Posts tagged intellectual disability
Articles and news from the latest research reports.
Gene Technique Identifies Hidden Causes of Brain Malformation
Howard Hughes Medical Institute (HHMI) scientists have developed a strategy for finding disease-causing mutations that lurk in only a small fraction of the body’s cells. Such mutations can cause significant problems, but cannot be detected with traditional methods of genetic testing, as well as newer, more costly genome sequencing technologies.
The scientists report in the August 21, 2014, issue of the New England Journal of Medicine, that they used the technique to find disease-causing mutations in patients with brain malformations whose genetic causes were unknown despite previous testing.
By sequencing hundreds of copies of the genes in a panel of candidate genes, scientists led by HHMI investigator Christopher A. Walsh identified somatic mutations—gene mutations present in some, but nor all, cells – in more than a quarter of patients that could be successfully diagnosed genetically. Walsh and his colleagues, including Saumya Jamuar, a clinical fellow in Walsh’s lab at Boston Children’s Hospital who is now at the KK Women’s and Children’s Hospital in Singapore and Timothy Yu, also at Boston Children’s Hospital, were authors of the study.
Walsh says his team was surprised to discover so many somatic mutations in patients who had already undergone genetic testing. “This tells us just how poorly other methods perform in detecting somatic mutations,” he says. “You’re not going to find these things unless you go looking for them—unless you have a clinical test that is set up to detect them in a sensitive way.”
Somatic mutations are not inherited from parents, but instead, arise sometime after fertilization. They are most often seen in some forms of cancer, in which genetic differences between tumor cells and the rest of the body drive tumor growth and metastasis. But they’ve been implicated in other diseases, as well.
“Somatic mutations have been discovered to cause milder forms of a wide range of diseases, especially neuropsychiatric ones,” Walsh says, citing as examples Rett syndrome and tuberous sclerosis, two disorders that cause seizures and intellectual disability. In his own lab, he had found that some of his patients with double cortex syndrome, a brain malformation that can cause some of the same kinds of neurological problems, have somatic mutations. And in a new study published August 21, 2014, in Cell Reports, Walsh’s team analyzed the genomes of individual cells in healthy and diseased brains and found that large segments of DNA had been duplicated or deleted in most cells. “No neuron’s genome is pristine,” he says. “There’s a lot of variability, and some of these mutations have occurred at a stage where they’re present in more than one cell.”
“We think these somatic mutations are probably more common as causes of intellectual disability, and maybe even some psychiatric conditions, than people have generally realized.” Walsh says. “It’s really time to start investigating that systematically.”
He decided to begin with his own patients. A genetic diagnosis is important for counseling patients and their parents about risks to future children, and can, in some cases, influence treatment decisions. But many patients who had come to Walsh’s lab with neurodevelopmental problems were still without answers. “We’d successfully identified causative mutations in many families. But there remained a subset where—even after 10 or more years of searching—we had been unable to identify the causative genes. This made us wonder whether there might be certain kinds of mutations not well discovered by present methods,” he says.
Walsh’s team questioned whether it had missed somatic mutations in those patients by using traditional methods of genetic testing? It seemed possible. Those techniques are not designed to find mutations that occur only in a small fraction of cells, Walsh says. “Even if you are looking at the right gene, you can still miss the mutation.”
Most diagnostic gene testing is done by sequencing specific genes using a traditional DNA sequencing technique known as the Sanger method. When this strategy fails, the search for mutations is sometimes broadened to all of the protein-coding regions of the genome—the exome—or further, to the entire genome. Both approaches have limitations, Walsh says.
“Whole-exome sequencing tends to sample the genome about 30 or 50 times over,” he explains. “But if a mutation is only in five or 10 percent of the cells, then it’s only going to be in a very small fraction of the data, and it’s hard to separate from the noise. The same is true of Sanger sequencing: it has not been optimized to detect a mutation that’s present in a small fraction of the reads.”
To find the kinds of mutations they were looking for, Walsh’s team knew they would have to deepen their search. They devised a strategy in which they would use next-generation sequencing technology to sequence a panel of genes known or suspected to be associated with brain malformations. “We said we’d shoot to sequence them a thousand times over,” Walsh says. “Even if a mutation is only present in five percent of the cells, it will be obvious that it’s a mutation, because we’ll see that mutation 50 times.”
