Acute health events in adult patients with genetic disorders: The Marshfield Epidemiologic Study Area

Novel Insight Into Chromosome 21 And Its Effect On Down Syndrome

A UCL-led research team has, for the first time, identified specific regions of chromosome 21, which cause memory and decision-making problems in mice with Down syndrome, a finding that provides valuable new insight into the condition in humans.

Most people have 46 chromosomes in each cell, divided into 23 pairs: people with Down syndrome (DS) have an extra copy of chromosome 21, which carries over 200 genes.

In this study, published in Cell Reports, researchers at UCL, supported by Cardiff University and the Francis Crick Institute, used mouse models to try and find out how having these extra genes causes learning disability.

Chromosome 21 and its genes are also found in mice, although the genes have dispersed onto three smaller regions on three different mouse chromosomes. These are mouse chromosomes 16, 10 and 17 containing 148 genes, 62 genes and 19 genes respectively.

The researchers looked at the effect of the genes in each of these three different mouse regions (chromosomes) on learning and memory. To do this three different mouse strains (groups of mice), were genetically modified to carry an extra copy of one of the gene groups on mouse chromosomes 16, 10 or 17.

During navigation tests, where mice needed to negotiate a simple 'left-right' T-maze, each group was measured for both memory and decision-making ability.

During these tests, the electrical activity of brain regions important for memory and decision making was also monitored, using an electroencephalogram (EEG).

The researchers found that one of the mouse strains ('Dp10Yey' mice) had worse memory, and had irregular brain circuity (signals) in a part of the brain called hippocampus -- which is known to be very important for memory.

They also found another strain ('Dp1Tyb' mice) had worse decision-making ability and had poor brain signalling between the hippocampus and the pre-frontal cortex -- needed for planning and decision-making. And the third strain ('Dp17Yey' mice) had no unusual electrical activity in the brain.

Co-author, Professor Matthew Walker (UCL Queen Square Institute of Neurology), said: "These findings are a complete surprise -- we did not expect the three different gene groups would act completely differently.

"Scientists have traditionally worked on the hypothesis that a single gene, or single genes, was the likely cause of intellectual disabilities associated with Down syndrome.

"We have shown -- for the first time -- that different and multiple genes are contributing to the various cognitive problems associated with Down syndrome."

Researchers will now look to discover specifically which gene or genes, within the smaller gene groups, are responsible for impaired memory and decision-making.

Corresponding author Professor Elizabeth Fisher (UCL Queen Square Institute of Neurology) said: "Our study provides critical insights into the mechanisms underlying neuro-disability in Down syndrome and indicates that intellectual disability in Down syndrome may result from different underlying genetic, functional and regional brain abnormalities.

"This implies that therapies for people with Down syndrome should perhaps target multiple processes, and we have made the initial steps in identifying what some of these processes are."

Note: Mouse strains Dp1Tyb, Dp10Yey and Dp17Yey were genetically modified to carry an extra copy of one of the gene groups on mouse chromosomes 16, 10 and 17 respectively.

New Chromosome Abnormality Linked To Autism Spectrum Disorders

A whole-genome DNA analysis, using sensitive new research tools to thoroughly examine the chromosomes of more than 3,000 people, reveals a section of chromosome 16 that is deleted or duplicated in some people with autism spectrum disorders (ASDs). The findings were released Online First by The New England Journal of Medicine on January 9, 2008.

The analysis--representing the largest, most complete genome scan for ASDs to date--was completed in October using three independent data sources. One analysis, using stored DNA samples from a national research repository known as the Autism Genome Research Exchange (AGRE), was conducted by the Autism Consortium, a collaboration involving 14 leading universities and medical centers, including Children's Hospital Boston.

An independent analysis at Children's Hospital Boston, using clinical samples from its own patients, provided real-world validation and extended the findings. Findings were also replicated by deCODE Genetics, Inc. In Iceland.

The Autism Consortium researchers scanned DNA samples from more than 3,000 children and families, of whom 1,441 were diagnosed with an ASD. Five individuals with ASDs had a chromosome 16 deletion. The deCODE team found the same deletion in three of 299 people.

The Children's researchers, using a high-resolution genomic copy-number variant analysis technique, designed by the hospital's laboratory team for clinical use, tested close to 1,000 patient samples and found five more instances of the deletion among 512 patients referred for developmental delay and/or suspected ASDs.

