Genetic counseling for pre-implantation genetic testing of monogenic disorders (PGT-M)
Missing Gene May Be Key To Autistic-Like Behavior In Disorder
Researchers at the UC San Diego School of Medicine have developed a mouse model that connects the genetic defects of Jacobsen syndrome to effects on brain function consistent with autism disorders.
About half of children with Jacobsen syndrome experience social and behavioral issues consistent with autism disorders.
"While this study focused on mice with a specific type of genetic mutation that led to autism-like symptoms, these findings could lead to a better understanding of the molecular mechanisms underlying other autism spectrum disorders, and provide a guide for the development of new potential therapies," said study co-author Paul Grossfeld, MD, clinical professor of pediatrics at UC San Diego School of Medicine and pediatric cardiologist at Rady Children's Hospital-San Diego.
The study also found the anti-anxiety drug clonazepam reduces autistic features in the Jacobsen syndrome mice.
Jacobsen syndrome is a rare genetic disorder in which a child is born missing a portion of one copy of chromosome 11.
The gene loss can lead to multiple clinical challenges, such as congenital heart disease, intellectual disability, developmental and behavioral problems, slow growth and failure to thrive.
Previous research by Grossfield and others suggested that PX-RICS, the dominant isoform expressed in nervous system development, might be the missing chromosome 11 gene in children with Jacobsen syndrome.
Researchers at the University of Tokyo found PX-RICS to be the most likely gene responsible for autism-like symptoms in Jacobsen syndrome.
They found mice without PX-RICS were less social and more apathetic to other mice. They also spent twice as much time on repetitive behaviors than mice with the gene and were less able to adapt to new situations. They found mice lacking PX-RICS were also deficient in GABAAR, a protein crucial for normal neuron function.
PX-RICS-deficient mice treated with clonazepam, which works by boosting GABAAR, behaved almost normally in social tests, experienced improvements in learning performance and were better able to deviate from established habits.
"We now hope in the future to carry out a small pilot clinical trial on people with Jacobsen syndrome and autism to determine if clonazepam might help improve their autistic features," Grossfeld said.
Study co-authors include Tsutomu Nakamura, Fumiko Arima-Yoshida, Fumika Sakaue, Yukiko Nasu-Nishimura, Yasuko Takeda, Ken Matsuura, Toshiya Manabe, Tetsu Akiyama, University of Tokyo; Natacha Ackshoomoff, UC San Diego; and Sarah Mattson, San Diego State University.
Chromosomal Abnormalities - News-Medical.net
Chromosomal abnormalities, alterations and aberrations are at the root of many inherited diseases and traits. Chromosomal abnormalities often give rise to birth defects and congenital conditions that may develop during an individual's lifetime. Examining the karyotype of chromosomes (karyotyping) in a sample of cells can allow detection of a chromosomal abnormality and counselling can then be offered to parents or families whose offspring are at risk of growing up with a genetic disorder.
Types of chromosomal abnormalityA chromosomal abnormality may be numerical or structural and examples are described below:
Numerical abnormalitiesThe normal human chromosome contains 23 pairs of chromosomes, giving a total of 46 chromosomes in each cell, called diploid cells. A normal sperm or egg cell contains only one half of these pairs and therefore 23 chromosomes. These cells are called haploid.
The euploid state describes when the number of chromosomes in each cell is some multiple of n, which may be 2n (46, diploid), 3n (69, triploid) 4n (92, tetraploid) and so on. When chromosomes are present in multiples beyond 4n, the term polyploid is used.
Aneuploidy refers to the presence of an extra chromosome or a missing chromosome and is the most common form of chromosomal abnormality. In the case of Down's syndrome or Trisomy 21, there is an additional copy of chromosome 21 and therefore 47 chromosomes. Turner's syndrome on the other hand arises from the absence of an X chromosome, meaning only 45 chromosomes are present.
Occasionally, aneuploid and regular diploid cells exist simultaneously and this is called mosaicism. The condition involves two or more different cell populations from a single fertilized egg. Mosaicism usually involves the sex chromosomes, although it can involve autosomal chromosomes.
In contrast to mosaicism, a condition called chimaerism occurs when different cell lines derived from more than one fertilized egg are involved.
Structural abnormalitiesStructural abnormalities occur when the chromosomal morphology is altered due to an unusual location of the centromere and therefore abnormal lengths of the chromosome's short (p) and long arm (q).
Some of the most common chromosomal abnormalities include:
What's Missing May Be Key To Understanding Genetics Of Autism - Science News
Each person with autism may have their own genetic version of the developmental disorder, a new large-scale study finds.