Jamuar set up a test to screen blood samples from 158 patients whose brain malformations remained unexplained. For each patient, a panel of 14 or 54 genes (depending on the patient’s condition) was sequenced hundreds or thousands of times. The design of the panel and sequencing took about 2-3 months to carry out. He then fine-tuned existing bioinformatics algorithms to search for somatic mutations in the sequences. Though the initial sequencing was fast, follow-up validation of potential somatic mutations took additional months because it remains labor-intensive.
In this way, the team uncovered mutations likely to cause disease—either because their role was already known or because they disrupted protein function—in 27 of the 158 patients in their study. Eight of these were somatic mutations, present in just five to 35 percent of the sequenced DNA. Jamuar confirmed these sequencing findings with laboratory experiments in which the patients’ DNA was replicated in bacterial cells and analyzed by Sanger sequencing.
“We have a genetic diagnosis. This ends the diagnostic odyssey for these eight individuals,” says Jamuar.
Five of the eight somatic mutations that they identified would never have been found with traditional sequencing methods, the scientists say. “All of the mutations that were present at less than about 15 percent of the reads were completely undetectable by Sanger sequencing,” Walsh says. “One of them had been missed by whole-exome sequencing, as well.”
“The gold standard of clinical diagnosis is Sanger sequencing,” Jamuar adds. “But you’re missing a big chunk of patients with mutations in these genes, because you are using a test that’s not designed to look for them.”
Now that they have demonstrated their method’s sensitivity in detecting somatic mutations, Walsh and Jamuar say medical geneticists should consider using the approach before turning to more costly whole-exome sequencing. Neither offers a single solution for all patients, but their complementary strengths give geneticists a more complete set of tools. “Look deep, and you may find the answer,” says Jamuar.
Researcher discovers two new genes linked to intellectual disability
Researchers at the Centre for Addiction and Mental Health have discovered two new genes linked to intellectual disability, according to two research studies published concurrently in early March in the journals Human Genetics and Human Molecular Genetics.
“Both studies give clues to the different pathways involved in normal neurodevelopment,” says CAMH Senior Scientist Dr. John Vincent, who heads the MiND (Molecular Neuropsychiatry and Development) Laboratory in the Campbell Family Mental Health Research Institute at CAMH. “We are building up a body of knowledge that is informing us which kinds of genes are important to, and involved in, intellectual disabilities.”
In the first study, Dr. Vincent and his team used microarray genotyping to map the genes of a large consanguineous (intermarriage within the extended family) Pakistani family, in which five members of the youngest generation were affected with mild to moderate intellectual disability. Dr. Vincent identified a truncation in the FBXO31 gene, which plays a role in the way that proteins are processed during neuronal development, particularly in the cerebellar cortex.
In the second study, using the same techniques, Dr. Vincent and his team analyzed the genes of two consanguineous families, one Austrian and one Pakistani, and identified a disruption in the METTL23 gene linked to mild recessive intellectual disability. The METTL23 gene is involved in methylation—a process important to brain development and function.
About one per cent of children worldwide are affected by non-syndromic (i.e., the absence of any other clinical features) intellectual disability, a condition characterized by an impaired capacity to learn and process new or complex information, leading to decreased cognitive functioning and social adjustment. Although trauma, infection and external damage to the unborn fetus can lead to an intellectual disability, genetic defects are a principal cause.
These studies were part of an ongoing study of affected families in Pakistan, where the cultural tradition of large families and consanguineous marriages among first cousins increases the likelihood of inherited intellectual disability in offspring.
“Although it is easier to find and track genes in consanguineous families, these genes are certainly not limited to them,” Dr. Vincent points out. A recent study estimated that 13–24 per cent of intellectual disability cases among individuals of European descent have autosomal recessive causes, meaning that results of this study are very relevant to populations such as Canada.
