Dup15q syndrome is the common name for chromosome 15q11.2-q13.1 duplication syndrome. This is a
neurodevelopmental disorder
Neurodevelopmental disorders are a group of disorders that affect the development of the nervous system, leading to abnormal brain function which may affect emotion, learning ability, self-control, and memory. The effects of neurodevelopmental ...
, caused by the partial duplication of
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 DNA ...
, that confers a strong risk for
autism spectrum disorder
The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental disorder, neurodevelopmental condition (or conditions) ...
,
epilepsy
Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrical ...
, 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 signifi ...
.
[Frohlich, Joel; Senturk, Damla; Saravanapandian, Vidya; Golshani, Peyman; Reiter, Lawrence; Sankar, Raman; Thibert, Ronald; DiStefano, Charlotte; Huberty, Scott; Cook, Edwin; Jeste, Shafali (December 2016)]
"A Quantitative Electrophysiological Biomarker of Duplication 15q11.2-q13.1 Syndrome" (PDF)
PLOS One. Retrieved 4 January 2017. It is the most common genetic cause of autism, accounting for approximately 1-3% of cases. Dup15q syndrome includes both interstitial duplications and isodicentric duplications (i.e.,
Idic15
Isodicentric 15, also called marker chromosome 15 syndrome, idic(15), partial tetrasomy 15q, or inverted duplication 15 (inv dup 15), is a chromosome abnormality in which a child is born with extra genetic material from chromosome 15. People wit ...
) of 15q11.2-13.1.
Important genes likely involved in the etiology of Dup15q syndrome include ''
UBE3A
Ubiquitin-protein ligase E3A (UBE3A) also known as E6AP ubiquitin-protein ligase (E6AP) is an enzyme that in humans is encoded by the ''UBE3A'' gene. This enzyme is involved in targeting proteins for degradation within cells.
Protein degradation ...
'', ''
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
gamma-aminobutyric acid, GABA is the major inhibitory neurotransmitter in the mammalian brain where ...
'', ''
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 ...
''. ''UBE3A'' is a ubiquitin-protein ligase that is involved in targeting proteins for degradation and plays an important role in synapse function. ''GABRA5'', ''GABRB3'', and ''GABRG3'' are gamma aminobutyric acid type A (GABA
A) receptor subunit genes and are likely important in Dup15q syndrome given the established role of GABA in the etiologies of autism and epilepsy.
Diagnosis
Genetic testing methods such as
fluorescence in situ hybridization
Fluorescence ''in situ'' hybridization (FISH) is a molecular cytogenetic technique that uses fluorescent probes that bind to only particular parts of a nucleic acid sequence with a high degree of sequence complementarity. It was developed b ...
(FISH) and chromosomal
microarray
A microarray is a multiplex lab-on-a-chip. Its purpose is to simultaneously detect the expression of thousands of genes from a sample (e.g. from a tissue). It is a two-dimensional array on a solid substrate—usually a glass slide or silicon t ...
are available for diagnosing Dup15q syndrome and similar genetic disorders.
With the increase in genetic testing availability, more often duplications outside of the 15q11.2-13.1 region are being diagnosed. The global chromosome 15q11.2-13.1 duplication syndrome specific groups only provide medical information and research for chromosome 15q11.2-13.1 duplication syndrome and not the outlying 15q duplications.
Clinical presentation
Individuals with Dup15q syndrome are at high risk for epilepsy, autism, and intellectual disability. Motor impairments are very common in individuals with the disorder. Rates of epilepsy in children with isodicentric duplications are higher than in children with interstitial duplications. A majority of patients with either duplication type (isodicentric or interstitial) have a history of gastrointestinal problems.
A study 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 St ...
(UCLA) of 13 children with Dup15q syndrome and 13 children with nonsyndromic ASD (i.e., autism not caused by a known genetic disorder) found that, compared to children with nonsyndromic autism, children with Dup15q had significantly lower autism severity as measured by the Autism Diagnostic Observation Schedule (ADOS) (all children in the study met diagnostic criteria for ASD). However, children with Dup15q syndrome had significantly greater motor impairment and impairment of daily living skills than children in the nonsyndromic ASD group. Within the Dup15q syndrome cohort, children with epilepsy had greater cognitive impairment.
Genetics
Dup15q syndrome is caused by
copy number variation
Copy number variation (CNV) is a phenomenon in which sections of the genome are repeated and the number of repeats in the genome varies between individuals. Copy number variation is a type of structural variation: specifically, it is a type of d ...
(CNV) in which extra copies of certain genes are present in the genome. Two duplication types are commonly described in Dup15q syndrome, interstitial and isodicentric. Interstitial duplications are typically partial trisomies (i.e., one extra copy of each gene) and features these extra gene copies on the Chromosome 15 alongside the "original" copies. Isodicentric duplications are typically partial tetrasomies (i.e., two extra copies of each gene) and feature an extranumerary chromosome that contains the extra genes.
Many important genes in the 15q11.2-13.1 region likely play crucial roles in the etiology of Dup15q syndrome. ''UBE3A'' is the causative gene of
Angelman syndrome
Angelman syndrome or Angelman's syndrome (AS) is a genetic disorder that mainly affects the nervous system. Symptoms include a small head and a specific facial appearance, severe intellectual disability, developmental disability, limited to no f ...
and has been associated with autism. It is involved in protein degradation via the ubiquitin pathway and also plays an important role in synaptic functioning.
[Greer, Paul L., et al. "The Angelman Syndrome protein Ube3A regulates synapse development by ubiquitinating arc." Cell 140.5 (2010): 704-716.] ''GABRA5'', ''GABRB3'', and ''GABRG3'' encode the α
5, β
3, and γ
3 subunits of GABA
A receptors, respectively. Because GABA is the principal inhibitory neurotransmitter of the human brain, it is likely that duplications of these GABA
A receptor genes affect or disrupt inhibitory neural transmission in Dup15q syndrome.
EEG biomarker
Patients with Dup15q syndrome feature a distinctive
electroencephalography
Electroencephalography (EEG) is a method to record an electrogram of the spontaneous electrical activity of the brain. The biosignals detected by EEG have been shown to represent the postsynaptic potentials of pyramidal neurons in the neocortex ...
(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, ...
in the form of high amplitude spontaneous
beta
Beta (, ; uppercase , lowercase , or cursive ; grc, βῆτα, bē̂ta or ell, βήτα, víta) is the second letter of the Greek alphabet. In the system of Greek numerals, it has a value of 2. In Modern Greek, it represents the voiced labiod ...
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 UCLA 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
Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, ...
drugs that modulate GABA
A receptors, suggesting that the signature is driven by overexpression of duplicated GABA
A receptor genes ''GABRA5'', ''GABRB3'', and ''GABRG3''. Treatment monitoring and identification of molecular disease mechanisms may be facilitated by this biomarker.
Advocacy
Dup15q Alliance is an advocacy organization in the United States for families affected by the disorder. The organization holds biannual family conferences to bring together families, as well as annual science conferences to bring together Dup15q syndrome researchers from around the world.
References
{{Reflist
External links
Dup15q AllianceIdic15 CanadaIdic15 SpainDup15q e.V. Germany Austria Switzerland
Genetics of autism
Autism spectrum disorders