In addition, the Children's team identified four patients with a duplication, rather than a deletion, of the chromosome 16 region, a seeming paradox that is not uncommon in genetics.

"Genes may need to be expressed at exactly the right level within particular tissues," says David Miller, MD, PhD, assistant director of the Genetics Diagnostic Laboratory at Children's and a coauthor on the paper. "Expressing them at half of the normal amount within the cells, or twice the normal amount, can throw things out of balance within a cell, especially if they're involved in a complicated network where they're interacting with other genes."

The chromosome 16 deletion/duplication accounts for an estimated 1 percent of autism cases, adding to the roughly 15 percent of cases of autism with known genetic causes, says Miller, who is also a clinical geneticist and a member of the Consortium.

"I don't think we're going to find one cause that explains 50 percent of autism," Miller notes. "It's going to be an incremental process. Even if it's 1 percent at a time, that's still progress. And we'll eventually get to the point where we can figure out what's going on in each particular family, and help them figure out their chances of having another child affected with autism."

Bai-Lin Wu, PhD, director of Children's Genetics Diagnostic Laboratory, one of the two senior authors on the study, and a Consortium member, notes that the findings have direct and immediate application in evaluating children for developmental delay and autism. "We are gratified that our research observations have jumped the gap to the clinic and become part of the diagnostic testing we offer to patients," he says.

ASDs are diagnosed in as many as 1 in 150 children under the age of three. Symptoms can range from mild to severe and can include social, cognitive and behavioral deficits. Genetic causes have been difficult to identify for many reasons. ASDs are difficult to diagnose accurately, published studies use different criteria for defining them, and ASDs are complex conditions with many potential genetic causes, making it hard to pinpoint any single one.

The Children's team used a high-resolution genomic copy-number variant analysis to identify the chromosome 16 deletion/duplication. Very high-resolution microarrays such as this one, capable of spotting very small missing or extra pieces of DNA, have only become available within the past 6 to 8 months.

Other research teams have identified chromosome 16 deletions in patients with autism, but the new study is largest to date; confirmed its findings independently in three populations, including a group of current patients that can be studied further; identified patients with both duplications and deletions; and provides the most precise genetic information, identifying a very narrow region of chromosome 16 that is altered.

The chromosome 16 region that is missing or duplicated contains some 25 genes whose function is not yet known. But it is small enough that researchers at Children's can go back and study their nine patients more thoroughly, in hopes of understanding the role of that stretch of DNA and how its deletion or duplication affects brain function. Similar studies are planned by other Consortium members.

"We don't know from this study which of those genes is the critical one, or whether abnormalities in more than one of the genes are causing autism," says Christopher Walsh, MD, PhD, chief of Genetics at Children's, chair of the Autism Consortium Advisory Board, and consortium member, and a coauthor on the study. "Since these children are in our backyard, we can go back and ask them more questions and learn more about them."

"It is rare to have the opportunity to take information from a large database such as AGRE and then be able to quickly verify your findings among a group of children under clinical care at an affiliated hospital which has state-of-the art technology," says study leader Mark J. Daly, PhD, an Autism Consortium member with the Center for Human Genetic Research and the Department of Medicine at Massachusetts General Hospital and a senior associate member of the Broad Institute of Massachusetts Institute of Technology and Harvard.

In the majority of cases the chromosome 16--deletion occurred de novo, meaning that it was not inherited from a parent, but instead occurred during embryonic development. This information is helpful in counseling families because it suggests that the chances of another child in the family having autism are small, perhaps five percent rather than 50 percent if the trait is inherited from parent, Miller says. "We would need to have more data from more individuals before we could give families an exact number," he adds.

The discovery of the chromosome 16 abnormality was made possible by new, highly sensitive chromosome scanning technology based on microarrays from Affymetrix (NASDAQ: AFFX) and Agilent Technologies (NYSE: A). "The ability to do these very high-resolution microarrays to look for very small missing or extra pieces of DNA is very new," says Wu.

"The resolution has evolved to the point that we can find such small pieces and find them reliably just within the last six to eight months," adds coauthor Yiping Shen, PhD, director of R&D at the Children's Genetics Diagnostic Lab.

