Chromosome 15
Duplication syndrome 15q11-q13, a condition whose characteristics may include weak muscle tone (hypotonia), intellectual disability, recurrent seizures (epilepsy), characteristics of the autism spectrum disorder that affects communication and social interaction, and other behavioral problems. Dup15q syndrome is caused by the presence of at least one additional copy of a region of chromosome 15 called 15q11.2-q13.1. This region is also called the Prader-Willi / Angelman critical region (PWACR) because genetic changes in it are also involved in conditions called Prader-Willi syndrome and Angelman syndrome. Dup15q syndrome arises only if the chromosomal abnormality occurs in the copy of the inherited chromosome from the mother (the maternal copy). People usually inherit a copy of chromosome 15 from each parent. However, some genes on this chromosome, including some of those in the 15q11.2-q13.1 region, are activated only in the maternal copy.
The most common chromosomal abnormality that leads to duplication of 15q11.2-q13.1, which occurs in approximately 80 percent of people with dup15q syndrome, is called isodicetric chromosome 15, a condition also known as tetrasomy. In approximately 20 percent of cases of dup15q syndrome, duplication occurs in the long arm (q) of one of two copies of chromosome 15 in each cell; This situation is called interstitial duplication. In all cases of dup15q syndrome, duplicate genetic material results in additional copies of certain genes involved in development. This additional genetic material disrupts normal development, causing the characteristic features of this disorder.
Microdeletion 15q13.3 is a chromosomal change in which a small portion of chromosome 15 is removed in each cell. The deletion occurs in the arm q of the chromosome in a designated position q13.3. Most people with a 15q13.3 microdeletion do not have a sequence of approximately 2 million base pairs of DNA, also written as 2 megabases (Mb). The exact size of the deleted region varies, but generally contains at least six genes. It is not clear how a loss of these genes increases the risk of intellectual disability, seizures, behavioral problems and psychiatric disorders in some people with a 15q13.3 microdeletion. While other people with a 15q13.3 microdeletion have no obvious signs or symptoms related to chromosomal change. In these individuals, microdeletion is often detected when they undergo genetic testing because they have an affected relative. It is unknown why the 15q13.3 microdeletion causes cognitive and behavioral problems in some individuals, but few or no health problems in others.
Microdeletion 15q24 is a chromosomal change in which a small portion of chromosome 15 is removed in each cell. Specifically, affected individuals are missing between 1.7 Mb and 6.1 Mb of DNA at position q24 on chromosome 15. The exact size of the deletion varies, but all individuals lack the same 1.2 Mb region. This region contains several genes that are considered important for normal development. It is not clear how a loss of these genes leads to intellectual disability, distinctive facial features and other abnormalities.
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 of chromosome 15 with part of the RARA gene of chromosome 17. This mutation is acquired during the life of a person and is present only in certain cells. The translocation t (15; 17) is called balanced reciprocal translocation because the pieces of the chromosome exchange with each other (reciprocal) and no genetic material (balanced) is gained or lost. The protein produced from this fused gene is known as PML-RARĪ±.
Due to the translocation the PML-RARĪ± protein cannot fulfill its function correctly. As a result, blood cells get stuck in the promyelocyte stage and proliferate abnormally. Excess promyelocytes accumulate in the bone marrow and normal white blood cells cannot form, which leads to acute promyelocytic leukemia.
Angelman Syndrome results from a loss of genetic activity (expression) in a specific part of chromosome 15 in each cell. This region is located on the q arm of the chromosome and is designated as 15q11-q13. This region contains a gene called UBE3A that is possible responsible for neurological changes. In most cases (about 70 percent), Angelman syndrome results from a deletion in the maternal copy of chromosome 15. Because the copy of the UBE3A gene inherited from a person's father (the paternal copy) normally is inactive in certain parts of the brain, an elimination on the maternal chromosome 15 leaves no active copies of the UBE3A gene in these regions of the brain. In 3 to 7 percent of Angelman syndrome cases, the condition occurs when a person inherits two copies of chromosome 15 from their father instead of one copy from each parent. This phenomenon is called paternal uniparental disomy (UPD). People with paternal UPD for chromosome 15 have two copies of the UBE3A gene, but both are inherited from the father and, therefore, are inactive in the brain. Children with this condition have a cheerful and smiling character, little attention and concentration, mental disability and developmental delay; they usually sleep less than average and suffer seizures frequently. The life expectancy is almost normal.
Prader-Willi syndrome is caused by a loss of active genes in a region of chromosome 15. This region is located on the q arm of the chromosome and is designated 15q11-q13. It is the same part of chromosome 15 that is usually affected in people with Angelman syndrome, although different genes are associated with the two disorders. People may have Prader-Willi syndrome or Angelman syndrome, but generally they cannot have both. In childhood, this condition is characterized by weak muscle tone (hypotonia), feeding difficulties, poor growth and developmental delay. Starting in childhood, affected people develop an insatiable appetite, which leads to chronic overfeeding (hyperphagia) and obesity. Some people with Prader-Willi syndrome, particularly those with obesity, also develop type 2 diabetes (the most common form of diabetes). People with Prader-Willi syndrome generally have mild to moderate intellectual impairment and learning disabilities. Behavioral problems are common, including outbursts of temperament, stubbornness and compulsive behavior, such as scratching the skin. Sleep abnormalities can also occur.
In approximately 70 percent of cases, Prader-Willi syndrome occurs when the 15q11-q13 region of the paternal chromosome 15 is removed in each cell. A person with this chromosomal change will lack certain critical genes in this region because the genes in the paternal copy have been deleted and the genes in the maternal copy are deactivated (inactive). In approximately 25 percent of cases, people with Prader-Willi syndrome inherit two copies of chromosome 15 from their mother instead of one copy from each parent. This phenomenon is called maternal UPD. A person with two maternal copies of chromosome 15 will not have active copies of certain genes in the 15q11-q13 region.
Sensorineural deafness and male infertility are caused by the removal of genetic material in the arm q of chromosome 15. The symptoms are related to the loss of multiple genes in this region. The size of the elimination varies among the people affected. Researchers have determined that the loss of a particular gene on chromosome 15, STRC, is responsible for hearing loss in affected people. The loss of another gene, CATSPER2, in the same region of chromosome 15 is responsible for sperm abnormalities, which lead to an inability to father children (infertility).
Other changes in the number or structure of chromosome 15 can cause intellectual disability, stunted growth and development, hypotonia and characteristic facial features. These changes include an additional copy of part of chromosome 15 in each cell (partial trisomy 15), a missing segment of the chromosome in each cell (partial monosomy 15) and a circular structure called a ring.
