Isodicentric Chromosome 15 Syndrome
Isodicentric chromosome 15 syndrome is a rare genetic condition caused by extra genetic material from chromosome 15, leading to challenges with development, learning, and sometimes seizures.
Table of contents
- What Is Isodicentric Chromosome 15 Syndrome?
- Other Names for This Condition
- Medical Classification Codes
- Types of Chromosome 15 Duplications
- Signs and Symptoms
- What Causes This Condition?
- How Common Is It?
- How Is It Diagnosed?
- Treatment and Management
- Inheritance and Genetic Counseling
What Is Isodicentric Chromosome 15 Syndrome?
Isodicentric chromosome 15 syndrome, also called Dup15q syndrome, is a chromosomal abnormality in which a child is born with extra genetic material from chromosome 15. In their body cells, people with this condition typically have 47 chromosomes instead of the normal 46. The extra chromosome is made up of a piece of chromosome 15 that has been duplicated end-to-end like a mirror image.[1]
This extra genetic material comes from a specific region of chromosome 15 labeled 15q11.2-q13.1. This region is also known as the Prader-Willi/Angelman critical region (PWACR). Instead of the usual two copies of this region, individuals with isodicentric chromosome 15 syndrome have four copies in total.[2][3]
The term isodicentric refers to a duplication and inversion of a part of a chromosome that contains a centromere (the point where chromosome copies attach during cell division). The syndrome affects development, learning, behavior, and can cause seizures in many affected individuals.[1][4]
Other Names for This Condition
Marker chromosome 15 syndrome, idic(15), Partial tetrasomy 15q, Non-telomeric tetrasomy 15q, Inverted duplication 15, inv dup(15), Chromosome 15q11.2-q13.1 Duplication Syndrome, Dup15q syndrome, Isodicentric 15, Non-distal tetrasomy 15q, Duplication/inversion 15q11
Medical Classification Codes
Q99.8
C580205
10081682
Types of Chromosome 15 Duplications
There are two main types of chromosome 15 duplication that can cause this syndrome, and they differ in how severe the symptoms typically are.[2][9]
The first and more common type is called isodicentric chromosome 15, often abbreviated as idic(15). This accounts for about 60 to 80 percent of cases. In this type, there is a small extra chromosome containing two additional copies of the 15q11.2-q13.1 region. This means the person has a total of four copies of this region instead of the usual two, a condition called tetrasomy. People with idic(15) are typically more severely affected than those with the other type.[2][3]
The second type is called interstitial duplication, often abbreviated as int dup(15). This accounts for about 20 to 40 percent of cases. In this type, the extra genetic material is inserted within one of the two existing copies of chromosome 15 rather than forming a separate small chromosome. This results in three copies of the 15q11.2-q13.1 region instead of two, a condition called trisomy. Individuals with interstitial duplication usually have milder symptoms than those with isodicentric chromosome 15.[1][2]
Occasionally, the extra chromosome is found in only some cells of the body, a situation called mosaicism. Because the marker chromosome can be unstable and lost during cell division, some cells may be completely normal with 46 chromosomes. In rare cases, cells may have more than one idic(15), resulting in 48 or 49 chromosomes.[1]
Signs and Symptoms
The severity of symptoms in isodicentric chromosome 15 syndrome varies greatly between individuals. Two people with the same genetic pattern may be very different in terms of their abilities. However, certain features are commonly seen.[6][14]
Most babies with this condition are born with hypotonia, which means reduced muscle tone. They may appear floppy and have difficulty sucking and feeding. This low muscle tone contributes to delays in reaching motor milestones such as sitting up and walking. Most affected children do learn to walk independently, typically after age 2 or 3, though they may have a wide-based or uncoordinated walking pattern.[3][4]
Developmental delays are typical in early childhood, with speech and language being particularly affected. Many individuals never develop functional speech, while others develop limited speech that may be echolalic (repeating words or phrases spoken by others). Understanding of language is also limited and depends heavily on context.[1][4]
Most children and adults with this condition have moderate to severe intellectual disability. Learning difficulties affect the ability to acquire new skills and knowledge throughout life.[3][4]
Many individuals with isodicentric chromosome 15 syndrome display features of autism spectrum disorder (ASD). These include problems with social interaction, difficulty with changes in routine, repetitive behaviors such as hand flapping or rocking, obsessional interests (often with interactive mechanisms like wheels or switches), and language problems associated with autism.[1][3]