Brain Imaging Links Language Delay To Chromosome Deletion In Children ...

Children born with a DNA abnormality on chromosome 16 already linked to neurodevelopmental problems show measurable delays in processing sound and language, says a study team of radiologists and psychologists.

By strengthening the case that the deleted gene disrupts a key biological pathway, the research may lay the foundation for future medical treatments for specific subtypes of autism, along with cognitive and language disabilities.

"This study shows an important connection between gene differences and differences in neurophysiology," said study leader Timothy P.L. Roberts, Ph.D., vice chair of Radiology Research at The Children's Hospital of Philadelphia (CHOP) and a researcher at CHOP's Center for Autism Research. "It may also help to bridge a largely unexplored gap between genetics and behavior."

Roberts, who holds the Oberkircher Family Endowed Chair in Pediatric Radiology at CHOP, led the study published online Feb. 11 in Cerebral Cortex, collaborating with a group led by Elliott H. Sherr, M.D., Ph.D., of the University of California, San Francisco (UCSF).

The researchers examined children with copy number variants -- either deletions or duplications¬ of DNA -- at the genetic site 16p11.2. Previous researchers had found that this location on chromosome 16 was associated with a subset of autism spectrum disorders (ASDs) and with language impairments and developmental delays.

Roberts and colleagues used magnetoencephalography (MEG), which detects magnetic fields in the brain, just as electroencephalography (EEG) detects electrical fields. As each child heard a series of tones, the MEG machine analyzed changing magnetic fields in the child's brain, measuring an auditory processing delay called the M100 response latency.

The researchers analyzed 115 children: 43 with the 16p11.2 deletion, 23 with the 16p11.2 duplication, and 49 healthy controls. The children were from two centers, CHOP and UCSF. Only a fraction of the children had ASD diagnoses: 11 of the 43 with the deletion, and 2 of the 23 with the duplication.

In children with the deletion, the researchers found a significant delay: 23 milliseconds (ms), a figure that Roberts called "stunningly high" compared to the healthy children. There was no such delay among children with the duplication, who actually had a non-significant tendency to process sounds faster than the control subjects.

The 23-ms delay, about one-fortieth of a second, was twice as high as the 11-ms M100 delay that Roberts found in a 2010 MEG study of children with ASDs. In that study, Roberts remarked that 11 milliseconds is a brief interval, but that it meant that a child hearing the word 'elephant' would still be processing the 'el' sound while other children moved on, with delays cascading as a conversation progresses.

While the 2010 study focused on children diagnosed with ASDs, Roberts added, the current study took a "genetics first" approach, analyzing children known to have genetic variants with or without ASD diagnoses. "We have approached the problem from both ends," he said. The previous study found a link between the brain and behavior, while this new study found a link between genetics and the brain."

Although not all of the children with CNVs had autism, all of them had some neurological or learning disabilities, he added. Because the severity of neurodevelopmental symptoms did not correlate with the length of the auditory processing delay, the M100 delay may not become a clear-cut diagnostic biomarker in neurological disorders, but it may be a clue to an important common pathway in neurobiology.

"We don't yet know the significance of the 23-millisecond delay, but we have established its origin in genetics," Roberts said. "It seems to be a proxy for something of biological significance." He noted that this finding meshes with a current research strategy articulated by the National Institutes of Health -- focusing on research domains criteria in neurological diseases. Because ASDs and mental disorders are very diverse and heterogeneous, involving many different genes, a research domains approach seeks to discover genes that may overlap differing disorders but operate on common biological pathways and processes.

Further studies, said Roberts, will investigate other genes previously implicated in ASDs and other psychiatric disorders, to determine whether they also involve M100 response delays. "Our goal is to unify diverse genes along a few common pathways, some of which may be treatable with specific therapies," said Roberts.

He added that his laboratory is planning a very small pilot study of children with ASDs who have the M100 response latency. Using a drug that acts on synaptic transmissions (signals across nerve cells), he will analyze whether this drug reduces the M100 auditory delays.

This research is at an early stage, Roberts stressed, adding that the biological mechanisms underlying the chromosome deletion and auditory delays remain undiscovered. "We don't know, for instance, whether the abnormality that leads to the delay happens at the synapses or in the brain's white matter, which acts as highway for carrying brain signals. Our next studies may help answer that question."

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