Rare Disease Database.)

rarediseases.org/rare-diseases/setbp1-disorder SETBP1 Disorder NORD gratefully acknowledges Bregje van Bon, MD, PhD and the SETBP1 Society, for assistance in the preparation of this report. Synonyms of SETBP1 Disorder SETBP1-related disorder SETBP1-related intellectual disability SETBP1-related developmental delay General Discussion Summary SETBP1 disorder is an extremely rare genetic neurodevelopmental disorder in which there is a variation (mutation) in the SETBP1 gene. Variations in the SETBP1 gene can potentially cause a variety of signs and symptoms; how the disorder affects one child can be very different from how it affects another. Neurodevelopmental disorders are ones that impair or alter the growth and development of the brain and the central nervous system. Common symptoms include varying degrees of intellectual disability, delays in reaching developmental milestones (developmental delays), delays or difficulty in being able to speak (speech delays), and distinctive facial features. In most instances, variations in the SETBP1 gene occur spontaneously and there is no family history of the disorder (de novo variations). Treatment is based on the specific symptoms present in each individual. Introduction Schinzel Giedion syndrome (SGS) is an extremely rare genetic disorder that is caused by a new (de novo), gain-of-function variation in the SETBP1 gene that is not inherited from the parents. Although SGS and SETBP1 disorder are associated with the same gene, they are completely different disorders. Individuals with SGS develop characteristic facial features, skeletal abnormalities, and obstruction of the tube that carries urine from the kidney to the bladder (ureter). This obstruction may lead to enlarged and damaged kidneys (hydronephrosis). Additional symptoms include excessive hair-growth (hypertrichosis), a flat midface (midface retraction), seizures, clubfeet, broad ribs, profound intellectual disability and short arms and 1/8 legs. SGS is a severe progressive syndrome and most affected individuals do not survive infancy. (For more information on this disorder, choose “Schinzel Gideon” as your search term in the Rare Disease Database.) Signs & Symptoms Although researchers have been able to establish a clear syndrome with characteristic or “core” symptoms, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis. The majority of children with SETBP1 disorder have intellectual disability that can range from mild to moderate to severe. The degree of intellectual disability may be hard to determine at first, because other symptoms may make evaluation difficult. Most children experience delays in reaching developmental milestones like sitting up or crawling. Speech delays are also common, and can be significant. Most children have better receptive language skills, which means that they can understand more information spoken to them than they are able to speak themselves (expressive language skills). The degree of speech difficulty can vary. Some children may have problems moving the muscles needed to speak and forming the mouth movements needed to speak (apraxia of speech) while others may not speak at all (nonverbal). Additional symptoms include diminished muscle tone (hypotonia) so that infants may appear ‘floppy,’ and, less often, seizures. Other children may have increased muscle tone (hypertonia) so that muscles are stiff and hard to move. Some individuals may have difficulty planning and processing motor tasks (dyspraxia). Motor tasks are those that require the movement and coordination of the muscles. Affected individuals may experience fine and gross motor delays. Fine motor skills are those that require small movements involving the hands and wrists. Gross motor skills are those that require whole body movements and involve large muscles. Some individuals with SETBP1 disorder have behavioral issues including attention deficit hyperactivity disorder (ADHD) and autism-like traits such as repetitive behaviors, fixation on objects, anxiety and poor social skills. Repetitive behaviors can include stereotypic hand movements, which include hand clapping, hand flapping, flicking hands, hand washing, fingers crossing, and frequent hand-to-mouth movements. Some children may show aggression or self-injury including head banging or persistent scratching. Affected individuals may have distinctive facial features including a long, pointed chin, which contributes to the face appearing longer than normal, mild drooping of the upper eyelid (mild ptosis), a prominent forehead, sparse eyebrows, a thin upper lip, and abnormal fullness of the 2/8 area around the eyes (periorbital fullness). Misalignment of the eyes (strabismus) has also been reported. The skull may appear shorter (brachycephaly) or longer (dolichocephaly) than usual. Causes SETBP1 disorder is caused by a variation in the SET binding protein 1 ( SETBP1) gene, or in a small loss (microdeletion) of genetic material on chromosome 18 that contains the SETBP1 gene, but no other genes. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain. The SETBP1 gene contains instructions to produce (encode) the SET binding protein 1. This protein is found in cells throughout the body including the brain and binds to another protein called SET. The exact function of this protein is not fully understood, but the SET binding protein 1 may be extremely important in the development of and/or function of brain cells. Affected individuals have a loss-of-function variation in the SETBP1 gene that leads to low levels of SET binding protein 1. A different type of variation, called a gain-of-function variation, can lead to overproduction of this protein. This leads to a different, more severe disorder called Schinzel Giedion syndrome (see the Related Disorders section below). In cases where a variation in SETBP1 is disease is causing the disorder, it almost always occurs as a new (sporadic or de novo) variation, which means that in nearly all instances the gene change has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. The disorder is usually not inherited from or “carried” by a healthy parent. However, affected individuals can pass on the altered gene in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females. Affected Populations SETBP1 disorder affects males and females in equal numbers. More than 45 people from many different countries are known to have the disorder. The exact number of affected individuals is unknown. Rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. SETBP1 disorder is likely under-recognized and underdiagnosed. Related Disorders 3/8 Symptoms of the following disorders can be similar to those of SETBP1 disorder. Comparisons may be useful for a differential diagnosis. The SETBP1 gene is found on chromosome 18. Researchers defined a syndrome in which there is a loss of genetic material (deletion or monosomy) on the long arm, called q, on chromosome 18. This is known as deletion 18q(q12.2-q21.). This deletion includes the loss of the SETBP1 gene. Symptoms include diminished muscle tone (hypotonia), speech and language delays, and behavioral problems. There are many disorders that can cause signs and symptoms similar to those seen in people with SETBP1 disorder. These include better known disorders such as cerebral palsy, and a wide variety of other genetic neurodevelopmental disorders. The signs and symptoms of SETBP1 disorder alone are not varied enough to distinguish the disorder from many of these other, similar disorders. Some affected individuals have symptoms that are consistent with those for individuals with an autism spectrum disorder. Childhood apraxia of speech is a disorder where children know what they want to say, but have difficulty forming the words. This may be because the brain has trouble directing the muscles of the mouth to move properly to be able to speak. It can occur as part of SETBP1 disorder, or as part of other disorder or because of damage to the brain. Diagnosis A diagnosis of SETBP1 disorder is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. Children with mild or moderate intellectual disability and speech development problems, but

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