Two new case studies highlight how complex rearrangements of chromosome 15 can lead to different disorders, including autism and the related disorder Prader-Willi syndrome.
The 15q11-13 chromosomal region contains a number of DNA repeats. These can bind together, causing the chromosome to break and rejoin at different points. As a result, the region is highly susceptible to copy number variations — large duplications or deletions of DNA.
What’s more, some genes in the region, such as the autism candidate UBE3A, are expressed only from the maternally derived chromosome, whereas others are expressed only from the paternal copy.
Deletions of the maternally derived region lead to the autism-like disorder Angelman syndrome, which is characterized by developmental delay, seizures and a happy demeanor. Deletions of the paternal region result in Prader-Willi syndrome, which leads to low muscle tone, cognitive disability and severe, chronic hunger. Duplications of the maternal region are linked to autism.
There is also variability in the type of maternal duplication. The most commonly described version generates a large duplication that makes up an extra chromosome. However, researchers are identifying smaller, interstitial, duplications. These may be more common that previously believed, as children with interstitial duplications have relatively mild symptoms and so may not be referred for genetic testing, researchers say.
The first new study, published in the October issue of the American Journal of Medical Genetics B, describes a Brazilian boy who has unusual interstitial repeats in the maternal copy of 15q11-131. The boy has three copies of the region between 15q11.2 and 15q13.2 and two copies of the section between 15q13.2 and 15q13.3. The triplication includes UBE3A and GABRB3, which inhibits brain signals and has been implicated in autism.
The boy has developmental delay, intellectual disability, unusual facial features and epilepsy. He was diagnosed with autism using the Autism Behavior Checklist, the Childhood Autism Rating Scale and the Vineland Adaptive Behavioral Scales. The researchers did not use the Autism Diagnostic Observation Schedule as a Brazilian version was not available at the time of the study, they say.
The second study, published in the October issue of the American Journal of Medical Genetics A, describes an infant girl who has three interstitial copies of the 15q11-13 region on the maternal chromosome2. One of these is the paternal copy, which is joined on to the maternal chromosome, resulting in a lack of this region on the paternal chromosome.
The infant has poor muscle tone, makes few spontaneous movements and has some abnormal facial features. She is diagnosed with Prader-Willi syndrome, but is likely to develop symptoms of autism later in life, the researchers say.
1: Christofolini D.M. et al. Am. J. Med. Genet. B Neurospsychiatric Genet. 159B, 823-838 (2012) PubMed
2: Burrage L.C. et al. Am. J. Med. Genet. A. 158A, 2557-2563 (2012) PubMed