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Newswise In the largest family study on autism spectrum disorder (ASD) to date, researchers from the Icahn School of Medicine at Mount Sinai, along with a research team from the Karolinska Institutet in Stockholm Sweden and Kings College in London found that individual risk of ASD and autistic disorder increased with greater genetic relatedness in families that is, persons with a sibling, half-sibling or cousin diagnosed with autism have an increased likelihood of developing ASD themselves. Furthermore, the research findings showed that environmental factors unique to the individual (birth complications, maternal infections, etc.) were more of a determinant for ASD than previously believed.

The population-based, longitudinal study, titled "The Familial Risk of Autism," was led by Abraham Reichenberg, PhD, Professor of Psychiatry and Preventive Medicine at the Icahn School of Medicine at Mount Sinai, and was first published online in the Journal of the American Medical Association.

The findings from this extensive, prospective study will help improve how we counsel families with children who suffer from ASD and autistic disorder, said Dr. Reichenberg. Currently, ASD affects nearly one percent of all children born in the United States. This study tells us that while we continue to study the genetic risk factors associated with ASD, we should find what environmental factors may play a role as well. ASD is defined as impairment in social interaction and communication and the presence of restricted interests and repetitive behaviors; in the U.S., approximately one percent of the population is believed to have ASD. For purposes of this study, ASD included the definition for Asperger syndrome.

The study cohort comprised more than two million Swedish children born in 1982 through 2006, and included more than 1.6 million unique families. The breadth of this study allowed researchers the opportunity to examine a large spectrum of relatedness, including monozygotic (identical) and dizygotic (fraternal) twins; full siblings; maternal and paternal half siblings; and cousins. Single-child families were excluded from this study. Researchers studied the relative recurrence risk, or RRR, for autism spectrum disorder and autistic disorder in these families and used it to determine heritability. Recurrence risk expresses the risk of having another affected family member in an already-affected family that is, the likelihood of a person in a family to be diagnosed with ASD if they have a sibling or cousin with autism spectrum disorder. RRR measures this recurrence in relation to disease in families without any affected members.

In calculating RRR for the different genetic relations, the researchers found that the closer the genetic relatedness, the greater the risk a sibling or cousin would also be diagnosed. Monozygotic twins had the highest adjusted RRR for ASD (estimated to be 153 times more likely to develop ASD); followed by full siblings (10.3 times), dizygotic twins (8.2), maternal half-siblings (3.3), paternal half-siblings (2.9) and cousins (2.0). Similar, if slightly higher, adjusted RRRs are found for autistic disorder: monozygotic twins (116.8), dizygotic twins (16.9), full siblings (14.6), maternal half-siblings (4.3), paternal half-siblings (2.9), and cousins (2.3).

Participants were followed for 20 years or until 2009, whichever came first. (Regular medical and developmental examinations are required for Swedish children as infants and throughout preschool.) At four years of age, a mandatory developmental assessment is conducted. From that assessment, children with suspected developmental disorders are referred for additional assessment. These assessments ensured completeness of data for the study.

This study held several advantages over previous studies, which may account for differences in research findings. The large sample size, established using data from multiple Swedish national registries, provided researchers with an unbiased population-based sample. Additionally, the length of follow-up time in this study increased the reliability of the finding results. This study was also one of the first to be able to accurately calculate RRR, by including twice as many cases of ASD and more detailed family data, including monozygotic and dizygotic twins and cousins, than previous studies.

This study was supported, in part, by grants from the National Institutes of Health: Grant HD073978 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Environmental Health Sciences, and National Institute of Neurological Disorders and Stroke; and Grant MH097849 from the National Institute of Mental Health; and by the Beatrice and Samuel A. Seaver Foundation.

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Genetic and Environmental Influences Are Equally Important Risk Factors for Autism Spectrum Disorder

by Andrea Lutz

KTVB.COM

Posted on May 4, 2014 at 9:41 PM

Updated today at 11:04 PM

BOISE -- Modern medicine and early detection are helping women in the fight against breast cancer, but recently a decision in our nation's highest court has made it easier to afford the cost of genetic cancer testing.

The Saint Alphonsus Breast Cancer Center in Boise reports that one in 500 breast cancer cases women have what's called the BRCA gene mutation.

Saint Als Breast Surgeon Elizabeth Prier says knowledge of the BRCA gene has been around for the last decade, and identifying at-risk women has intesified in the last five years.

A lot of women with BRCA1 will end up with breast cancer in their 30s sometimes in their late 20s, said Dr. Prier.

That means women end up starting their fight with the disease earlier.

Annie Pierce, a wife and mother of two, ended her battle with breast cancer before it even started.

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Breast cancer test made famous by Angelina Jolie now more affordable

PUBLIC RELEASE DATE:

30-Apr-2014

Contact: Scott LaFee slafee@ucsd.edu 619-543-6163 University of California - San Diego

Numerous studies have suggested a relationship between cardiovascular disease risk factors and prostate cancer. A new study by researchers at the University of California, San Diego School of Medicine, with colleagues in Norway, significantly refines the association, highlighting genetic risk factors associated with low density lipoprotein (LDL) cholesterol and triglycerides as key players and identifying 17 related gene loci that make risk contributions to levels of these blood lipids and to prostate cancer

The findings, published in the April 30, 2014 online issue of the International Journal of Epidemiology, provide new insights into the pathobiology of prostate cancer and may point to novel therapies to lower blood lipid levels that might help prevent prostate cancer the second most common cause of cancer death among American men.