Autosomal recessive gene mutations have traditionally been more difficult to trace, resulting in a paucity of research in this area. Parents of affected children show no symptoms, and the child must inherit one defective copy of the gene from each parent, so that only one in four offspring are likely to be affected. Smaller families, therefore, show a decreased incidence and are less amenable to this kind of study.
Dr. Vincent is currently engaged in a study that will screen Canadian populations with autism and intellectual disability for autosomal recessive gene mutations. Results will be available later this year.
A total of 42 genes linked to non-syndromic autosomal recessive forms of intellectual disability have now been identified; estimates suggest that up to 2,500 autosomal genes might be linked with intellectual disability, the majority being recessive.
(Source: camh.ca)
Critical role of one gene to our brain development
New research from the University of Adelaide has confirmed that a gene linked to intellectual disability is critical to the earliest stages of the development of human brains.
Known as USP9X, the gene has been investigated by Adelaide researchers for more than a decade, but in recent years scientists have begun to understand its particular importance to brain development.
In a new paper published online in the American Journal of Human Genetics, an international research team led by the University of Adelaide’s Robinson Research Institute explains how mutations in USP9X are associated with intellectual disability. These mutations, which can be inherited from one generation to the next, have been shown to cause disruptions to normal brain cell functioning.
Speaking during Brain Awareness Week, senior co-author Dr Lachlan Jolly from the University of Adelaide’s Neurogenetics Research Program says the USP9X gene has shed new light on the mysteries of brain development and disability.
Dr Jolly says the base framework for the brain’s complex network of cells begins to form at the embryo stage.
"Not surprisingly, disorders that cause changes to this network of cells, such as intellectual disabilities, epilepsy and autism, are hard to understand, and treat," Dr Jolly says.
"By looking at patients with severe learning and memory problems, we discovered a gene - called USP9X - that is involved in creating this base network of nerve cells. USP9X controls both the initial generation of the nerve cells from stem cells, and also their ability to connect with one another and form the proper networks,” he says.
"This work is critical to understanding how the brain develops, and how it is altered in individuals with brain disorders.
"We hope that by learning more about genes such as USP9X, we will create new opportunities to understand brain disorders at a much deeper level than currently known, which could lead to future treatment opportunities.”
Scientists Uncover Trigger for Most Common Form of Intellectual Disability and Autism
A new study led by Weill Cornell Medical College scientists shows that the most common genetic form of mental retardation and autism occurs because of a mechanism that shuts off the gene associated with the disease. The findings, published today in Science, also show that a drug that blocks this silencing mechanism can prevent fragile X syndrome — suggesting similar therapy is possible for 20 other diseases that range from mental retardation to multisystem failure.
(Image caption: A key brain signaling protein, seen here in green, that is normally lost in Fragile X syndrome neurons is restored by an experimental drug. Image: Dilek Colak)
Fragile X syndrome occurs mostly in boys, causing intellectual disability as well as telltale physical, behavioral and emotional traits. While researchers have known for more than two decades that the culprit behind the disease is an unusual mutation characterized by the excess repetition of a particular segment of the genetic code, they weren’t sure why the presence of a large number of these repetitions — 200 or more — sets the disease process in motion.
Using stem cells from donated human embryos that tested positive for fragile X syndrome, the scientists discovered that early on in fetal development, messenger RNA — a template for protein production — begins sticking itself onto the fragile X syndrome gene’s DNA. This binding appears to gum up the gene, making it inactive and unable to produce a protein crucial to the transmission of signals between brain cells.
"Until 11 weeks of gestation, the fragile X syndrome gene is active — it produces its messenger RNA and protein normally. Then, all of a sudden it turns off, and stays off for the rest of the patient’s lifetime, causing fragile X syndrome. But scientists have not understood why this gene gets shut off," says senior author Dr. Samie Jaffrey, a professor of pharmacology at Weill Cornell Medical College. "We discovered that the messenger RNA can jam up one strand of the gene’s DNA, shutting down the gene — which was not known before.
"This is new biology — an interaction between the RNA and the DNA of the fragile X syndrome gene causes disease," Dr. Jaffrey says. "We are coming to understand that RNAs are powerful molecules that can regulate gene expression, but this mechanism is completely novel — and very exciting."
