Researchers sequenced the genomes of members of 13 families severely affected by autism and compared the sequences to those of healthy controls.
They identified genetic variants that had never before been linked to autism.
One affected gene, CTNND2, plays a critical role in brain development and regulates how many other genes function.
Using a novel approach that homes in on rare families severely affected by autism, a Johns Hopkins-led team of researchers has identified a new genetic cause of the disease. The rare genetic variant offers important insights into the root causes of autism, the researchers say. And, they suggest, their unconventional method can be used to identify other genetic causes of autism and other complex genetic conditions.
In recent years, falling costs for genetic testing, together with powerful new means of storing and analysing massive amounts of data, have ushered in the era of the genomewide association and sequencing studies. These studies typically compare genetic sequencing data from thousands of people with and without a given disease to map the locations of genetic variants that contribute to the disease. While genome-wide association studies have linked many genes to particular diseases, their results have so far failed to lead to predictive genetic tests for common conditions, such as Alzheimer’s, autism or schizophrenia.
“In genetics, we all believe that you have to sequence endlessly before you can find anything,” says Aravinda Chakravarti, Ph.D., a professor in the Johns Hopkins University School of Medicine’s McKusick-Nathans Institute of Genetic Medicine. “I think whom you sequence is as important — if not more so — than how many people are sequenced.”
With that idea, Chakravarti and his collaborators identified families in which more than one female has autism spectrum disorder, a condition first described at Johns Hopkins in 1943. For reasons that are not understood, girls are far less likely than boys to have autism, but when girls do have the condition, their symptoms tend to be severe. Chakravarti reasoned that females with autism, particularly those with a close female relative who is also affected, must carry very potent genetic variants for the disease, and he wanted to find out what those were.
The research team compared the gene sequences of autistic members of 13 such families to the gene sequences of people from a public database. They found four potential culprit genes and focused on one, CTNND2, because it fell in a region of the genome known to be associated with another intellectual disability. When they studied the gene’s effects in zebrafish, mice and cadaveric human brains, the research group found that the protein it makes affects how many other genes are regulated. The CTNND2 protein was found at far higher levels in foetal brains than in adult brains or other tissues, Chakravarti says, so it likely plays a key role in brain development.
While autism-causing variants in CTNND2 are very rare, Chakravarti says, the finding provides a window into the general biology of autism. “To devise new therapies, we need to have a good understanding of how the disease comes about in the first place,” he says. “Genetics is a crucial way of doing that.”
John Hopkins Medicine
Nobody likes getting the flu, but for some people, fluids and rest aren’t enough. A small number of children who catch the influenza virus fall so ill they end up in the hospital — perhaps needing ventilators to breathe — even while their family and friends recover easily. New research by Rockefeller University scientists, helps explain why: a rare genetic mutation.
The researchers scrutinized blood and tissue samples from a young girl who, at the age of two-and-a-half, developed acute respiratory distress syndrome after catching the flu, and ended up fighting for her life in the hospital. Years after her ordeal, which she survived, scientists led by Jean-Laurent Casanova discovered that it could be explained by a rare mutation she carries that prevented her from producing a protein, interferon, that helps fight off the virus.
“This is the first example of a common, isolated and life-threatening infection of childhood that is shown to be also a genetic disease,” says Casanova. The good news from these results, however, is that clinicians have a new treatment option for children who mysteriously develop severe cases of the flu. “This finding suggests that one could treat severe flu of childhood with interferon, which is commercially available,” says Casanova, who is professor and head of the St. Giles Laboratory of Human Genetics of Infectious Disease at Rockefeller, as well as a Howard Hughes Medical Institute investigator.
The fact that a child’s genes could affect the severity of her illness wasn’t a surprise to the members of Casanova’s lab, who have been studying this phenomenon for decades. For instance, they have discovered genetic differences that help explain why the herpes simplex virus — which causes innocuous cold sores in most people — can, in rare cases, lead to potentially fatal infections that spread to the brain.
Turning their attention to influenza, Michael J. Ciancanelli, a research associate and senior member of Casanova’s lab, and his colleagues sequenced all genes in the genomes of the young girl who survived her dangerous bout of the flu and her parents, looking for mutations that might explain her vulnerability. Knowing how rare her reaction to the flu was, they narrowed their search to mutations that were unique to her, then focused only on those that affected the immune system.
What emerged from their work was the finding that the girl had inherited two differently mutated copies of the gene IRF7, which encodes a protein that amplifies the production of interferon, a critical part of the body’s response to viral infections. “No other mutations could have explained her reaction to the influenza virus,” says Ciancanelli. “Each mutation is very uncommon and thus the likelihood of carrying two damaged copies of the gene is extremely rare.”
Indeed, when they infected a sample of her blood cells that normally produce interferon —plasmacytoid dendritic cells — the researchers measured no interferon. In contrast, blood cells from her parents, who each carried only one mutated version of the gene, produced healthy amounts of interferon when exposed to influenza. “That really was definitive proof that a single, non-mutated copy of this gene is enough to allow people to mount a response to the virus,” says Ciancanelli.
Rockefeller Hospital
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Researchers have identified a new host of gene variants that could make people vulnerable to sporadic motor neurone disease.
Until recently, it was thought that genetics made little contribution to the disease – also termed amyotrophic lateral sclerosis (ALS) – and that the environment was mostly to blame.
Motor neurone disease (MND) is a group of diseases in which the nerve cells in the brain and spinal cord controlling the muscles that enable us to move, speak, breathe and swallow to slowly degenerate and die.
Death is caused by respiratory failure, which typically occurs within 2 to 5 years of developing this debilitating condition.
