The Say-Barber-Biesecker-Young-Simpson (SBBYS) variant of Ohdo syndrome is a rare condition characterized by genital abnormalities in males, missing or underdeveloped kneecaps (patellae), intellectual disability, distinctive facial features, and abnormalities affecting other parts of the body.

Males with the SBBYS variant of Ohdo syndrome typically have undescended testes (cryptorchidism). Females with this condition have normal genitalia.

Missing or underdeveloped patellae is the most common skeletal abnormality associated with the SBBYS variant of Ohdo syndrome. Affected individuals also have joint stiffness involving the hips, knees, and ankles that can impair movement. Although joints in the lower body are stiff, joints in the arms and upper body may be unusually loose (lax). Many people with this condition have long thumbs and first (big) toes.

The SBBYS variant of Ohdo syndrome is also associated with delayed development and intellectual disability, which are often severe. Many affected infants have weak muscle tone (hypotonia) that leads to breathing and feeding difficulties.

The SBBYS variant of Ohdo syndrome is characterized by a mask-like, non-expressive face. Additionally, affected individuals may have distinctive facial features such as prominent cheeks, a broad nasal bridge or a nose with a rounded tip, a narrowing of the eye opening (blepharophimosis), droopy eyelids (ptosis), and abnormalities of the tear (lacrimal) glands. About one-third of affected individuals are born with an opening in the roof of the mouth called a cleft palate. The SBBYS variant of Ohdo syndrome can also be associated with heart defects and dental problems.

The SBBYS variant of Ohdo syndrome is caused by mutations in the KAT6B gene. This gene provides instructions for making a type of enzyme called a histone acetyltransferase. These enzymes modify histones, which are structural proteins that attach (bind) to DNA and give chromosomes their shape. By adding a small molecule called an acetyl group to histones, histone acetyltransferases control the activity of certain genes. Little is known about the function of the histone acetyltransferase produced from the KAT6B gene. It appears to regulate genes that are important for early development, including development of the skeleton and nervous system.

The mutations that cause the SBBYS variant of Ohdo syndrome likely prevent the production of functional histone acetyltransferase from one copy of the KAT6B gene in each cell. Studies suggest that the resulting shortage of this enzyme impairs the regulation of various genes during early development. However, it is unclear how these changes lead to the specific features of the condition.

Normal Function

The KAT6B gene provides instructions for making a type of enzyme called a histone acetyltransferase. These enzymes modify histones, which are structural proteins that attach (bind) to DNA and give chromosomes their shape. By adding a small molecule called an acetyl group to particular locations on histones, histone acetyltransferases control the activity of certain genes.

Little is known about the function of the histone acetyltransferase produced from the KAT6B gene. It is active in cells and tissues throughout the body, where it interacts with many other proteins. It appears to regulate genes that are important for early development, including development of the skeleton and nervous system.

Health Conditions Related to Genetic Changes

Genitopatellar syndrome

At least eight mutations in the KAT6B gene have been identified in people with genitopatellar syndrome, a rare condition characterized by genital abnormalities, missing or underdeveloped kneecaps (patellae), intellectual disability, and abnormalities affecting other parts of the body. The mutations that cause genitopatellar syndrome occur near the end of the KAT6B gene in a region known as exon 18. These mutations lead to the production of a shortened histone acetyltransferase enzyme. Researchers suspect that the shortened enzyme may function differently than the full-length version, altering the regulation of various genes during early development. Because the altered enzyme takes on a different function, these mutations are described as "gain-of-function." However, it is unclear how these changes lead to the specific features of genitopatellar syndrome.

Ohdo syndrome, Say-Barber-Biesecker-Young-Simpson variant

More than 10 mutations in the KAT6B gene have been found to cause the Say-Barber-Biesecker-Young-Simpson (SBBYS) variant of Ohdo syndrome. This condition has signs and symptoms that overlap with those of genitopatellar syndrome (described above), although some of the specific developmental abnormalities differ between the two conditions. Mutations that cause the SBBYS variant of Ohdo syndrome have been identified throughout the KAT6B gene, although many of them occur in exon 18. Studies suggest that these mutations likely prevent the production of functional histone acetyltransferase from one copy of the KAT6B gene in each cell. A shortage of this enzyme impairs the regulation of various genes during early development. Because these mutations lead to a reduction in the enzyme, they are described as "loss-of-function." However, it is unclear how these changes lead to the specific features of the condition.

Coloboma

MedlinePlus Genetics provides information about Coloboma

Cancers

Genetic changes involving the KAT6B gene have been associated with certain types of cancer. These mutations are somatic, which means they are acquired during a person's lifetime and are present only in certain cells. The genetic changes are chromosomal rearrangements (translocations) that disrupt the region of chromosome 10 containing the KAT6B gene. Researchers have found a translocation that attaches this region of chromosome 10 to part of chromosome 16 in some people with a cancer of blood-forming cells called acute myeloid leukemia (AML). This translocation has also been identified in some people with therapy-related myelodysplastic syndrome, a blood disorder that can occur after a person has undergone chemotherapy for another form of cancer.

It is unclear how translocations involving the KAT6B gene are related to the development of cancer. These changes likely alter histone modification, which could prevent normal regulation of gene activity. Impaired gene regulation may contribute to the growth of cancers by allowing abnormal cells to grow and divide uncontrollably.

Tumors

Somatic changes involving the KAT6B gene have also been identified in some people with uterine leiomyomas, which are noncancerous growths in the uterus that are also known as uterine fibroids. Uterine leiomyomas are common in adult women. These growths can cause pelvic pain and abnormal bleeding, and, in some cases, lead to an inability to have biological children (infertility). The genetic change associated with uterine leiomyomas is a translocation between the region of chromosome 10 containing the KAT6B gene and a particular region of chromosome 17. It is unclear how this translocation is related to tumor development. Changes in histone modification that impair normal gene regulation may allow certain cells to divide in an uncontrolled way, leading to the growth of a tumor.

Other Names for This Gene

• GTPTS
• histone acetyltransferase KAT6B
• histone acetyltransferase MORF
• histone acetyltransferase MOZ2
• histone acetyltransferase MYST4
• K(lysine) acetyltransferase 6B
• KAT6B_HUMAN
• monocytic leukemia zinc finger protein-related factor
• MORF
• MOZ-related factor
• MOZ2
• MYST histone acetyltransferase (monocytic leukemia) 4
• MYST-4
• MYST4
• qkf
• querkopf
• ZC2HC6B

Genomic Location

This condition has an autosomal dominant inheritance pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Almost all reported cases have resulted from new mutations in the gene and have occurred in people with no history of the disorder in their family.

The SBBYS variant of Ohdo syndrome is estimated to occur in fewer than 1 per million people. At least 19 cases have been reported in the medical literature.