17q12 deletion syndrome

17q12 deletion syndrome is a condition that results from the deletion of a small piece of chromosome 17 in each cell. Signs and symptoms of 17q12 deletion syndrome can include abnormalities of the kidneys and urinary system, a form of diabetes called maturity-onset diabetes of the young type 5 (MODY5), developmental delays, intellectual disabilities, and behavioral or psychiatric disorders. Some people with this chromosomal change have Mayer-Rokitansky-Küster-Hauser syndrome, which is characterized by the underdevelopment or absence of the vagina and uterus. The features that are associated with 17q12 deletion syndrome vary widely, even among affected members of the same family.

Most people with 17q12 deletion syndrome are missing about 1.4 million base pairs, also written as 1.4 megabases (Mb), on the long (q) arm of the chromosome at a position designated q12. It is the same region of chromosome 17 that is abnormally copied (duplicated) in people with a 17q12 duplication (described below). This chromosome segment is prone to rearrangement during cell division. 

The segment that is most often deleted in people with 17q12 deletion syndrome includes 15 genes. Some of the features associated with the condition likely result from the loss of two of these genes, HNF1B and LHX1. Studies suggest that a loss of one copy of the HNF1B gene in each cell causes kidney and urinary tract abnormalities, as well as diabetes. Missing one copy of LHX1 is thought to contribute to intellectual disabilities, behavioral and psychiatric conditions, and Mayer-Rokitansky-Küster-Hauser syndrome. The loss of other genes in the deleted region may also influence the signs and symptoms that can occur in people with 17q12 deletion syndrome.

17q12 duplication

17q12 duplication is a chromosomal change in which a small piece of chromosome 17 is abnormally duplicated in each cell. The signs and symptoms that are caused by this duplication vary significantly, even among members of the same family. Some individuals with the duplication have no apparent signs or symptoms or have features that are very mild. Other individuals can have intellectual disabilities, developmental delays, and a wide range of physical abnormalities.

Most people with 17q12 duplications have an extra copy of about 1.4 Mb of DNA at position q12 on chromosome 17. It is the same region of chromosome 17 that is deleted in people with 17q12 deletion syndrome. 

The duplicated segment of 17q12 includes at least 15 genes. It is unclear which of these duplicated genes contribute to the intellectual disabilities, developmental delays, and other features that are associated with a 17q12 duplication. Because some people with this duplication have no obvious signs or symptoms, researchers suspect that additional genetic factors may play a role.

Acute promyelocytic leukemia

A type of blood cancer known as acute promyelocytic leukemia is caused by a rearrangement (translocation) of genetic material between chromosomes 15 and 17. This translocation, written as t(15;17), fuses part of the PML gene from chromosome 15 with part of the RARA gene from chromosome 17. This genetic change is somatic, which means it is acquired during a person's lifetime and is present only in certain cells.

The t(15;17) translocation is called a balanced reciprocal translocation because the pieces of chromosome are exchanged with each other and no genetic material is gained or lost. The protein produced from this fused gene is known as PML-RARα.

The PML-RARα protein functions differently than the proteins produced from the normal PML and RARA genes. The RARA gene on chromosome 17 provides instructions for making a transcription factor called the retinoic acid receptor alpha (RARα). A transcription factor is a protein that attaches (binds) to specific regions of DNA and helps control the activity (transcription) of particular genes. 

Normally, the RARα protein controls the activity of genes that are important for the maturation (differentiation) of immature white blood cells (promyelocytes). The PML gene on chromosome 15 provides instructions for a protein that acts as a tumor suppressor, which means it prevents cells from growing in an uncontrolled way. The PML protein plays a role in blocking cell growth and division (proliferation) and encouraging cells to self-destruct when they are no longer needed (apoptosis). 

The PML-RARα protein interferes with the normal function of both the PML and the RARα proteins. As a result, blood cells stay in the promyelocyte stage, and they proliferate abnormally. Excess promyelocytes accumulate in the bone marrow, which interferes with the production of normal white blood cells and leads to acute promyelocytic leukemia.

Charcot-Marie-Tooth disease

Duplication of a small piece of chromosome 17 at position p12 that includes the PMP22 gene causes most cases of Charcot-Marie-Tooth disease type 1A, or CMT1A. Charcot-Marie-Tooth disease damages the peripheral nerves, which connect the brain and spinal cord to the muscles and to the cells that detect sensations such as touch, pain, heat, and sound. Peripheral nerve damage can result in a loss of sensation and wasting (atrophy) of muscles in the feet, legs, and hands.

The protein produced from the PMP22 gene is a component of myelin, a protective substance that covers nerves and promotes the efficient transmission of nerve impulses. Before they become part of myelin, newly produced PMP22 proteins are processed and packaged within cells. Completion of these processing and packaging steps is critical for proper myelin development, maintenance, and function.