‘This is an advance in knowledge about the role genetics is likely to play in sporadic forms of motor neurone disease,’ says the University of Sydney’s Associate Professor Roger Pamphlett, a co-author of the new study.
‘The findings indicate that the genetic changes underlying many cases of sporadic motor neurone disease could stem from one of two sources,’ Associate Professor Pamphlett says.
‘Sufferers either have a rare combination of genetic changes they inherited from their otherwise normal parents, or they have newly-arising changes in genes that were not present in their parents.’
In an effort to identify genetic variants that may play a role in the disease, the researchers sequenced the protein-coding genes of 44 MND-affected individuals and their parents.
They found that two in five MND-affected individuals had inherited rare, recessive gene variants from their parents, and a quarter had developed novel gene variants that were not present in their parents. The researchers believe these gene variants are ‘promising candidates’ for playing a role in the development of motor neurone disease.
Many of these ‘genetic suspects’ have been identified in other brain-related disease, including Alzheimer’s disease, Parkinson’s disease and autism. Also, many are involved in biological processes or metabolic pathways implicated in the development of motor neurone disease.
While the researchers cannot yet point to a potential therapeutic application of their findings, identifying genetic changes that underlie MND is the first step in finding ways to manipulate these changes using gene therapy.
University of Sydney
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A blood test undertaken between 10 to 14 weeks of pregnancy may be more effective in diagnosing Down syndrome and two other less common chromosomal abnormalities than standard non-invasive screening techniques, according to a multicentre study led by a UC San Francisco researcher.
In the study, which followed pregnancy outcomes in close to 16,000 women, the cell-free DNA blood test resulted in correctly identifying all 38 foetuses with Down syndrome, a condition associated with cognitive impairments and an increased risk of several medical disorders. The diagnosis was confirmed by newborn exam, prenatal or postnatal genetic analysis.
The test focuses on the small percentage of foetal DNA found floating in a pregnant woman’s blood. DNA is amplified by PCR, and sequenced so that comparisons can be made between relative amounts of each chromosome’s DNA. A greater quantity of DNA is indicative of some chromosomal conditions, including Down syndrome, which is characterized by an extra copy of chromosome 21, one of the 23 pairs of chromosomes.
When the same women underwent standard screening, 30 of the 38 foetuses with Down syndrome were flagged, according to the study published on April 1, 2015, in the New England Journal of Medicine. The screening comprises a blood draw in which hormones and proteins associated with chromosomal defects are identified, together with an ultrasound of the nuchal fold fluid in the back of the neck, an excess of which is suggestive of Down syndrome.
The average age of the pregnant women was 30 and approximately one-quarter were over 35 – the age at which women have traditionally been considered high risk and offered prenatal invasive testing with procedures like amniocentesis.
A second compelling advantage of cell-free DNA analysis, reported by the researchers who were led by first author Mary Norton, MD, professor of clinical obstetrics and gynaecology at UCSF, was the relatively low incidence of Down syndrome misdiagnoses. While standard testing is acknowledged to result in a large number of false positives, these were significantly less likely with the cell-free DNA tool. There were nine false positives resulting from this method, vs. 854 with standard screening.
University of Central Florida
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Genetic studies in humans, zebrafish and mice have revealed how two different types of genetic variations team up to cause a rare condition called Hirschsprung’s disease. The findings add to an increasingly clear picture of how flaws in early nerve development lead to poor colon function, which must often be surgically corrected. The study also provides a window into normal nerve development and the genes that direct it.
About one in every 5,000 babies is born with Hirschsprung’s disease, which causes bowel obstruction and can be fatal if not treated. The disease arises early in development when nerves that should control the colon fail to grow properly. Those nerves are part of the enteric nervous system, which is separate from the central nervous system that enables our brains to sense the world.
The genetic causes of Hirschsprung’s disease are complex, making it an interesting case study for researchers like Aravinda Chakravarti, Ph.D., a professor in the Johns Hopkins University School of Medicine’s McKusick-Nathans Institute of Genetic Medicine. His research group took on the condition in 1990, and in 2002, it performed the first-ever genomewide association study to identify common variants linked to the disease.
But while Chakravarti’s and other groups have identified several genetic variants associated with Hirschsprung’s, those variants do not explain most cases of the disease. So Chakravarti and colleagues conducted a new genomewide association study of the disease, comparing the genetic markers of more than 650 people with Hirschsprung’s disease, their parents and healthy controls. One of their findings was a variant in a gene called Ret that had not been previously associated with the disease, although other variations in Ret had been fingered as culprits.
The other finding was of a variant near genes for several so-called semaphorins, proteins that guide developing nerve cells as they grow toward their final targets. Through studies in mice and zebrafish, the researchers found that the semaphorins are indeed active in the developing enteric nervous system, and that they interact with Ret in a system of signals called a pathway.
‘It looks like the semaphorin variant doesn’t by itself lead to Hirschsprung’s, but when there’s a variant in Ret too, it causes the pathway to malfunction and can cause disease,’ Chakravarti says. ‘We’ve found a new pathway that guides development of the enteric nervous system, one that nobody suspected had this role.’
Chakravarti notes that the genetic puzzle of Hirschsprung’s is still missing some pieces, and no clinical genetic test yet exists to assess risk for the disease. Most of the genetic variants that have so far been connected to this rare disease are themselves relatively common and are associated with less severe forms of the disease. The hunt continues for rare variants that can explain more severe cases.
EurekAlert
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A new blood test promises to predict which people will have severe allergic reactions to foods according to a new study led by Mount Sinai researchers.
