Potocki-Lupski syndrome is a condition that results from having an extra copy (duplication) of a small piece of chromosome 17 in each cell. The duplication occurs on the short (p) arm of the chromosome at a position designated p11.2. This condition is also known as 17p11.2 duplication syndrome.

Infants with Potocki-Lupski syndrome may have weak muscle tone (hypotonia) and swallowing difficulties (dysphagia) that lead to feeding problems. Some affected babies do not grow and gain weight at the expected rate (described as failure to thrive), and children with this condition tend to be shorter and weigh less than their peers. About 40 percent of babies with Potocki-Lupski syndrome are born with a heart defect, which in some cases is life-threatening.

Babies and children with Potocki-Lupski syndrome have delayed development, including delayed speech and language skills and gross motor skills such sitting, standing, and walking. As they get older, affected individuals have intellectual disability, which is usually mild to moderate, and ongoing difficulties with speech. Potocki-Lupski syndrome is also associated with behavioral problems, which can include attention problems, hyperactivity, compulsive or impulsive behaviors, and anxiety. Many people with this condition have charateristics of autism spectrum disorder, which affects social interaction and communication.

Other signs and symptoms of Potocki-Lupski syndrome can include vision and hearing problems, dental and skeletal abnormalities, and abnormal kidney development and function. Many affected individuals have problems with sleep, including short pauses in breathing during sleep (sleep apnea) and trouble falling asleep and staying asleep. The condition can also have subtle differences in facial features, including outside corners of the eyes that point downward (down-slanting palpebral fissures), a triangular face with a broad forehead and a small jaw (micrognathia), and widely spaced eyes (hypertelorism).

Potocki-Lupski syndrome affects an estimated 1 in 25,000 people worldwide. More than 50 affected individuals have been described in the medical literature.

Potocki-Lupski syndrome results from a duplication of genetic material at 17p11.2. In about two-thirds of affected individuals, the duplicated segment includes approximately 3.7 million DNA building blocks (base pairs), also written as 3.7 megabases (Mb). (A deletion of this segment causes a related condition called Smith-Magenis syndrome.) In the remaining one-third of cases, the duplication is larger or smaller, ranging 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, underlies many of the characteristic features of Potocki-Lupski syndrome. All of the duplications 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. 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 with Potocki-Lupski syndrome. It is unclear how an extra copy of the RAI1 gene leads to intellectual disability and the other signs and symptoms of this condition. Extra copies of other genes at 17p11.2 likely also contribute to the features of this disorder; the role of these genes is under study.

Normal Function

The RAI1 gene provides instructions for making a protein that is active in cells throughout the body, particularly nerve cells (neurons) in the brain. Located in the nucleus of the cell, the RAI1 protein helps control the activity (expression) of certain genes. Most of the genes regulated by RAI1 have not been identified. However, studies suggest that this protein controls 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 development of the brain and of bones in the head and face (craniofacial bones).

Health Conditions Related to Genetic Changes

Potocki-Lupski syndrome

Having an extra copy of the RAI1 gene in each cell is thought to underlie many of the major features of Potocki-Lupski syndrome. This condition is characterized by delayed development, mild to moderate intellectual disability, autism spectrum disorder (which affects social interaction and communication), sleep disturbances, and other health problems. The condition results from abnormal copying (duplication) of a small piece of the short (p) arm of chromosome 17 at position p11.2. In about two-thirds of affected individuals, the duplicated segment includes approximately 3.7 million DNA building blocks (base pairs), also written as 3.7 megabases (Mb). (A deletion of this segment causes Smith-Magenis syndrome, described below.) In the remaining one-third of cases, the duplication is larger or smaller, ranging 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.

All of the duplications known to cause Potocki-Lupski syndrome contain the RAI1 gene. 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 with Potocki-Lupski syndrome. Too much RAI1 protein may also disrupt brain development, which could account for delayed development, intellectual disability, behavioral problems, and other neurological features of this condition. 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

Researchers believe that a partial or total loss of function of the RAI1 gene accounts for most of the signs and symptoms of Smith-Magenis syndrome. The major features of this condition include mild to moderate intellectual disability, delayed speech and language skills, distinctive facial features, sleep disturbances, behavioral problems, and other abnormalities affecting many parts of the body.

In most people with Smith-Magenis syndrome, the condition results from a deletion of a small piece of chromosome 17 in each cell. Most often, this chromosome segment, located at 17p11.2, is the same one that is duplicated in Potocki-Lupski syndrome (described above). Occasionally the deletion is larger or smaller. All of the deletions affect one of the two copies of chromosome 17 in each cell.

All of the deletions known to cause Smith-Magenis syndrome contain the RAI1 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 with Smith-Magenis syndrome. It is unclear how a loss of one copy of the RAI1 gene leads to the other physical, mental, and behavioral problems associated with this condition.

A small percentage of people with Smith-Magenis syndrome have a mutation in the RAI1 gene instead of a chromosomal deletion. Although these individuals have many of the major features of the condition, they are less likely than people with a deletion to have certain other features, including short stature, hearing loss, and heart or kidney abnormalities. It is likely that, in people with a deletion, the loss of other genes in the deleted region accounts for these additional signs and symptoms; the role of these genes is under study.

Yuan-Harel-Lupski syndrome

Having an extra copy of the RAI1 gene in each cell is thought to underlie many of the major features of Yuan-Harel-Lupski (YUHAL) syndrome, which is characterized by multiple neurological problems. This condition results from duplication of a small piece of chromosome 17 in a region designated p12-p11.2. In YUHAL syndrome, the duplicated segments can range in size from 3.2 Mb to 19.7 Mb. These duplications affect one of the two copies of chromosome 17 in each cell.

The duplications that cause YUHAL syndrome all contain the RAI1 gene and a nearby gene called PMP22; the segments may also contain additional genes. Some features of YUHAL syndrome, such as delayed development, behavioral and sleep problems, and unusual facial features, are similar to those of Potocki-Lupski syndrome (described above) and are likely caused by an extra copy of the RAI1 gene. Other features of YUHAL syndrome, such as muscle weakness and decreased sensitivity to touch, heat, and cold in the lower legs and feet, likely result from an extra copy of the PMP22 gene.

Other Names for This Gene

• KIAA1820
• RAI1_HUMAN
• SMCR
• SMS

Genomic Location

This condition has an autosomal dominant pattern of inheritance, which means one copy of a 17p11.2 duplication in each cell is sufficient to cause the disorder.

Most cases of Potocki-Lupski syndrome result from a new (de novo) chromosomal duplication and occur in people with no history of the disorder in their families. Less commonly, an affected person inherits the duplication from one affected parent.

• Congenital heart defects (present at birth) or heart problems that develop with age
• Low muscle tone (hypotonia) beginning in infancy
• Poor feeding beginning in infancy
• Failure to thrive beginning in infancy
• Developmental delay of motor and verbal milestones
• Intellectual disability
• Behavioral difficulties such as attention problems, hyperactivity, or withdrawal
• Features of autism spectrum disorder
• Neuropsychiatric disorders (such as bipolar disorder or anxiety disorder)
• Sleep apnea, which often is not apparent but found during sleep studies