The duplication of part of chromosome 17 creates an extra copy of the PMP22 gene, which leads to an overproduction of the PMP22 protein. Research suggests that excess PMP22 protein may overwhelm the cells' ability to process the protein correctly, leading to a buildup of unprocessed, nonfunctional protein. This buildup may impair the formation of new myelin and lead to the instability and loss of existing myelin (demyelination). A lack of functional myelin reduces the ability of the peripheral nerves to activate the muscles used for movement or to relay information from sensory cells back to the brain, leading to the signs and symptoms of CMT1A.

Dermatofibrosarcoma protuberans

Translocation of genetic material between chromosomes 17 and 22, written as t(17;22), causes most cases of dermatofibrosarcoma protuberans, a rare type of skin cancer. This translocation fuses part of the COL1A1 gene from chromosome 17 with part of the PDGFB gene from chromosome 22. The translocation is found on one or more extra chromosomes that can be either linear or circular. Extra chromosomes that are circular are known as supernumerary ring chromosomes. This translocation is somatic.

The fused COL1A1-PDGFB gene provides instructions for making a fused protein that researchers believe functions like the active PDGFB protein. In the translocation, the PDGFB gene loses the part of its DNA that limits its activity, and production of the COL1A1-PDGFB fusion protein is controlled by COL1A1 gene sequences. As a result, the gene fusion leads to the production of a larger amount of active PDGFB protein than normal. Excess PDGFB protein abnormally stimulates cells to divide (proliferate) and mature (differentiate), leading to the tumor formation seen in people with dermatofibrosarcoma protuberans.

Koolen-de Vries syndrome

Deletion of a small amount of genetic material (a microdeletion) on chromosome 17 can cause Koolen-de Vries syndrome. This disorder is characterized by developmental delays, intellectual disabilities, a cheerful and sociable disposition, and a variety of physical abnormalities.

Most people with Koolen-de Vries syndrome are missing a sequence of about 500,000 base pairs, also written as 500 kilobases (kb), at position q21.31 on chromosome 17. The exact size of the deletion varies among affected individuals, but it contains at least six genes, including KANSL1. This deletion affects one of the two copies of chromosome 17 in each cell.

Because variants (also called mutations) in the KANSL1 gene cause the same signs and symptoms as the deletion, researchers have concluded that the loss of this gene accounts for the features of Koolen-de Vries syndrome. The protein produced from the KANSL1 gene is involved in controlling the activity of other genes and plays an important role in the development and function of many parts of the body. Although the loss of this gene impairs normal development and function, its relationship to the specific features of Koolen-de Vries syndrome is unclear.

Koolen-de Vries syndrome is usually not inherited. However, most individuals with the deletion have at least one parent with a common variant of the q21.31 region of chromosome 17 called the H2 lineage. This variant is found in 20 percent of people of European and Middle Eastern descent, although it is rare in other populations. In the H2 lineage, a 900 kb segment of DNA, which includes the region deleted in most people with Koolen-de Vries syndrome, has undergone an inversion. An inversion involves two breaks in a chromosome; the resulting piece of DNA is reversed and reinserted into the chromosome.

People with the H2 lineage have no health problems related to the inversion. However, genetic material can be lost or duplicated when the inversion is passed to the next generation. Researchers believe that a parental inversion is probably necessary for a child to have the 17q21.31 microdeletion that is most often associated with Koolen-de Vries syndrome, but other factors are also thought to play a role. So, while the inversion is very common, only an extremely small percentage of parents with the inversion have a child affected by Koolen-de Vries syndrome.

Miller-Dieker syndrome

Miller-Dieker syndrome is caused by a deletion of genetic material near the end of the short (p) arm of chromosome 17. Miller-Dieker syndrome is a condition characterized by intellectual disabilities and developmental delays caused by an abnormally smooth brain that does not have the normal folds and grooves (lissencephaly). The signs and symptoms of Miller-Dieker syndrome are related to the loss of multiple genes, particularly the PAFAH1B1 and the YWHAE genes. Though the size of the deletion varies among affected individuals, the deletion always occurs in a specific area of chromosome 17 called the MDS critical region. 

The loss of the PAFAH1B1 gene causes lissencephaly. Lissencephaly is associated with severe intellectual disabilities, developmental delays, seizures, weak muscle tone (hypotonia), and feeding difficulties. The loss of YWHAE contributes to the severe lissencephaly seen in people with Miller-Dieker syndrome. Additional genes in the deleted region contribute to the other features of this disorder.

Potocki-Lupski syndrome

Potocki-Lupski syndrome results from a duplication of a small piece of chromosome 17 in each cell, specifically a region of the p arm designated p11.2. This condition is characterized by developmental delays, mild to moderate intellectual disabilities, autism spectrum disorder (which affects social interaction and communication), sleep disturbances, and other health problems.

In about two-thirds of affected individuals, the duplicated segment is approximately 3.7 Mb in size. In the remaining one-third of cases, the duplication ranges from less than 1 Mb to almost 20 Mb. All of these duplications affect one of the two copies of chromosome 17 in each cell.