To detect food allergies, physicians typically use skin prick tests or blood tests that measure levels of allergen-specific IgE (sIgE), a protein made by the immune system. However, these tests cannot predict the severity of allergic reactions.
Oral food challenges, in which specific allergens are given to patients to ingest under physician supervision to test for signs or symptoms of an allergic reaction, remain the gold standard for diagnosing food allergy even though the tests themselves can trigger severe reactions.
In the newly published study, Mount Sinai researchers from The Mindich Child Health and Development Institute and the Jaffe Food Allergy Institute report that by counting the numbers of one type of immune cell activated by exposure to a food, a simple, safe blood test can accurately predict the severity of each person’s allergic reaction to it. The immune cell measured is the basophil, and the blood test, the basophil activation test or BAT, requires only a small blood sample and provides quick results.
“While providing crucial information about their potential for a severe allergic reaction to a food, having blood drawn for BAT testing is a much more comfortable procedure than food challenges.” says first author Ying Song, MD. “Although food challenges are widely practiced, they carry the risk of severe allergic reactions, and we believe BAT testing will provide accurate information in a safer manner,” says Dr. Song, also a researcher in the Jaffe Food Allergy Institute at The Mount Sinai Hospital.
“Although the blood basophil activation test has been shown to be an important addition to the tools available for discriminating between allergic and non-allergic individuals and predicting the severity of food allergy reactions, at this time it is only approved for research purposes,” says senior author Xiu-Min Li, MD, Professor of Pediatrics at the Icahn School of Medicine.
Mount Sinai Hospital
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Separating circulating cancer cells from blood cells for diagnostic, prognostic and treatment purposes may become much easier using an acoustic separation method and an inexpensive, disposable chip, according to a team of engineers.
‘Looking for circulating tumour cells in a blood sample is like looking for a needle in a haystack,’ said Tony Jun Huang, professor of engineering science and mechanics. ‘Typically, the CTCs are about one in every one billion blood cells in the sample.’
Existing methods of separation use tumour-specific antibodies to bind with the cancer cells and isolate them, but require that the appropriate antibodies be known in advance. Other methods rely on size, deformability or electrical properties. Unlike conventional separation methods that centrifuge for 10 minutes at 3000 revolutions per minute, surface acoustic waves can separate cells in a much gentler way with a simple, low-cost device.
Acoustic-based separations are potentially important because they are non-invasive and do not alter or damage cells. However, in order to be effective for clinical use, they also need to be rapidly and easily applicable.
‘In order to significantly increase the throughput for capturing those rare CTCs, device design has to be optimized for much higher flow rates and longer acoustic working length,’ said Ming Dao, principal research scientist, materials science and engineering, Massachusetts Institute of Technology. ‘With an integrated experimental/modelling approach, the new generation of the device has improved cell sorting throughput more than 20 times higher than previously achieved and made it possible for us to work with patient samples.’
The researchers worked both experimentally and with models to optimize the separation of CTCs from blood. They used an acoustic-based microfluidic device so that the stream of blood could continuously pass through the device for separation. Using the differential size and weight of the different cells they chose appropriate acoustic pressures that would push the CTCs out of the fluid stream and into a separate channel for collection.
Tilted-angle standing surface acoustic waves can separate cells using very small amounts of energy. The power intensity and frequency used in this study are similar to those used in ultrasonic imaging, which has proven to be extremely safe, even for fetuses. Also, each cell experiences the acoustic wave for only a fraction of a second. In addition, cells do not require labelling or surface modification. All these features make the acoustic separation method, termed acoustic tweezers, extremely biocompatible and maximize the potential of CTCs to maintain their functions and native states.
If two sound sources are placed opposite each other and each emits the same wavelength of sound, there will be a location where the opposing sounds cancel each other. Because sound waves have pressure, they can push very small objects, so a cell or nanoparticle will move with the sound wave until it reaches the location where there is no longer lateral movement, in this case, into the fluid stream that moves the separated cells along.
The researchers used two types of human cancer cells to optimize the acoustic separation — HELA cells and MCF7 cells. These cells are similar in size. They then ran an experiment separating these cells and had a separation rate of more than 83 percent. They then did the separation on other cancer cells, ones for which the device had not been optimized, and again had a separation rate of more than 83 percent.
‘Because these devices are intended for use with human blood, they need to be disposable,’ said Huang. ‘We are currently figuring out manufacturing and mass production possibilities.’
Physicians could use the devices to monitor how patients reacted to chemotherapy, for initial diagnosis and for determining treatment and prognosis.
Penn State University
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Scientists at the Translational Genomics Research Institute (TGen), using state-of-the-art genetic technology, have discovered the likely cause of a child’s rare type of severe muscle weakness.
The child was one of six cases in which TGen sequenced – or decoded – the genes of patients with Neuromuscular Disease (NMD) and was then able to identify the genetic source, or likely genetic source, of each child’s symptoms.
‘In all six cases of myopathy, or muscle weakness, these children had undergone extensive, expensive and invasive testing – often over many years – without a successful diagnosis, until they enrolled in our study,’ said Dr. Lisa Baumbach-Reardon, an Associate Professor of TGen’s Integrated Cancer Genomics Division and the study’s senior author.
This is a prime example of the type of ‘personalized medicine’ TGen uses to zero in on diagnoses for patients, and to help their physicians find the best possible treatments.
‘Our results demonstrate the diagnostic value of a comprehensive approach to genetic sequencing,’ said Dr. Baumbach-Reardon. ‘This type of next-generation sequencing can greatly improve the ability to identify pathogenic, or disease-causing, genetic variants with a single, timely, affordable test.’
