Autism and Chromosome 15
About one in every 10,000 babies is born with two few or too many genes on chromosome 15. The likelihood that these babies will be on the autism spectrum is as high as 80%, making these rare genetic events a target for autism research.
Gene targets. Of the estimated 30,000 genes that make up the human genome, between 700-900 genes lie on chromosome 15. Specific segments of this chromosome are associated with autism, narrowing the number of genes of interest to fewer than 30. These genes are located on the long arm of chromosome 15, called q. The most studied region so far is known as 15q11-13, where 11-13 describes an exact physical location on the chromosome (the region in red in the picture). Sometimes babies will have extra copies within this area, beyond the normal two parental 15q11-13 regions, resulting in 3, 4, 5, or even 6 extra copies of all the genes in the duplicated region. In other cases, portions of this region are deleted, leaving no copies of these genes.
How do chromosome copy variations occur? Autism Speaks interviewed a key researcher, Dr. Carolyn Schanen, in an article ‘Understanding the Role of Chromosome 15 in Autism’, that explains these events in detail (link to e-Speaks). The basic concept is that, during cell division, the DNA sequences of our chromosomes literally break apart and recombine; during this process, sometimes there is an aberrant duplication of genetic material. Some forms of 15q11-13 duplications are inherited and some occur in the child and are not found in the parents. Sorting out all of the possibilities is one of the goals of the research of 15q duplication and deletions.
Overlapping syndromes in 15q11-13. Deletions of genes in the 15q11-13 region are associated with Angelman’s Syndrome or Prader-Willi Syndrome, whereas duplication of such genes results in a different syndrome (15q11-13 Duplication Syndrome). A syndrome is named when common physical features or behaviors are observed. Prader-Willi occurs in about 1 in every 10,000 births and is characterized by hypotonia, hyperphagia (obsessive eating = characteristic weight gain) and diagnosis of an Autism Spectrum Disorder (ASD) in 25-45% of individuals. The occurrence of Angleman Syndrome is about 1/12,000 and is characterized by sleep disturbance, ataxia (unstable walking), frequent laughter, excitable personality and hand flapping movements. ASD is also linked with this syndrome.
Babies with 15q11-13 duplications typically have hypotonia (low muscle tone), minor facial differences (nose, eyes, ears), intellectual disability and are diagnosed with autism spectrum disorder. Seizures can be present in the newborn or develop later resulting in epilepsy that is hard to control, and sometimes lethal.
What are these genes doing? A gene’s job is to be a faithful blueprint of information, such as the code for the production of a protein. The level of production of any particular protein is carefully regulated by the cell and irregularities in the levels of proteins can impair cell function, or even lead to cell death.
For example, the product of gene UBE3A in the 15q11-13 region is involved in targeting proteins to be broken down (degraded) within cells and deficits are linked to brain pathology in both Angelman’s Syndrome and autism. Another gene in the region, called ABPA2, makes a protein crucial in getting neurotransmitters out of neurons. And the CHRNA7 gene is an acetylcholine receptor that mediates fast signal transmission at synapses. The general idea is that too little of these gene products would be linked to low muscle tone and ataxia. A new report from an international group shows that deletion of genes at 15q13.3 is linked to epilepsy. Three genes in the 15q11-13 region make protein subunits that need to aggregate with other subunits to form the receptor for the brain’s main inhibitory neurotransmitter, GABA. The extra copies are thought to create an unstable receptor and the lack on inhibition leads to excessive cell firing (seizures). Researchers are just beginning to measure gene products in brain cells of those with 15q duplications.
Changes in the brain. A special project evolved to thoroughly examine postmortem brain tissue of young adults and children with 15q duplications. In 2006, sudden deaths in otherwise healthy individuals with 15q duplications created a concern about mortality risk in these families (Isodicentric 15q Exchange Advocacy and Support– IDEAS) posted a Physician Advisory on their site at to provide information to concerned parents. The group also encouraged families to request an autopsy in the event of death as well as brain donation to the Autism Speaks’ Autism Tissue Program (ATP). Since then there have been 10 brain donations and in collaboration with the New York Institute for Basic Research, this tissue has been made available for research. The preliminary results show a disorganization of cell production and placement. The arrow in this picture of a brain section of a preadolescent boy shows a whole extra row of cells that are not typically seen in a region of the hippocampus termed the dentate gyrus, an area of the brain associated with memory and attention functions. Disturbances of brain architecture like this are linked to alterations in brain cognitive function, and often to seizure activity.
Many more changes have been observed that will be described as the research continues. The goal is to link anatomical changes to specific types of gene copy variations and behavioral characteristics linked to autism that include social deficits, communication deficits, ritualistic behaviors, mental retardation, aggression, anxiety, epilepsy, sensory abnormalities, sleep disorder as well as unique abilities. These behaviors are generated by the brain and it will take time, effort and funds to keep up with the discovery of syndromes identified by chromosome copy variations (an abnormal number of chromosomes is called aneuploidy) and the particular characteristics of those with the disorders and the patterns of brain changes seen by researchers.
This understanding of how genes contribute to physical features and behavioral characteristics requires ongoing support by dedicated families who are partnering with scientists to help better understand their child’s disorder. With increased understanding of the underlying biological processes, we may someday be able to develop treatments that can significantly reduce the impairments associated with these conditions. Contribution of biomaterial resources like DNA and brain donation is vital to this effort.
Additional reading. An excellent open access article by another of the science advisors, Agatino Battaglia, is http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2613132. Brain research papers by investigators focused on autism and related disorders are posted on www.atpportal.org.
Autism Speaks’ Autism Tissue Program supports specialized neuropathology research by providing approved scientists access to the most rare and necessary of resources, post mortem human brain tissue. We wish to recognize the commitment and generosity by our ATP donor families. More information can be found at www.autismtissueprogram.org or call 877-333-0999 for information or to initiate a brain donation.