Isodicentric 15, also called
marker chromosome 15 syndrome,
idic(15), partial tetrasomy 15q, or inverted duplication 15 (inv dup 15), is a
chromosome abnormality
A chromosomal abnormality, chromosomal anomaly, chromosomal aberration, chromosomal mutation, or chromosomal disorder, is a missing, extra, or irregular portion of Chromosome, chromosomal DNA. These can occur in the form of numerical abnormalities ...
in which a child is born with extra genetic material from
chromosome 15
Chromosome 15 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 15 spans about 102 million base pairs (the building material of DNA) and represents between 3% and 3.5% of the total DN ...
. People with idic(15) are typically born with 47 chromosomes in their body cells, instead of the normal 46. The extra chromosome, which is classified as a
small supernumerary marker chromosome
A small supernumerary marker chromosome (sSMC) is an abnormal extra chromosome. It contains copies of parts of one or more normal chromosomes and like normal chromosomes is located in the cell's nucleus, is replicated and distributed into each d ...
,
is made up of a piece of chromosome 15 that has been duplicated end-to-end like a mirror image. It is the presence of this extra genetic material that is thought to account for the symptoms seen in some people with idic(15). Individuals with idic(15) have a total of four copies of this chromosome 15 region instead of the usual two copies (1 copy each on the
maternal
]
A mother is the female parent of a child. A woman may be considered a mother by virtue of having given birth, by raising a child who may or may not be her biological offspring, or by supplying her ovum for fertilisation in the case of gestat ...
and
paternal
A father is the male parent of a child. Besides the paternal bonds of a father to his children, the father may have a parental, legal, and social relationship with the child that carries with it certain rights and obligations. An adoptive fathe ...
chromosomes).
The syndrome is also often referred to by the term Chromosome 15q11.2-q13.1 Duplication Syndrome, shortened to Dup15q Syndrome, or marker chromosome 15 syndrome (mainly in the United States). Dup15q Syndrome includes both idic(15) and interstitial 15q11.2-q13.1, another type of duplication that causes similar clinical traits.
The extra chromosome is occasionally found in the
mosaic
A mosaic is a pattern or image made of small regular or irregular pieces of colored stone, glass or ceramic, held in place by plaster/mortar, and covering a surface. Mosaics are often used as floor and wall decoration, and were particularly pop ...
state, i.e. some of the cells carry the marker chromosome. However, mostly because of the marker's instability and tendency to be lost during cell division (
mitosis), some cells are completely normal with 46 chromosomes. Occasionally, cells may have more than one idic(15), resulting in 48 or 49 chromosomes in all or some of their cells. A similar clinical picture albeit to a milder degree could be expected in individuals that have the extra chromosome 15 material as an interstitial duplication (when the extra piece of chromosome 15 is included ''within'' the long arm of one of the two copies of chromosome 15, rather than as a small extra 'marker' chromosome) - often abbreviated to int dup(15); the individual thus having 46 chromosomes.
Signs and symptoms
The severity of symptoms of idic(15) vary greatly between individuals. Individuals with idic(15) usually have delays in language development and motor skills such as walking or sitting up. Other traits may include low muscle tone (
hypotonia
Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases ...
),
seizures
An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with l ...
(>50%), short stature, and
intellectual disability
Intellectual disability (ID), also known as general learning disability in the United Kingdom and formerly mental retardation, Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010). is a generalized neurodevelopmental disorder characterized by signif ...
. Distinctive facial features associated with idic(15) - where present at all - are usually very subtle but may include
epicanthal fold
An epicanthic fold or epicanthus is a skin fold of the upper eyelid that covers the inner corner (medial canthus) of the eye. However, variation occurs in the nature of this feature and the possession of "partial epicanthic folds" or "slight ...
s (
skin fold
Skin folds or skinfolds are areas of skin that are naturally folded. Many skin folds are distinct, heritable anatomical features, and may be used for identification of animal species, while others are non-specific and may be produced either by ind ...
s at the inner corners of one or both eyes), downward slanting
palpebral fissure
The palpebral fissure is the elliptic space between the medial and lateral canthi of the two open eyelids. In simple terms, it is the opening between the eyelids. In adult humans, this measures about 10 mm vertically and 30 mm horizontally.
Va ...
s, broad forehead, a flattened nasal bridge, button nose, and a high arched
palate
The palate () is the roof of the mouth in humans and other mammals. It separates the oral cavity from the nasal cavity.
A similar structure is found in crocodilians, but in most other tetrapods, the oral and nasal cavities are not truly separ ...
(roof of the mouth). Some individuals show other signs that can often be associated with chromosomal conditions, such as
pectus excavatum
Pectus excavatum is a structural deformity of the anterior thoracic wall in which the sternum and rib cage are shaped abnormally. This produces a caved-in or sunken appearance of the chest. It can either be present at birth or develop after pubert ...