In one of the six cases, TGen researchers found a unique disease-causing variant, or mutation, in the CACNA1S gene for a child with severe muscle weakness in addition to ophthalmoplegia, or the inability to move his eyes. Properly functioning CACNA1S is essential for muscle movement. More specifically, CACNA1S senses electrical signals from the brain and enables muscles to contract.
‘To our knowledge, this is the first reported case of severe congenital myopathy with ophthalmoplegia resulting from pathogenic variants in CACNA1S,’ said Dr. Jesse Hunter, a TGen Senior Post-Doctoral Fellow, and the study’s lead author.
Learning the specific genetic cause of symptoms is a key step in finding new therapeutic drugs that could treat the patient’s disease.
Translational Genomics Research Institute (TGen)
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Massachusetts General Hospital (MGH) investigators have identified an inflammatory molecule that appears to play an essential role in the autoimmune disorder systemic lupus erythematosus, commonly known as lupus. In their report, the researchers describe finding that a protein that regulates certain cells in the innate immune system – the body’s first line of defence against infection – activates a molecular pathway known to be associated with lupus and that the protein’s activity is required for the development of lupus symptoms in a mouse model of the disease.
“This study is the first demonstration that the receptor TREML4 amplifies the cellular responses transmitted through the TLR7 receptor and that a lack of such amplification prevents the inflammatory overactivation underlying lupus,” says Terry Means, PhD, of the Center for Immunology and Inflammatory Diseases in the MGH Division of Rheumatology, Allergy, and Immunology. “Our preliminary results suggest that TREML4-regulated signalling through TLR7 may be a potential drug target to limit inflammation and the development of autoimmunity.”
Lupus is an autoimmune disorder characterized by periodic inflammation of joints, connective tissues and organs including heart, lungs, kidneys and brain. TLR7 is one of a family of receptors present on innate immune cells like macrophages that have been linked to chronic inflammation and autoimmunity. Animal studies have suggested that overactivation of TLR7 plays a role in lupus, and a gene variant that increases expression of the receptor has been associated with increased lupus risk in human patients. The current study was designed to identify genes for other molecules required for TLR7-mediated immune cell activation.
The MGH-based team conducted an RNA-interference-based genome-scale screen of mouse macrophages, selectively knocking down the expression of around 8,000 genes, and found that TREML4 – one of a family of receptors found on granulocytes and monocytes – amplifies the response of innate immune cells to activation via TLR7. Immune cells from mice lacking TREML4 showed a weakened response to TLR7 activation. When a strain of mice genetically destined to develop a form of TLR7-dependent lupus was crossbred with a strain in which TREML4 expression was suppressed, offspring lacking TREML4 were protected from the development of lupus-associated kidney failure and had significantly lower blood levels of inflammatory factors and autoantibodies than did mice expressing TREML4.
Means notes that identifying the potential role of TREML4 in human lupus may lead to the development of drugs that could prevent or reduce the development or progression of lupus and another autoimmune disorder called Sjögren’s syndrome, which also appears to involve TLR7 overactivation. Future studies are needed to better define the molecular mechanism behind TREML4-induced amplification of TLR7 signaling and to clarify beneficial reactions controlled by TREML4 – for example, the immune response to influenza virus, which the current study found was inhibited by TREML4 deficiency.
Massachusetts General Hospital
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The link between taking aspirin, non-steroidal anti-inflammatory drugs, or NSAIDS, and colorectal cancer prevention is well established, but the mechanisms behind the protective effect have not been understood. A new study, co-led by investigators at Fred Hutchinson Cancer Research Center suggests this protection differs according to variations in DNA.
“We’ve known for a very long time that aspirin, ibuprofen and other NSAIDs are protective for colorectal cancer, but they can’t be used as a preventive agent because of the uncertainty of the risk-benefit ratio – longtime use can lead to gastrointestinal bleeding and other side effects,” said Ulrike “Riki” Peters, Ph.D., M.P.H., co-senior author of the paper and a cancer prevention researcher in the Public Health Sciences Division at Fred Hutchinson Cancer Research Center. “We wanted to investigate if genetic variation determined who is responding particularly well with aspirin – for whom aspirin and NSAID use has particular benefit and for whom it doesn’t.”
For the study, Peters and colleagues – including co-corresponding author and lead biostatistician Li Hsu, Ph.D., also of Fred Hutch, analyzed data from 10 large population-based studies in North America, Australia and Germany. They compared genetic and lifestyle data from 8,624 people who developed colorectal cancer with that of 8,553 people who did not (both groups were matched by age and gender).
While regular use of aspirin and NSAIDS was associated with an overall reduced risk of colorectal cancer, the researchers found no such protective effect among about 9 percent of the study participants who had genetic variations on chromosome 15. What’s more, about 4 percent of the participants who carried two even rarer genotypes on chromosome 12 had an increased risk of colorectal cancer.
Understanding the interplay between such genetic variations and the use of aspirin and NSAIDs, also known as “gene-by-environment interactions,” eventually may help identify those who could benefit most from these medications for cancer prevention as well as those who should steer clear of them.
“Our hope is that we can find a subgroup of the population where the benefits so outweigh the risks that it makes sense to take aspirin or NSAIDs,” Peters said. “But we’re not there yet.”
Fred Hutchinson Cancer Research Center
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New autism-causing genetic variant identified
, /in E-News /by 3wmediaResearchers sequenced the genomes of members of 13 families severely affected by autism and compared the sequences to those of healthy controls.
They identified genetic variants that had never before been linked to autism.
One affected gene, CTNND2, plays a critical role in brain development and regulates how many other genes function.