More than half of people with this syndrome experience seizures (epilepsy). Seizures usually begin between the ages of 6 months and 9 years. The types of seizures can vary widely and may include infantile spasms (which usually appear before age 1), focal seizures (affecting one part of the brain), myoclonic seizures (rapid muscle jerks), tonic-clonic seizures (convulsions with loss of consciousness), tonic seizures (stiffening), atonic seizures (sudden loss of muscle tone causing falls), and absence seizures (brief staring spells). Some individuals develop complex, difficult-to-treat seizure patterns.[2][3][4]
According to a survey of families affected by this condition, 63 percent of people with idic(15) had seizures, compared to 25 percent of those with int dup(15). Among those with seizures, most had multiple seizure types, with tonic-clonic being the most common. The rate of active seizures appeared to increase with age, and 65 percent of respondents experienced worsening of seizures during puberty.[8][11]
Other features may include unpredictable sleep cycles with reduced need for sleep, sensory processing difficulties (especially affecting the vestibular system that controls balance), and a high pain threshold. Behavioral difficulties can include hyperactivity, anxiety, and frustration leading to tantrums. In some teenagers and young adults, mood disorders and psychosis may occur.[1][2]
Facial features associated with isodicentric chromosome 15 syndrome are usually subtle and may not be very noticeable. When present, they may include skin folds at the inner corners of the eyes (epicanthal folds), downward slanting of the space between the eyelids, a broad or flattened nasal bridge with a short upturned nose, nostrils that open to the front, a long space between the nose and upper lip, full lips, a high arched roof of the mouth, low-set ears, and a flattened back of the head. About 30 percent of individuals are born with eyes that do not look in the same direction (strabismus).[1][3]
Hearing loss in childhood is common and usually results from ear infections that cause fluid buildup in the middle ear. This hearing loss is often temporary, but if ear infections are left untreated during early childhood, it can interfere with language development.[3]
Other problems that may occur in some individuals include a spine that curves to the side (scoliosis), recurrent respiratory infections in childhood, a skin condition called eczema, and joint hyperextensibility with drooling. Rarely, sudden unexpected death during sleep (called sudden unexpected death in epilepsy, or SUDEP) can occur, particularly in individuals with epilepsy.[2][3][4]
What Causes This Condition?
Isodicentric chromosome 15 syndrome is caused by extra copies of a portion of chromosome 15 at the region 15q11.2-q13.1. Chromosome region 15q11-q13 is known for its instability and is highly susceptible to rearrangements that can cause disease.[4][9]
The extra genetic material forms either a small extra chromosome (supernumerary marker chromosome) containing an inverted duplication of this region, or the duplication occurs within one of the existing chromosome 15 copies. Large rearrangements containing the Prader-Willi/Angelman syndrome critical region are responsible for the symptoms seen in isodicentric chromosome 15 syndrome.[4]
When the duplication comes from the mother’s chromosome, it causes the symptoms associated with this syndrome. Maternally inherited duplications tend to result in more severe symptoms than paternally inherited ones. This difference occurs because genes in this region are subject to a phenomenon called genomic imprinting, where genes are expressed differently depending on whether they come from the mother or father.[2][13]
Although there are several important genes in the 15q11.2-13.1 segment, the gene called UBE3A appears to play a particularly important role. When functioning normally, the UBE3A gene from the mother helps the brain develop properly. The extra copies of genes in this region are thought to account for the symptoms seen in individuals with this condition.[9]
How Common Is It?
Prevalence at birth is estimated at 1 in 30,000, though this may be an underestimate. The prevalence in the general population is estimated to be about 1 in 14,000 people.[4][9]
In patients with developmental concerns such as developmental delay, intellectual disability, or autism spectrum disorder, or in those with multiple congenital anomalies, the prevalence of partial tetrasomy of chromosome 15 is estimated to range between 1 in 253 to 1 in 584.[4]
Isodicentric chromosome 15 syndrome is one of the most common chromosomal abnormalities in people with autism spectrum disorder, affecting around 1 in 500 people with autism. There is an observed male predilection with a ratio of 2 males to 1 female affected.[4][9]
How Is It Diagnosed?
