and tissues, resulting in the abnormalities of development and function characteristic of Kabuki syndrome.

Although lysine-specific demethylase 6A is believed to act as a tumor suppressor, a loss of this enzyme's function does not seem to increase cancer risk in people with Kabuki syndrome.

Bladder cancer

Some gene variants are acquired during a person's lifetime and are present only in certain cells. These changes, which are called somatic variants, are not inherited. Somatic variants in the KDM6A gene have been found in some cases of bladder cancer. Bladder cancer is a disease in which certain cells in the bladder become abnormal and multiply uncontrollably to form a tumor. Bladder cancer may cause blood in the urine, pain during urination, frequent urination, the feeling to of needing to urinate without being able to, or lower back pain.

Bladder cancer is generally divided into two types, non-muscle invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC), based on where in the bladder the tumor is located. About half of NMIBC tumors have KDM6A gene variants. These KDM6A gene variants change single protein building blocks (amino acids) in the enzyme, which appears to impair the enzyme's role in histone demethylation. As a result, regulation of certain genes in bladder cells is disrupted, which likely leads to uncontrolled cell division and the formation of bladder cancer.

Cancers

Somatic variants in the KDM6A gene have been identified in cancers of the breast, esophagus, colon, kidney, and brain, and cancers of blood-forming cells called myeloid leukemia and multiple myeloma. Most of these variants result in an abnormally short, nonfunctional lysine-specific demethylase 6A enzyme that cannot perform its role as a tumor suppressor, resulting in the development of cancer.

Other Names for This Gene

• bA386N14.2
• bA386N14.2 (ubiquitously transcribed X chromosome tetratricopeptide repeat protein (UTX))
• histone demethylase UTX
• KABUK2
• KDM6A_HUMAN
• lysine (K)-specific demethylase 6A
• lysine-specific demethylase 6A
• ubiquitously transcribed tetratricopeptide repeat protein X-linked
• ubiquitously-transcribed TPR gene on the X chromosome
• ubiquitously-transcribed TPR protein on the X chromosome
• UTX

Genomic Location

Kabuki syndrome is most often caused by a change (mutation) in the KMT2D gene, which is inherited in an autosomal dominant manner. This means that having a mutation in only one copy of the responsible gene in each cell is enough to cause features of the condition. When a person with a mutation that causes an autosomal dominant condition has children, each child has a 50% (1 in 2) chance to inherit that mutation.

Some cases are caused by mutations in the KDM6A gene, inherited in an X-linked dominant manner. This means that the gene responsible for the condition is located on the X chromosome, and having only one mutated copy of the gene is enough to cause the condition.

Because males have only one X chromosome (and one Y chromosome) and females have two X chromosomes, X-linked dominant conditions affect males and females differently. Both males and females can have an X-linked dominant condition. However, because males don't have a second, working copy of the gene (as females do), they usually have more severe disease than females.

If a father has the mutated X-linked gene:

• all of his daughters will inherit the mutated gene (they will all receive his X chromosome)
• none of his sons will inherit the mutated gene (they only inherit his Y chromosome)

If a mother has the mutated X-linked gene, each of her children (both male and female) has a 50% chance to inherit the mutated gene.

Most cases of Kabuki syndrome are not inherited from a parent and result from a new mutation in one of these genes (in people with no family history of Kabuki syndrome). In a few cases an affected person is believed to have inherited the mutation from an affected parent. In either case, a person with a disease-causing mutation may still pass it on to his/her offspring.

Kabuki syndrome is present from birth (it is congenital). People with Kabuki syndrome have similar, characteristic facial features. These include arched eyebrows; wide eyes that often slant upwards; long and thick eyelashes; a blue tint to the whites of the eyes (blue sclerae); prominent ears; downward slanting corners of the mouth; and a depressed tip of the nose. People with Kabuki syndrome may also have cleft lip; a highly arched or cleft palate; and widely spaced, irregular teeth.

Most people with Kabuki syndrome have mild to moderate intellectual disability, although this varies considerably. Early speech and language delay is common and some language-related difficulties usually persist.Other medical problems may also be present. Congenital heart defects are common. Skeletal abnormalities may include a short and curved pinky finger (clinodactyly); spine abnormalities; and joint dislocations. Affected people often have weak muscle tone (hypotonia); feeding difficulties; seizures; and a small head size (microcephaly). Vision and hearing problems may also be present. Some affected children are more susceptible to infections, particularly ear infections.

Kabuki syndrome occurs in approximately 1 in 32,000 newborns.