Using a novel approach that homes in on rare families severely affected by autism, a Johns Hopkins-led team of researchers has identified a new genetic cause of the disease. The rare genetic variant offers important insights into the root causes of autism, the researchers say. And, they suggest, their unconventional method can be used to identify other genetic causes of autism and other complex genetic conditions.
In recent years, falling costs for genetic testing, together with powerful new means of storing and analysing massive amounts of data, have ushered in the era of the genomewide association and sequencing studies. These studies typically compare genetic sequencing data from thousands of people with and without a given disease to map the locations of genetic variants that contribute to the disease. While genome-wide association studies have linked many genes to particular diseases, their results have so far failed to lead to predictive genetic tests for common conditions, such as Alzheimer’s, autism or schizophrenia.
“In genetics, we all believe that you have to sequence endlessly before you can find anything,” says Aravinda Chakravarti, Ph.D., a professor in the Johns Hopkins University School of Medicine’s McKusick-Nathans Institute of Genetic Medicine. “I think whom you sequence is as important — if not more so — than how many people are sequenced.”
With that idea, Chakravarti and his collaborators identified families in which more than one female has autism spectrum disorder, a condition first described at Johns Hopkins in 1943. For reasons that are not understood, girls are far less likely than boys to have autism, but when girls do have the condition, their symptoms tend to be severe. Chakravarti reasoned that females with autism, particularly those with a close female relative who is also affected, must carry very potent genetic variants for the disease, and he wanted to find out what those were.
The research team compared the gene sequences of autistic members of 13 such families to the gene sequences of people from a public database. They found four potential culprit genes and focused on one, CTNND2, because it fell in a region of the genome known to be associated with another intellectual disability. When they studied the gene’s effects in zebrafish, mice and cadaveric human brains, the research group found that the protein it makes affects how many other genes are regulated. The CTNND2 protein was found at far higher levels in foetal brains than in adult brains or other tissues, Chakravarti says, so it likely plays a key role in brain development.
While autism-causing variants in CTNND2 are very rare, Chakravarti says, the finding provides a window into the general biology of autism. “To devise new therapies, we need to have a good understanding of how the disease comes about in the first place,” he says. “Genetics is a crucial way of doing that.” John Hopkins Medicine
Genetic mutation helps explain why, in rare cases, flu can kill
, /in E-News /by 3wmediaNobody likes getting the flu, but for some people, fluids and rest aren’t enough. A small number of children who catch the influenza virus fall so ill they end up in the hospital — perhaps needing ventilators to breathe — even while their family and friends recover easily. New research by Rockefeller University scientists, helps explain why: a rare genetic mutation.
The researchers scrutinized blood and tissue samples from a young girl who, at the age of two-and-a-half, developed acute respiratory distress syndrome after catching the flu, and ended up fighting for her life in the hospital. Years after her ordeal, which she survived, scientists led by Jean-Laurent Casanova discovered that it could be explained by a rare mutation she carries that prevented her from producing a protein, interferon, that helps fight off the virus.
“This is the first example of a common, isolated and life-threatening infection of childhood that is shown to be also a genetic disease,” says Casanova. The good news from these results, however, is that clinicians have a new treatment option for children who mysteriously develop severe cases of the flu. “This finding suggests that one could treat severe flu of childhood with interferon, which is commercially available,” says Casanova, who is professor and head of the St. Giles Laboratory of Human Genetics of Infectious Disease at Rockefeller, as well as a Howard Hughes Medical Institute investigator.
The fact that a child’s genes could affect the severity of her illness wasn’t a surprise to the members of Casanova’s lab, who have been studying this phenomenon for decades. For instance, they have discovered genetic differences that help explain why the herpes simplex virus — which causes innocuous cold sores in most people — can, in rare cases, lead to potentially fatal infections that spread to the brain.
Turning their attention to influenza, Michael J. Ciancanelli, a research associate and senior member of Casanova’s lab, and his colleagues sequenced all genes in the genomes of the young girl who survived her dangerous bout of the flu and her parents, looking for mutations that might explain her vulnerability. Knowing how rare her reaction to the flu was, they narrowed their search to mutations that were unique to her, then focused only on those that affected the immune system.
What emerged from their work was the finding that the girl had inherited two differently mutated copies of the gene IRF7, which encodes a protein that amplifies the production of interferon, a critical part of the body’s response to viral infections. “No other mutations could have explained her reaction to the influenza virus,” says Ciancanelli. “Each mutation is very uncommon and thus the likelihood of carrying two damaged copies of the gene is extremely rare.”
Indeed, when they infected a sample of her blood cells that normally produce interferon —plasmacytoid dendritic cells — the researchers measured no interferon. In contrast, blood cells from her parents, who each carried only one mutated version of the gene, produced healthy amounts of interferon when exposed to influenza. “That really was definitive proof that a single, non-mutated copy of this gene is enough to allow people to mount a response to the virus,” says Ciancanelli. Rockefeller Hospital
Motor Neurone Disease – researchers identify new group of gene suspects
, /in E-News /by 3wmediaResearchers have identified a new host of gene variants that could make people vulnerable to sporadic motor neurone disease.
Until recently, it was thought that genetics made little contribution to the disease – also termed amyotrophic lateral sclerosis (ALS) – and that the environment was mostly to blame.
Motor neurone disease (MND) is a group of diseases in which the nerve cells in the brain and spinal cord controlling the muscles that enable us to move, speak, breathe and swallow to slowly degenerate and die.
Death is caused by respiratory failure, which typically occurs within 2 to 5 years of developing this debilitating condition.
‘This is an advance in knowledge about the role genetics is likely to play in sporadic forms of motor neurone disease,’ says the University of Sydney’s Associate Professor Roger Pamphlett, a co-author of the new study.
