Dup15q

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 (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 (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 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. GABRA5, GABRB3, and GABRG3 encode the α₅, β₃, and γ₃ 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 (EEG) signature or biomarker 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 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 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.