Dup15q
Dup15q syndrome is the common name for maternally inherited chromosome 15q11.2-q13.1 duplication syndrome. This is a genomic copy number variant that leads to a type of neurodevelopmental disorder, caused by partial duplication of the proximal long arm of Chromosome 15. This variant confers a strong risk for autism spectrum disorder, epilepsy, and intellectual disability. 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 of 15q11.2-13.1.
Important genes likely involved in the etiology of Dup15q syndrome include UBE3A, GABRA5, GABRB3, and GABRG3. 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 receptor subunit genes and are likely important in Dup15q syndrome given the established role of GABA in the etiologies of autism and epilepsy.
Diagnosis
methods such as fluorescence in situ hybridization and chromosomal microarray 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 have a history of gastrointestinal problems.A study at the University of California, Los Angeles of 13 children with Dup15q syndrome and 13 children with nonsyndromic ASD found that, compared to children with nonsyndromic autism, children with Dup15q had significantly lower autism severity as measured by the Autism Diagnostic Observation Schedule . 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 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 and features these extra gene copies on the Chromosome 15 alongside the "original" copies. Isodicentric duplications are typically partial tetrasomies 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 GABAA receptors, respectively. Because GABA is the principal inhibitory neurotransmitter of the human brain, it is likely that duplications of these GABAA receptor genes affect or disrupt inhibitory neural transmission in Dup15q syndrome.