Although the duplicated region contains multiple genes, researchers believe that having an extra copy of one particular gene, RAI1, may be responsible for many of the characteristic features of Potocki-Lupski syndrome. All of the duplications that are known to cause the condition contain this gene. 

The RAI1 gene provides instructions for making a protein that helps regulate the activity (expression) of other genes. Although most of the genes regulated by the RAI1 protein have not been identified, this protein appears to control the expression of several genes involved in daily (circadian) rhythms, such as the sleep-wake cycle. The RAI1 protein also appears to play a role in the development of the brain and of the bones in the head and face. Studies suggest that the duplication increases the amount of RAI1 protein, which disrupts the expression of genes that influence circadian rhythms. These changes may account for the sleep disturbances that occur in people with Potocki-Lupski syndrome. 

Too much RAI1 protein may also disrupt brain development, which could account for the developmental delays, intellectual disabilities, behavioral problems, and other neurological features of this condition. The development of the bones in the head and face may also be affected, leading to subtle facial differences in people with Potocki-Lupski syndrome.

Smith-Magenis syndrome

Smith-Magenis syndrome usually results from a deletion of a small piece of chromosome 17 in each cell, specifically a region of the p arm designated p11.2. The features of Smith-Magenis syndrome include mild to moderate intellectual disabilities, delayed speech and language skills, distinctive facial features, sleep disturbances, and behavioral problems.

Typically, the chromosome segment deleted in people with Smith-Magenis syndrome is the same one that is duplicated in people with Potocki-Lupski syndrome. Occasionally the deletion is larger or smaller. All of the deletions affect one of the two copies of chromosome 17 in each cell.

Researchers believe that a loss of function of the RAI1 gene accounts for many of the signs and symptoms of Smith-Magenis syndrome. All of the deletions known to cause this condition contain this gene. Studies suggest that the deletion leads to a reduced amount of RAI1 protein in cells, which disrupts the expression of genes involved in circadian rhythms. These changes may account for the sleep disturbances that occur in people with Smith-Magenis syndrome. It is unclear how a loss of one copy of the RAI1 gene leads to the other physical, psychological, and behavioral problems that are associated with this condition. It is likely that the loss of other genes in the deleted region influences the signs and symptoms of Smith-Magenis syndrome.

Yuan-Harel-Lupski syndrome

Duplication of a small piece of chromosome 17 in a region designated p12-11.2 can cause Yuan-Harel-Lupski (YUHAL) syndrome, which is characterized by neurological problems similar to those seen in people with Potocki-Lupski syndrome and CMT1A. In people with YUHAL syndrome, the duplicated segment ranges in size from about 3 Mb to nearly 20 Mb and always contains the RAI1 and PMP22 genes; it may also include additional genes. Certain features of YUHAL syndrome, such as developmental delays and behavioral problems, are likely caused by an extra copy of the RAI1 gene. Other features, including muscle weakness and decreased sensitivity to touch, heat, and cold in the lower legs and feet, are likely due to the duplication of the PMP22 gene.

Other chromosomal conditions

A deletion of material near the end of the p arm of chromosome 17, which includes YWHAE and other genes, has been associated with intellectual disabilities, developmental delays, seizures, and distinctive facial features. Though this 17q13.3 deletion is in the same region as the deleted segment in people with Miller-Dieker syndrome, this set of features is considered distinct because it does not include lissencephaly.  

17p13.3 duplication syndrome, also called split-hand/foot malformation with long bone deficiency or SHFLD3, is a chromosomal change in which a small piece of chromosome 17 is abnormally copied in each cell. The duplicated segment contains a gene called BHLHA9, which is important for limb development. The signs and symptoms of SHFLD3 can vary from person to person but typically include abnormalities of a bone in the lower leg (tibia) combined with various malformations of the hands and feet. The duplication of the BHLHA9 gene is likely responsible for many of the characteristic features of SHFLD3.

Other changes in the number or structure of chromosome 17 can have a variety of effects, including intellectual disabilities, developmental delays, characteristic facial features, hypotonia, and short stature. These changes include an extra piece of chromosome 17 in each cell (partial trisomy 17), a missing segment of the chromosome in each cell (partial monosomy 17), and a circular structure called a ring chromosome 17. Ring chromosomes occur when a chromosome breaks in two places and the ends of the chromosome arms fuse together to form a circular structure.

Other cancers

Somatic genetic changes in chromosome 17 have been identified in several additional types of cancer. A particular chromosomal abnormality called an isochromosome 17q occurs frequently in some cancers. This abnormal version of chromosome 17 has two q arms instead of one q arm and one p arm. As a result, the chromosome has an extra copy of some genes and is missing copies of other genes.

An isochromosome 17q has been found in different cancers of blood-forming tissues. It has also been identified in certain solid tumors, including a type of brain tumor called a medulloblastoma and tumors of the brain and spinal cord known as primitive neuroectodermal tumors. Although an isochromosome 17q probably plays a role in both the development and progression of these cancers, the specific genetic changes related to cancer growth are unknown.