Diagnosis is established through genetic testing that detects extra copies of the 15q11.2-q13.1 region. Several different laboratory techniques can be used to make this diagnosis.[4][10]
Standard cytogenetic analysis (karyotyping) can identify the presence of an extra small chromosome. FISH (fluorescence in situ hybridization) analysis uses special probes from the chromosome 15 region and from the Prader-Willi/Angelman critical region to confirm that the extra material comes from this specific area of chromosome 15.[4][15]
Array comparative genomic hybridization (aCGH or chromosomal microarray) is now commonly used as a first-line test in patients presenting with developmental delays, intellectual disability, or autism spectrum disorder. This test can show how much extra chromosomal material is present and identify the extent of the duplication. When an imbalance is detected by aCGH, FISH studies are still essential to accurately diagnose isodicentric chromosome 15.[4][15]
Additional testing, such as microsatellite analysis on parental DNA or methylation analysis on the affected individual’s DNA, is needed to determine whether the extra genetic material comes from the mother or father. This is important because only maternally derived duplications cause the symptoms associated with this syndrome.[2][4]
Treatment and Management
There is no cure for isodicentric chromosome 15 syndrome. Treatment is tailored to each individual and focuses on managing specific symptoms and providing supportive care to help affected individuals reach their fullest potential.[2][15]
A multidisciplinary team approach is recommended, involving specialists such as a clinical geneticist, genetic counselor, neurologist, psychiatrist, psychologist, speech-language pathologist, physical therapist, occupational therapist, and social worker. This team evaluates motor and speech development and assists with referrals for appropriate educational programs.[2][5]
Supportive care may include feeding therapy for infants and young children with feeding difficulties, occupational and physical therapy to help with motor skills and daily living activities, and alternative and augmentative communication strategies for those with limited or absent speech. Behavioral therapy, such as applied behavioral analysis, can help with behavioral challenges and social skills.[2]
For individuals with seizures, standard management approaches are used. Various anti-seizure medications may be tried to find the most effective treatment for each person’s specific seizure types. For those with infantile spasms, specific treatments may include hormonal therapy or other specialized medications.[2][8]
Psychotropic medications may be used to help manage behavioral manifestations such as hyperactivity, anxiety, or mood disorders when these significantly affect quality of life.[2]
Regular monitoring is important and includes growth and nutritional assessment at each visit, periodic neurodevelopmental and developmental/behavioral assessments, and monitoring for evidence of seizures or changes in seizure type. It is recommended to avoid known seizure triggers such as sleep deprivation and stress.[2]
Specialized clinics for individuals with Dup15q syndrome exist at several centers, including the UNC Comprehensive Duplication 15q Syndrome Clinic. These clinics provide coordinated care and the opportunity to meet with an expert team in a single visit.[5][12]
Inheritance and Genetic Counseling
Most cases of isodicentric chromosome 15 syndrome are not inherited from parents. In the majority of cases (about 85 percent), the chromosome duplication occurs as a new (de novo) event during early embryonic development. This means the duplication happened randomly and was not present in either parent.[2][6]
For the isodicentric chromosome 15 form (idic(15)), all affected individuals reported to date have had a de novo occurrence. The risk to siblings is low but is presumed to be slightly greater than in the general population because of the possibility of maternal germline mosaicism (where some of the mother’s egg cells carry the duplication).[2]
For the interstitial duplication form (int dup(15)), about 85 percent of cases occur de novo, but approximately 15 percent are inherited from the mother. If the mother has the 15q interstitial duplication, the risk to future children depends on whether she inherited it from her mother or if it occurred de novo in her. Genetic testing of siblings of an affected individual may be considered, especially when an inherited maternal interstitial duplication is known, in order to provide early intervention and developmental support if needed.[2]
Genetic counseling is recommended for families affected by this condition. A genetic counselor can explain the specific genetic findings, discuss recurrence risks, and provide information about testing options for family members.[2]