‘The findings indicate that the genetic changes underlying many cases of sporadic motor neurone disease could stem from one of two sources,’ Associate Professor Pamphlett says.
‘Sufferers either have a rare combination of genetic changes they inherited from their otherwise normal parents, or they have newly-arising changes in genes that were not present in their parents.’
In an effort to identify genetic variants that may play a role in the disease, the researchers sequenced the protein-coding genes of 44 MND-affected individuals and their parents.
They found that two in five MND-affected individuals had inherited rare, recessive gene variants from their parents, and a quarter had developed novel gene variants that were not present in their parents. The researchers believe these gene variants are ‘promising candidates’ for playing a role in the development of motor neurone disease.
Many of these ‘genetic suspects’ have been identified in other brain-related disease, including Alzheimer’s disease, Parkinson’s disease and autism. Also, many are involved in biological processes or metabolic pathways implicated in the development of motor neurone disease.
While the researchers cannot yet point to a potential therapeutic application of their findings, identifying genetic changes that underlie MND is the first step in finding ways to manipulate these changes using gene therapy. University of Sydney
Detecting Down Syndrome in early pregnancy
, /in E-News /by 3wmediaA blood test undertaken between 10 to 14 weeks of pregnancy may be more effective in diagnosing Down syndrome and two other less common chromosomal abnormalities than standard non-invasive screening techniques, according to a multicentre study led by a UC San Francisco researcher.
In the study, which followed pregnancy outcomes in close to 16,000 women, the cell-free DNA blood test resulted in correctly identifying all 38 foetuses with Down syndrome, a condition associated with cognitive impairments and an increased risk of several medical disorders. The diagnosis was confirmed by newborn exam, prenatal or postnatal genetic analysis.
The test focuses on the small percentage of foetal DNA found floating in a pregnant woman’s blood. DNA is amplified by PCR, and sequenced so that comparisons can be made between relative amounts of each chromosome’s DNA. A greater quantity of DNA is indicative of some chromosomal conditions, including Down syndrome, which is characterized by an extra copy of chromosome 21, one of the 23 pairs of chromosomes.
When the same women underwent standard screening, 30 of the 38 foetuses with Down syndrome were flagged, according to the study published on April 1, 2015, in the New England Journal of Medicine. The screening comprises a blood draw in which hormones and proteins associated with chromosomal defects are identified, together with an ultrasound of the nuchal fold fluid in the back of the neck, an excess of which is suggestive of Down syndrome.
The average age of the pregnant women was 30 and approximately one-quarter were over 35 – the age at which women have traditionally been considered high risk and offered prenatal invasive testing with procedures like amniocentesis.
A second compelling advantage of cell-free DNA analysis, reported by the researchers who were led by first author Mary Norton, MD, professor of clinical obstetrics and gynaecology at UCSF, was the relatively low incidence of Down syndrome misdiagnoses. While standard testing is acknowledged to result in a large number of false positives, these were significantly less likely with the cell-free DNA tool. There were nine false positives resulting from this method, vs. 854 with standard screening. University of Central Florida
New genetic clues emerge on origin of Hirschsprung’s disease
, /in E-News /by 3wmediaGenetic studies in humans, zebrafish and mice have revealed how two different types of genetic variations team up to cause a rare condition called Hirschsprung’s disease. The findings add to an increasingly clear picture of how flaws in early nerve development lead to poor colon function, which must often be surgically corrected. The study also provides a window into normal nerve development and the genes that direct it.
About one in every 5,000 babies is born with Hirschsprung’s disease, which causes bowel obstruction and can be fatal if not treated. The disease arises early in development when nerves that should control the colon fail to grow properly. Those nerves are part of the enteric nervous system, which is separate from the central nervous system that enables our brains to sense the world.
The genetic causes of Hirschsprung’s disease are complex, making it an interesting case study for researchers like Aravinda Chakravarti, Ph.D., a professor in the Johns Hopkins University School of Medicine’s McKusick-Nathans Institute of Genetic Medicine. His research group took on the condition in 1990, and in 2002, it performed the first-ever genomewide association study to identify common variants linked to the disease.
But while Chakravarti’s and other groups have identified several genetic variants associated with Hirschsprung’s, those variants do not explain most cases of the disease. So Chakravarti and colleagues conducted a new genomewide association study of the disease, comparing the genetic markers of more than 650 people with Hirschsprung’s disease, their parents and healthy controls. One of their findings was a variant in a gene called Ret that had not been previously associated with the disease, although other variations in Ret had been fingered as culprits.
The other finding was of a variant near genes for several so-called semaphorins, proteins that guide developing nerve cells as they grow toward their final targets. Through studies in mice and zebrafish, the researchers found that the semaphorins are indeed active in the developing enteric nervous system, and that they interact with Ret in a system of signals called a pathway.
‘It looks like the semaphorin variant doesn’t by itself lead to Hirschsprung’s, but when there’s a variant in Ret too, it causes the pathway to malfunction and can cause disease,’ Chakravarti says. ‘We’ve found a new pathway that guides development of the enteric nervous system, one that nobody suspected had this role.’
Chakravarti notes that the genetic puzzle of Hirschsprung’s is still missing some pieces, and no clinical genetic test yet exists to assess risk for the disease. Most of the genetic variants that have so far been connected to this rare disease are themselves relatively common and are associated with less severe forms of the disease. The hunt continues for rare variants that can explain more severe cases. EurekAlert
Blood test predicts severity of peanut and seafood allergies
, /in E-News /by 3wmediaA new blood test promises to predict which people will have severe allergic reactions to foods according to a new study led by Mount Sinai researchers.