, or a unilateral or bilateral
single transverse palmar crease
In humans, a single transverse palmar crease is a single crease that extends across the palm of the hand, formed by the fusion of the two palmar creases (known in palmistry as the "heart line" and the "head line"). Although it is found more freque ...
. Many individuals with idic(15) display features of
autism, such as problems with communication and social interactions, obsessional interests (often with interactive mechanisms like wheels, doors or switches), unpredictable sleep cycles (and a reduced need for sleep), and repetitive and stereotyped behaviors (e.g., lining up toys, playing with a toy in the same manner over and over again, hand flapping, rocking back and forth). Sensory processing is often affected, especially the vestibular system. A high pain threshold is often observed. If speech develops, it is often
echolalic but some individuals do grasp some language. With a severely affected person there may be an inability to walk or talk.
Genetics
Generally, idic(15) is not inherited; it is said to appear
de novo, in one member of the family, by chance. In most cases, the abnormal chromosome is generated in the mother's germ cells: the
oocyte
An oocyte (, ), oöcyte, or ovocyte is a female gametocyte or germ cell involved in reproduction. In other words, it is an immature ovum, or egg cell. An oocyte is produced in a female fetus in the ovary during female gametogenesis. The femal ...
s. This finding is due to
ascertainment bias
In statistics, sampling bias is a bias in which a sample is collected in such a way that some members of the intended population have a lower or higher sampling probability than others. It results in a biased sample of a population (or non-human f ...
; cases with maternally derived idic(15) usually have clinical findings and attract attention, but those with paternally derived idic(15) usually do not. Thus, diagnosed cases are usually patients where the duplicated material is derived from the mother's egg cell rather than the father's sperm cell.
People with idic(15) have extra genetic material that has developed from chromosome 15. The material usually exists as a little extra chromosome 15; sometimes called a
marker chromosome
A marker chromosome (mar) is a small fragment of a chromosome which generally cannot be identified without specialized genomic analysis due to the size of the fragment.Thompson & Thompson Genetics in Medicine, Chapter 5, 57-74 https://www.clinicalk ...
or an extra structurally abnormal chromosome (ESAC). The marker usually exists as an isodicentric chromosome; i.e. 2 copies of a specific part of the long arm of chromosome 15q11.2-q13.1 that is mirrored and doubled, with 2
centromere
The centromere links a pair of sister chromatids together during cell division. This constricted region of chromosome connects the sister chromatids, creating a short arm (p) and a long arm (q) on the chromatids. During mitosis, spindle fibers ...
s and 2
DNA satellites. The smallest markers appear to be harmless and they may go undetected. However, if they are large enough to contain a number of important genes, they may result in "idic(15) syndrome" which is characterized by learning disabilities,
autism and other neurological symptoms.
[RJ McKinlay Gardner, Grant R. Sutherland. Chromosome Abnormalities and Genetic Counseling, 3rd Ed, Oxford University Press, New York 2004. ] One of the regions responsible for the symptoms of idic(15) syndrome is the critical PWS/AS-region named after the
Prader-Willi and/or
Angelman syndromes.
Isodicentric chromosome 15 and autism
For more than 12 years, scientists have noticed that some individuals with autism also have idic(15). In fact, idic(15) is the most frequently identified chromosome problem in individuals with
autism. (A chromosome anomaly involves extra or missing chromosomal material, not changes within the genes such as
Fragile X syndrome). It is suggested that the co-occurrence of autism and idic(15) is not by chance. There may be a gene or genes in the 15q11-q13 region that is/are related to the development of autism in some individuals.
Genetic research studies of individuals without chromosome anomalies also support this idea that an
autism-related gene may be present in 15q11.2-q13.1 Specifically, research studies found that certain
DNA markers from the (15q1.2-q13.1) region were found more often in individuals with autism than in individuals without autism. Although these DNA markers are too small to be genes, they suggest that researchers may be getting close to finding an autism gene in this region.
A recent study reported the introduction of two extra copies of just a single gene present in the 15q11.2-q13.1 region, Ube3a, into mice to model the gene copy number expressed in the brain in idic(15). These mice displayed autism-related behavioral deficits including impaired social interaction, reduced ultrasonic vocal communication, and increased repetitive behavior (self-grooming).
Diagnosis
The extra chromosome in people with idic(15) can be easily detected through
chromosome analysis (karyotyping). Additional tests are usually required. FISH (
Fluorescent in situ hybridization) is used to confirm the diagnosis by distinguishing idic(15) from other supernumerary marker chromosomes.
Array CGH Comparative genomic hybridization (CGH) is a molecular cytogenetic method for analysing copy number variations (CNVs) relative to ploidy level in the DNA of a test sample compared to a reference sample, without the need for culturing cells. The a ...
can be used to determine the gene content and magnitude of copy number variation so that the clinical picture can be foreseen.