Rare variations in which some parts of a person's genetic blueprints have been erased or repeated are responsible for some cases of autism, the study shows. Such missing or duplicated stretches of DNA are known as copy number variations and have been implicated in schizophrenia and other diseases (SN: 4/25/09, p. 16).
The new study, published online June 9 in Nature, shows that some people with autism may be missing all or parts of one or several genes involved in the development and function of the brain. The findings could lead to improved diagnosis of the disorder, perhaps even in infants, and may give new direction to research on drug treatments.
"The exciting thing about the findings of this study is that it highlights biological pathways that can be targets for therapy," says Geraldine Dawson, chief science officer of Autism Speaks, a national organization that helped to fund the new study.
Sign up for our newsletterWe summarize the week's scientific breakthroughs every Thursday.
Autism is a group of developmental disorders that impairs social interactions and often language development. Researchers don't know the exact causes of the disorder, but genetic factors are strong suspects. Studies of identical twins show that when one twin has autism, about 90 percent of the time the other twin will too. Autism affects about one in every 100 children in the United States and is more common in boys.
Previous studies have indicated people with autism may have more copy number variants overall than healthy people do. But the new study shows that people with autism had the same number of deletions as people in a healthy control group did. However, people with autism tend to have deletions that remove parts or all of genes, while healthy people carry deletions on stretches of DNA that don't contain genes.
"You and I may have just as many deletions in our genomes, but since they don't hit genes, we don't have autism" or other diseases, says Anthony Wynshaw-Boris, a medical geneticist at the University of California, San Francisco, who was not part of the new study. "This is a natural part of being a human being. We get mutations. Most of the time it's not a problem, but sometimes it hits a gene involved in autism."
In the new study, an international consortium of researchers analyzed the genetic makeup of 996 people with autism and 1,287 people without autism to discover genetic factors that contribute to the disorder. The researchers found more than 5,000 copy number variants in people with autism, usually places where DNA was missing. Many of the people with autism had more than one spot in the genome where they were missing large chunks of DNA, each about 30,000 base pairs long.
Each of the specific variants was rare on its own, with even the most common found in less than 1 percent of people in the study. Often, people with autism inherited the rare variants from their parents, but just under 6 percent of them had new deletions not found in their parents. Such new mutations may account for some sporadic cases of autism, the researchers say.
"Most individuals with autism are genetically unique," says Stephen Scherer, a genome scientist at the Hospital for Sick Kids in Toronto and one of the leaders of the study. He says that researchers are likely to find even more copy number variants involved in autism. Some people may have larger or smaller deletions than were examined in the study.
The new work may also help settle a scientific debate about whether common diseases and disorders are caused by genetic variations present in many people, or if rare variants contribute more to these diseases. "This definitely suggests a role for rare variations in autism," says Charles Lee, a clinical cytogeneticist at Brigham and Women's Hospital in Boston and Harvard Medical School.
Although each person with autism appears to have a distinct set of genetic variations, the genes affected by the variants tend to affect similar biological processes. Further studies of the genes involved promise to give researchers a better picture of what causes autism, Wynshaw-Boris says.
Study coauthor Louise Gallagher of Trinity College in Dublin adds, "There's a whole new definition of the underlying genetic mechanisms of autism."
Some of the deleted genes had a strong link to autism, meaning that missing just a single copy is enough to push a person across the autism threshold, Scherer says. Other genes had to be inherited along with more deletions or other genetic factors for autism to develop.
Sponsor Message
One gene strongly linked to autism in the new study is called DDX53-PTCHD1, and is located on the X chromosome. Women — who have two X chromosomes — may carry a deletion of the gene on one of their X chromosomes, but a healthy copy of the gene on the other X chromosome is enough to cover for the missing copy. Problems may arise if a woman passes the X chromosome with the deleted gene on to a son. With no healthy copy of the gene (the Y chromosome doesn't carry the gene) to compensate, he will get autism.
Researchers also identified several genes involved in forming connections, called synapses, between brain cells. The genes, SHANK2, SYNGAP1, and DLGAP2, had not been linked to autism before. Genes involved in a cell-to-cell communications system known as the Ras/GTPase pathway were also found to play a role in autism.
All together, the new study identified 25 places in the genome that may help in diagnosing autism. New genetic tests would probably focus on these markers, Lee says. If a person has a deletion in one of these places, he or she may have autism, but until scientists understand more about how genetic factors work together to cause disease, no one will be able to make a definitive diagnosis, he says.
Even with the new findings, scientists are able to explain genetic causes for only about 10 percent of autism cases, says Steven McCarroll, a geneticist at Harvard Medical School. "What causes autism in the other 90 percent of cases is still on the table," he says. "Every little victory is important, but it's still amazing how little we know."
Comments
Post a Comment