To detect food allergies, physicians typically use skin prick tests or blood tests that measure levels of allergen-specific IgE (sIgE), a protein made by the immune system. However, these tests cannot predict the severity of allergic reactions.
Oral food challenges, in which specific allergens are given to patients to ingest under physician supervision to test for signs or symptoms of an allergic reaction, remain the gold standard for diagnosing food allergy even though the tests themselves can trigger severe reactions.
In the newly published study, Mount Sinai researchers from The Mindich Child Health and Development Institute and the Jaffe Food Allergy Institute report that by counting the numbers of one type of immune cell activated by exposure to a food, a simple, safe blood test can accurately predict the severity of each person’s allergic reaction to it. The immune cell measured is the basophil, and the blood test, the basophil activation test or BAT, requires only a small blood sample and provides quick results.
“While providing crucial information about their potential for a severe allergic reaction to a food, having blood drawn for BAT testing is a much more comfortable procedure than food challenges.” says first author Ying Song, MD. “Although food challenges are widely practiced, they carry the risk of severe allergic reactions, and we believe BAT testing will provide accurate information in a safer manner,” says Dr. Song, also a researcher in the Jaffe Food Allergy Institute at The Mount Sinai Hospital.
“Although the blood basophil activation test has been shown to be an important addition to the tools available for discriminating between allergic and non-allergic individuals and predicting the severity of food allergy reactions, at this time it is only approved for research purposes,” says senior author Xiu-Min Li, MD, Professor of Pediatrics at the Icahn School of Medicine. Mount Sinai Hospital
Sound separates cancer cells from blood samples
, /in E-News /by 3wmediaSeparating circulating cancer cells from blood cells for diagnostic, prognostic and treatment purposes may become much easier using an acoustic separation method and an inexpensive, disposable chip, according to a team of engineers.
‘Looking for circulating tumour cells in a blood sample is like looking for a needle in a haystack,’ said Tony Jun Huang, professor of engineering science and mechanics. ‘Typically, the CTCs are about one in every one billion blood cells in the sample.’
Existing methods of separation use tumour-specific antibodies to bind with the cancer cells and isolate them, but require that the appropriate antibodies be known in advance. Other methods rely on size, deformability or electrical properties. Unlike conventional separation methods that centrifuge for 10 minutes at 3000 revolutions per minute, surface acoustic waves can separate cells in a much gentler way with a simple, low-cost device.
Acoustic-based separations are potentially important because they are non-invasive and do not alter or damage cells. However, in order to be effective for clinical use, they also need to be rapidly and easily applicable.
‘In order to significantly increase the throughput for capturing those rare CTCs, device design has to be optimized for much higher flow rates and longer acoustic working length,’ said Ming Dao, principal research scientist, materials science and engineering, Massachusetts Institute of Technology. ‘With an integrated experimental/modelling approach, the new generation of the device has improved cell sorting throughput more than 20 times higher than previously achieved and made it possible for us to work with patient samples.’
The researchers worked both experimentally and with models to optimize the separation of CTCs from blood. They used an acoustic-based microfluidic device so that the stream of blood could continuously pass through the device for separation. Using the differential size and weight of the different cells they chose appropriate acoustic pressures that would push the CTCs out of the fluid stream and into a separate channel for collection.
Tilted-angle standing surface acoustic waves can separate cells using very small amounts of energy. The power intensity and frequency used in this study are similar to those used in ultrasonic imaging, which has proven to be extremely safe, even for fetuses. Also, each cell experiences the acoustic wave for only a fraction of a second. In addition, cells do not require labelling or surface modification. All these features make the acoustic separation method, termed acoustic tweezers, extremely biocompatible and maximize the potential of CTCs to maintain their functions and native states.
If two sound sources are placed opposite each other and each emits the same wavelength of sound, there will be a location where the opposing sounds cancel each other. Because sound waves have pressure, they can push very small objects, so a cell or nanoparticle will move with the sound wave until it reaches the location where there is no longer lateral movement, in this case, into the fluid stream that moves the separated cells along.
The researchers used two types of human cancer cells to optimize the acoustic separation — HELA cells and MCF7 cells. These cells are similar in size. They then ran an experiment separating these cells and had a separation rate of more than 83 percent. They then did the separation on other cancer cells, ones for which the device had not been optimized, and again had a separation rate of more than 83 percent.
‘Because these devices are intended for use with human blood, they need to be disposable,’ said Huang. ‘We are currently figuring out manufacturing and mass production possibilities.’
Physicians could use the devices to monitor how patients reacted to chemotherapy, for initial diagnosis and for determining treatment and prognosis. Penn State University
Scientists find likely genetic source of muscle weakness
, /in E-News /by 3wmediaScientists at the Translational Genomics Research Institute (TGen), using state-of-the-art genetic technology, have discovered the likely cause of a child’s rare type of severe muscle weakness.
The child was one of six cases in which TGen sequenced – or decoded – the genes of patients with Neuromuscular Disease (NMD) and was then able to identify the genetic source, or likely genetic source, of each child’s symptoms.
‘In all six cases of myopathy, or muscle weakness, these children had undergone extensive, expensive and invasive testing – often over many years – without a successful diagnosis, until they enrolled in our study,’ said Dr. Lisa Baumbach-Reardon, an Associate Professor of TGen’s Integrated Cancer Genomics Division and the study’s senior author.
This is a prime example of the type of ‘personalized medicine’ TGen uses to zero in on diagnoses for patients, and to help their physicians find the best possible treatments.