Interstitial duplications of chromosome 15 can be more difficult to detect on a routine chromosome analysis but are clearly identifiable using a 15q FISH study. Families should always discuss the results of chromosome and FISH studies with a
genetic counselor
Genetic counseling is the process of investigating individuals and families affected by or at risk of genetic disorders to help them understand and adapt to the medical, psychological and familial implications of genetic contributions to disease; t ...
or other genetics professionals to ensure accurate interpretation.
Screening
In general, idic(15) occurs
de novo but the parents must be karyotyped to make sure it is not inherited, mostly because this will affect the course of
genetic counseling given to the family. If the abnormality is found prenatally and one of the parents harbour the marker, the child has a chance of not carrying the mutation. Further tests should however be done to prove the marker has not been rearranged while being inherited. This information is also necessary for counseling of future pregnancies. Each family is unique and should therefore be handled individually.
Management
At the present time, there is no specific treatment that can undo any chromosomal abnormality, nor the genetic pattern seen in people with idic(15). The extra chromosomal material in those affected was present at or shortly after
conception, and its effects on brain development began taking place long before the child was born. Therapies are available to help address many of the symptoms associated with idic(15). Physical, occupational, and speech therapies along with special education techniques can stimulate children with idic(15) to develop to their full potential.
In terms of medical management of the symptoms associated with Chromosome 15q11.2-q13.1 Duplication Syndrome, families should be aware that individuals with chromosome 15 duplications may tolerate medications differently and may be more sensitive to side effects for some classes of medications, such as the
serotonin reuptake inhibitor
A serotonin reuptake inhibitor (SRI) is a type of drug which acts as a reuptake inhibitor of the neurotransmitter serotonin (5-hydroxytryptamine, or 5-HT) by blocking the action of the serotonin transporter (SERT). This in turn leads to incre ...
type medications (SSRI).
Thus, these should be used with caution and any new medication should be instituted in a controlled setting, with slow titration of levels and with a clear endpoint as to what the expected outcome for treatment is.
There is an increased risk of sudden, unexpected death among children and adults with this syndrome. The full cause is not yet understood but it is generally attributed to SUDEP (Sudden Unexplained Death in Epilepsy).
Epidemiology
About half of all 'marker' chromosomes are idic(15) but idic(15) in itself is one of the rare chromosome abnormalities. Incidence at birth appears to be 1 in 30,000
with a sex ratio of almost 1:1; however, since dysmorphic features are absent or subtle and major malformations are rare, chromosome analysis may not be thought to be indicated, and some individuals, particularly in the older age groups, probably remain undiagnosed.
There are organizations for families with idic(15) children that offer extensive information and support.
Research
![Dup15q EEG signature](https://upload.wikimedia.org/wikipedia/commons/e/e0/Dup15q_EEG_signature.png)
Patients with idic(15) and int dup(15) often feature a distinctive
electroencephalography (EEG) signature or
biomarker
In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, p ...
in the form of high amplitude spontaneous
beta frequency (12–30 Hz) oscillations. This EEG signature was first noted as a qualitative pattern in clinical EEG readings and was later described quantitatively by researchers at the
University of California, Los Angeles
The University of California, Los Angeles (UCLA) is a public land-grant research university in Los Angeles, California. UCLA's academic roots were established in 1881 as a teachers college then known as the southern branch of the California S ...
and their collaborators within the network of national Dup15q clinics.
This group of researchers found that beta activity in children with Dup15q syndrome is significantly greater than that observed in (1) healthy, typically developing children of the same age and (2) children of the same age and
IQ with autism not caused by a known genetic disorder (i.e., nonsyndromic ASD). The EEG signature appears almost identical to beta oscillations induced by
benzodiazepine drugs that modulate
GABAA receptors, suggesting that the signature is driven by overexpression of duplicated GABA
A receptor genes ''
GABRA5
Gamma-aminobutyric acid (GABA) A receptor, alpha 5, also known as GABRA5, is a protein which in humans is encoded by the ''GABRA5'' gene.
Function
GABA is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABAA recept ...
'', ''
GABRB3
Gamma-aminobutyric acid receptor subunit beta-3 is a protein that in humans is encoded by the ''GABRB3'' gene. It is located within the 15q12 region in the human genome and spans 250kb. This gene includes 10 exons within its coding region. Due to a ...
'', and ''
GABRG3
GABAA receptor-γ3, also known as GABRG3, is a protein which in humans is encoded by the ''GABRG3'' gene.
Function
GABRG3 is a subunit of the GABAA receptor for the neurotransmitter gamma-Aminobutyric acid ( GABA).
Association with alcoholism ...
'' found on 15q11.2-q13.1. Treatment monitoring and identification of molecular disease mechanisms may be facilitated by this biomarker.
See also
*
marker chromosome 15 syndrome
References
External links
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Genetic disorders with no OMIM