The malfunction occurs suddenly — before the end of the first trimester in humans and after 50 days in laboratory embryonic stem cells. At that point, the messenger RNA produced by the fragile X syndrome gene makes what the researchers call an RNA-DNA duplex — a particular arrangement of molecules in which the messenger RNA is stuck onto its DNA complement. (DNA produces two complementary strands of the genetic code responsible for human development and function. The four nucleic acids in the genomic code — A, C, G, T — have specific complements. In the case of fragile X syndrome, the repeat sequence in question is CGG. Therefore, RNA binds to its GCC complement on one strand of DNA.)
The RNA-DNA duplex then shuts down production of the fragile X syndrome gene, causing the loss of a protein needed for communication between brain cells. The gene then remains inactive for life. A normal fragile X gene — one with fewer than 200 CGG repeats — stays active in a person without the disorder, and produces the necessary protein. However, the mutant fragile X gene contains more than 200 CGG repeats, resulting in fragile X syndrome. Fragile X occurs in about 1 in 4,000 males and 1 in 8,000 females.
"Because the fragile X syndrome mutation is a repeat sequence, it is very easy for just a small portion of this sequence in the messenger RNA to find a matching repeat sequence on the DNA," Dr. Jaffrey says. "This is a unique feature of repeat sequences. When there are 200 or more repeats, the RNA-DNA interaction locks into place."
Hope for treatment — and other disorders
Dr. Jaffrey and his team, which includes researchers from The Scripps Research Institute in Florida and Albert Einstein College of Medicine in the Bronx, sought to find out why the disease is switched on when the CGG repeat is present in 200 to as many as 1,000 copies.
"Utilizing traditional ways to solve this puzzle has been impossible," he says. "Human fragile X syndrome genes introduced into mice and cells in the laboratory never turn off, no matter how many CGG repeats the genes have."
So the scientists turned to human embryonic stem cells. Co-authors Dr. Zev Rosenwaks, director and physician-in-chief of the Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine and director of the Stem Cell Derivation Laboratory of Weill Cornell Medical College, and Dr. Nikica Zaninovic, assistant professor of reproductive medicine, generated stem cell lines from donated embryos that tested positive for fragile X syndrome. “These stem cells were critical to the success of this research, because they alone allowed us to mimic what happens to the fragile X gene during embryonic development,” says Dr. Dilek Colak, a postdoctoral scientist in Dr. Jaffrey’s laboratory and the first author of the study.
The stem cells were coaxed to become brain neurons, and at about 50 days, they differentiated in the same way that an embryo’s brain is developing at 11-plus weeks when the fragile X syndrome gene is switched off.
The researchers then used a drug developed by co-author Dr. Matthew Disney of the Scripps Research Institute that binds to CGG in the fragile X gene’s RNA before and after the 50-day switch. Strikingly, the gene never stopped producing its beneficial protein.
That suggests a potential prevention or treatment strategy for fragile X syndrome, Dr. Jaffrey says. “If a pregnant woman is told that her fetus carries the genetic mutation causing fragile X syndrome, we could potentially intervene and give the drug during gestation. This may delay or prevent the silencing of the fragile X gene, which could potentially significantly improve the outcome of these patients,” he says.
The researchers are now looking for similar RNA-DNA duplexes in other trinucleotide repeat diseases, including Huntington’s disease (a degenerative brain disease), myotonic dystrophy 1 and 2 (a multisystem progressive disease), Friedrich’s ataxia (a progressive nervous system disorder), Jacobsen syndrome (an intellectual disorder), and familial amyotrophic lateral sclerosis (a motor neuron disease), among others.
"This completely new mechanism by which RNAs can direct gene silencing may be involved in a lot of other diseases," Dr. Jaffrey says. "Our hope is that we can find drugs that interfere with this new type of disease process."
(Source: weill.cornell.edu)
Gene linked to common intellectual disability
University of Adelaide researchers have taken a step forward in unravelling the causes of a commonly inherited intellectual disability, finding that a genetic mutation leads to a reduction in certain proteins in the brain.