‘Our results demonstrate the diagnostic value of a comprehensive approach to genetic sequencing,’ said Dr. Baumbach-Reardon. ‘This type of next-generation sequencing can greatly improve the ability to identify pathogenic, or disease-causing, genetic variants with a single, timely, affordable test.’
In one of the six cases, TGen researchers found a unique disease-causing variant, or mutation, in the CACNA1S gene for a child with severe muscle weakness in addition to ophthalmoplegia, or the inability to move his eyes. Properly functioning CACNA1S is essential for muscle movement. More specifically, CACNA1S senses electrical signals from the brain and enables muscles to contract.
‘To our knowledge, this is the first reported case of severe congenital myopathy with ophthalmoplegia resulting from pathogenic variants in CACNA1S,’ said Dr. Jesse Hunter, a TGen Senior Post-Doctoral Fellow, and the study’s lead author.
Learning the specific genetic cause of symptoms is a key step in finding new therapeutic drugs that could treat the patient’s disease. Translational Genomics Research Institute (TGen)
Investigators have found a potential new treatment target lupus
, /in E-News /by 3wmediaMassachusetts General Hospital (MGH) investigators have identified an inflammatory molecule that appears to play an essential role in the autoimmune disorder systemic lupus erythematosus, commonly known as lupus. In their report, the researchers describe finding that a protein that regulates certain cells in the innate immune system – the body’s first line of defence against infection – activates a molecular pathway known to be associated with lupus and that the protein’s activity is required for the development of lupus symptoms in a mouse model of the disease.
“This study is the first demonstration that the receptor TREML4 amplifies the cellular responses transmitted through the TLR7 receptor and that a lack of such amplification prevents the inflammatory overactivation underlying lupus,” says Terry Means, PhD, of the Center for Immunology and Inflammatory Diseases in the MGH Division of Rheumatology, Allergy, and Immunology. “Our preliminary results suggest that TREML4-regulated signalling through TLR7 may be a potential drug target to limit inflammation and the development of autoimmunity.”
Lupus is an autoimmune disorder characterized by periodic inflammation of joints, connective tissues and organs including heart, lungs, kidneys and brain. TLR7 is one of a family of receptors present on innate immune cells like macrophages that have been linked to chronic inflammation and autoimmunity. Animal studies have suggested that overactivation of TLR7 plays a role in lupus, and a gene variant that increases expression of the receptor has been associated with increased lupus risk in human patients. The current study was designed to identify genes for other molecules required for TLR7-mediated immune cell activation.
The MGH-based team conducted an RNA-interference-based genome-scale screen of mouse macrophages, selectively knocking down the expression of around 8,000 genes, and found that TREML4 – one of a family of receptors found on granulocytes and monocytes – amplifies the response of innate immune cells to activation via TLR7. Immune cells from mice lacking TREML4 showed a weakened response to TLR7 activation. When a strain of mice genetically destined to develop a form of TLR7-dependent lupus was crossbred with a strain in which TREML4 expression was suppressed, offspring lacking TREML4 were protected from the development of lupus-associated kidney failure and had significantly lower blood levels of inflammatory factors and autoantibodies than did mice expressing TREML4.
Means notes that identifying the potential role of TREML4 in human lupus may lead to the development of drugs that could prevent or reduce the development or progression of lupus and another autoimmune disorder called Sjögren’s syndrome, which also appears to involve TLR7 overactivation. Future studies are needed to better define the molecular mechanism behind TREML4-induced amplification of TLR7 signaling and to clarify beneficial reactions controlled by TREML4 – for example, the immune response to influenza virus, which the current study found was inhibited by TREML4 deficiency. Massachusetts General Hospital
The link between aspirin, NSAIDs and colon cancer prevention may hinge on genetic variations
, /in E-News /by 3wmediaThe link between taking aspirin, non-steroidal anti-inflammatory drugs, or NSAIDS, and colorectal cancer prevention is well established, but the mechanisms behind the protective effect have not been understood. A new study, co-led by investigators at Fred Hutchinson Cancer Research Center suggests this protection differs according to variations in DNA.
“We’ve known for a very long time that aspirin, ibuprofen and other NSAIDs are protective for colorectal cancer, but they can’t be used as a preventive agent because of the uncertainty of the risk-benefit ratio – longtime use can lead to gastrointestinal bleeding and other side effects,” said Ulrike “Riki” Peters, Ph.D., M.P.H., co-senior author of the paper and a cancer prevention researcher in the Public Health Sciences Division at Fred Hutchinson Cancer Research Center. “We wanted to investigate if genetic variation determined who is responding particularly well with aspirin – for whom aspirin and NSAID use has particular benefit and for whom it doesn’t.”
For the study, Peters and colleagues – including co-corresponding author and lead biostatistician Li Hsu, Ph.D., also of Fred Hutch, analyzed data from 10 large population-based studies in North America, Australia and Germany. They compared genetic and lifestyle data from 8,624 people who developed colorectal cancer with that of 8,553 people who did not (both groups were matched by age and gender).
While regular use of aspirin and NSAIDS was associated with an overall reduced risk of colorectal cancer, the researchers found no such protective effect among about 9 percent of the study participants who had genetic variations on chromosome 15. What’s more, about 4 percent of the participants who carried two even rarer genotypes on chromosome 12 had an increased risk of colorectal cancer.
Understanding the interplay between such genetic variations and the use of aspirin and NSAIDs, also known as “gene-by-environment interactions,” eventually may help identify those who could benefit most from these medications for cancer prevention as well as those who should steer clear of them.
“Our hope is that we can find a subgroup of the population where the benefits so outweigh the risks that it makes sense to take aspirin or NSAIDs,” Peters said. “But we’re not there yet.” Fred Hutchinson Cancer Research Center