ARX is among the top four types of intellectual disability linked to the X-chromosome in males. So far, 115 families, including many large Australian families, have been discovered to carry an ARX (Aristaless related homeobox) mutation that gives rise to intellectual disability.
"There is considerable variation in the disability across families, and within families with a single mutation. Symptoms among males always include intellectual disability, as well as a range of movement disorders of the hand, and in some cases severe seizures," says Associate Professor Cheryl Shoubridge, Head of Molecular Neurogenetics with the University of Adelaide’s Robinson Institute.
ARX mutations were first discovered by the University of Adelaide’s Professor Jozef Gecz in 2002. To date, researchers have detected 52 different ARX mutations and 10 distinct clinical syndromes.
Associate Professor Shoubridge is lead author of a new paper on ARX intellectual disability published in the journal Human Molecular Genetics.
In laboratory studies, Associate Professor Shoubridge’s team has shown that mutations lead to a significant reduction in ARX proteins in the brain, but the actual causes and mechanisms involved in this remain unknown. Her team tested six genes that the ARX protein interacts with, and found that one of them - a gene likely to be important to early brain development - appears to be adversely affected by the reduction of ARX proteins.
"This plays an important role in setting up architecture and networks in the brain, which become disrupted due to the mutation", Associate Professor Shoubridge says.
"The discovery of this genetic link is an important step forward but there is still much work to be done. We’re now looking further at the mechanism of the reduction in ARX protein and what that means for the brain at a functional level."
Associate Professor Shoubridge says up to 3% of the population is affected by some kind of intellectual disability, costing $14.7 billion each year in Australia alone.
"The personal cost to families is enormous, especially in the most severe cases. Being able to unravel why and how these disabilities occur is very important to us and to the many people whose lives are affected by these conditions," she says.
(Source: adelaide.edu.au)
The white arrow highlights the primary neuronal cilium, a hair-like structure on nerve cells. The neuron on the right has no cilium because of the loss of a protein linked to intellectual disability in humans. Credit: YOSHIHO IKEUCHI
Intellectual disability linked to nerve cells that lose their ‘antennae’
An odd and little-known feature of nerve cells may be linked to several forms of inherited intellectual disability, researchers at Washington University School of Medicine in St. Louis have learned.
The scientists report that a genetic mutation that causes intellectual disability also blocks formation of the neuronal primary cilium, a hair-like structure that protrudes from the bodies of nerve cells.
"The primary cilium acts as a kind of antenna for nerve cells,” said first author Yoshiho Ikeuchi, PhD, a staff scientist. “It’s covered in receptors that monitor environmental conditions outside the cell and may influence the cell’s functions.”
Learning more about how the mutation sabotages production of the nerve cell cilium eventually will help scientists develop drugs to treat intellectual disability, according to senior author Azad Bonni, MD, PhD, the Edison Professor and chairman of the Department of Anatomy and Neurobiology.
"Intellectual disability—sometimes known as mental retardation—affects 1 to 2 percent of the general population, and researchers have identified more than 100 genes on the X chromosome that can cause these conditions,” Bonni said. “But we don’t know what most of these genes do, and that information is essential for new treatments.”
The research appears online Aug. 29 in Cell Reports.
Nearly every cell in the mammalian body has a primary cilium—a structure that acts as an environmental sensor. Some cells have many cilia that move together in waves. Problems with cilia are associated with disorders throughout the body, including illnesses of the kidneys, eyes and reproductive organs.
"Some of the X-linked intellectual disorders are syndromes that not only hamper brain development but also cause problems elsewhere in the body,” Bonni said. “That makes sense in the context of this new connection we’ve identified between intellectual disability and the primary cilium.”
Scientists only recently have recognized the potential of a primary cilium malfunction to impair nerve cell development and function. Studies have suggested that the primary cilium may be where nerve cells receive the growth signals that allow them to extend branches to each other and form circuits. Other research has shown that blocking of signal receptors on the primary cilium leads to memory problems in mice.
Bonni’s path to the primary cilium led through the nucleus, the command center that contains a cell’s DNA. Proteins found inside a cell’s nucleus often regulate the turning on or off of other genes, making them influential in orchestrating the responses and functions of cells.
Bonni and his colleagues scanned the literature on X chromosome genes linked to intellectual disability to learn which genes produce proteins found in the nucleus. When they disabled 15 such genes in individual nerve cells, they found that the loss of the gene for polyglutamine-binding protein 1 (PQBP1) produced the most dramatic effect, leaving nerve cells with shortened primary cilia or no cilia at all.
In other cell types outside the brain, PQBP1 is typically found only in the nucleus. But the new results show that in neurons the protein is present both in the nucleus and, surprisingly, at the base of the primary cilium.
The scientists learned PQBP1 binds to another protein outside the nucleus that suppresses growth of the primary cilium. By binding to the suppressor, PQBP1 gets that suppressor out of the way, allowing cilium formation to proceed normally.
Scientists may one day try to imitate this effect with drugs, potentially allowing the brain to develop more normally when PQBP1 is mutated. For now, the researchers want to learn more about the suppressor protein and also are investigating the possibility that PQBP1 may continue to influence the functions of the primary cilium after it is formed.
IVF for male infertility linked to increased risk of intellectual disability and autism in children
In the first study to compare all available IVF treatments and the risk of neurodevelopmental disorders in children, researchers find that IVF treatments for the most severe forms of male infertility are associated with an increased risk of intellectual disability and autism in children.
Autism and intellectual disability remain a rare outcome of IVF, and whilst some of the risk is associated with the risk of multiple births, the study provides important evidence for parents and clinicians on the relative risks of modern IVF treatments.
Published in JAMA today, the study is the largest of its kind and was led by researchers at King’s College London (UK), Karolinska Institutet (Sweden) and Mount Sinai School of Medicine in New York (USA).
By using anonymous data from the Swedish national registers, researchers analysed more than 2.5 million birth records from 1982 and 2007 and followed-up whether children had a clinical diagnosis of autism or intellectual disability (defined as having an IQ below 70) up until 2009. Of the 2.5m children, 1.2% (30,959) were born following IVF. Of the 6,959 diagnosed with autism, 103 were born after IVF; of the 15,830 with intellectual disability, 180 were born after IVF. Multiple pregnancies are a known risk factor for pre-term birth and some neurodevelopmental disorders, so the researchers also compared single to multiple births.
Sven Sandin, co-author of the study from King’s College London’s Institute of Psychiatry says: “IVF treatments are vastly different in terms of their complexity. When we looked at IVF treatments combined, we found there was no overall increased risk for autism, but a small increased risk of intellectual disability. When we separated the different IVF treatments, we found that ‘traditional’ IVF is safe, but that IVF involving ICSI, which is specifically recommended for paternal infertility is associated with an increased risk of both intellectual disability and autism in children.”
Compared to spontaneous conception, children born from any IVF treatment were not at an increased risk of autism, but were at a small increased risk of intellectual disability (18% increase – from 39.8 to 46.3 per 100,000 person years). However, the risk increase disappeared when multiple births were taken into account.
Secondly, the researchers compared all 6 different types of IVF procedures available in Sweden – whether fresh or frozen embryos were used; if intracytoplasmic sperm injection (ICSI) was used, and if so, whether sperm was ejaculated or surgically extracted. Developed in 1992, ICSI is recommended for male infertility and is now used in about half of all IVF treatments. The procedure involves injecting a single sperm directly into an egg, rather than fertilization happening in a dish, as in standard IVF.
Children born after IVF treatments with ICSI (with either fresh or frozen embryos) were at an increased risk of intellectual disability (51% increase – 62 to 93 per 100,000). This association was even higher when a preterm birth also occurred (73% increase – 96 to 167 per 100,000). Even when multiple and pre-term births were taken into account, IVF treatment with ICSI and fresh embryos was associated with an increased risk of intellectual disability (66% increase for singleton birth, term birth following ICSI with fresh embryos– 48 to 76 per 100,000).
Children born after IVF with ICSI using surgically extracted sperm and fresh embryos were at an increased risk of autism (360% increase - 29 to 136 per 100,000) but the association disappeared when multiple births were taken into account.
(Source: kcl.ac.uk)