The research team, headed by senior authors Anders M. Dale, PhD, professor in the departments of radiology, neurosciences and psychiatry at the UC San Diego School of Medicine, and Ole Andreassen, professor of psychiatry at Oslo University, applied a genetic epidemiology method to assess statistics from multiple genome-wide association studies, looking for genetic overlap between the phenotypes for prostate cancer and cardiovascular disease (CVD) risk factors. In the case of the latter, they specifically investigated triglycerides, LDL and high density lipoprotein cholesterol, systolic blood pressure, body mass index, waist-hip ratio and type 2 diabetes.

The researchers also examined enrichment of single nucleotide polymorphisms bits of DNA that vary among individuals associated with prostate cancer and CVD risk.

LDL cholesterol and triglycerides displayed a strong association with prostate cancer.

"It's fair to say that risk relationships of various sorts have been proposed between prostate cancer and cardiovascular disease, although not comorbidity per se," said co-author Ian G. Mills, PhD, of the University of Oslo and Oslo University Hospital in Norway. "There is a lack of consistency across cohorts, however, in size and direction of effects, depending on cardiovascular risk factor considered. The significant risk association with LDL cholesterol and triglycerides versus the other traits at a genetic level was novel and unexpected."

Mills said the identification of 17 pleiotropic loci specific sites in the genome which may affect the expression of a number of genes and influence a range of biological pathways, in this case affecting both prostate cancer and cardiovascular disease risk was a key finding. He said the loci provide clues to the common regulatory elements that affect expression of disease-related genes. They may be incorporated into future disease risk test panels. And they might, ultimately, help shape "genetically stratified dietary or chemoprevention studies repurposing clinically approved drugs that regulate blood lipid levels" to alter the risk of developing prostate cancer, he said.

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Prostate cancer and blood lipids share genetic links

PUBLIC RELEASE DATE:

30-Apr-2014

Contact: Gail Wilson gail.wilson@imperial.ac.uk 44-020-759-46702 Imperial College London

A distinctive genetic 'signature' found in the blood of children with tuberculosis (TB) offers new hope for improved diagnosis of the disease.

TB is very difficult to diagnose in children and is often recognised late when the child is already critically ill and the disease has spread from the lungs to the brain or other organs. Now an international team of researchers has shown that the disease can be identified in over 80 percent of cases by looking at 51 specific genes in the blood of affected children.

The researchers hope the findings published on 30 April in the New England Journal of Medicine could be used to develop a cheap, quick and effective diagnostic test.

Lead researcher, Professor Michael Levin, Director of the Wellcome Centre for Clinical Tropical Medicine at Imperial College London, explained: "We urgently need better methods to diagnose TB in children, so treatment can be started earlier and to avoid unnecessary treatment of children who are wrongly diagnosed. The symptoms of TB in children are common to many other childhood diseases, and the standard tests used on adults are not effective in children. Although the disease is treatable, thousands of children still die each year due to late diagnosis and many more are left with damage to their brain, bones and lungs."

The study funded through the EU and carried out at Wellcome Trust-supported units in Africa looked at over 2,800 children admitted to hospitals in South Africa, Malawi and Kenya with symptoms of TB. The researchers identified those who had proven TB and those in whom TB was excluded as the cause of the child's illness.

Blood samples from the South African and Malawian children were examined to see which genes were activated or suppressed in those with the disease. The researchers found that TB could be distinguished from other diseases by looking at just 51 genes from over 30,000 in the human genome and seeing whether they were activated or suppressed. This information was used to give a single TB risk score for each child which, when tested in the Kenyan patients, accurately diagnosed over 80 percent of the children with TB.

Professor Levin said: "It has taken seven years and the combined efforts of clinicians and scientists in the UK, Africa and Singapore to identify this gene signature of childhood TB. What we now need is collaboration from biotechnology and industrial partners to turn these findings into a simple, rapid and affordable test for TB that can be used in hospitals worldwide."

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Diagnosis of childhood TB could be improved by genetic discovery

By Vanessa Miller, The Gazette

Some patients with a suspected genetic disorder will go on what medical professionals call a diagnostic odyssey to find the cause of their symptoms.

But those explorations, on occasion, can come up empty, frustrating patients and prompting health care providers to seek outside expertise.

Last month, the Iowa Institute of Human Genetics at the University of Iowa began offering such expertise through whole exome sequencing.

The genetic test, which analyzes a portion of about 20,000 genes in the human genome in hopes of helping practitioners diagnose and treat a patient, is among several initiatives the institute is pursuing to further personalize medicine for patients in Iowa and across the country.

The research we do here is to develop new tests to bring precision medicine to the state, said Colleen Campbell, assistant director of the Iowa Institute of Human Genetics and associate with the UI Department of Otolaryngology.

Researchers with the institute also are conducting tests around secondary findings from exome sequencing the discovery of variants in genes unrelated to a patient's primary condition and how a person's genes interact with prescribed medication, including pain medication.

The technology is new, but officials with the Iowa institute said genetic sequencing one day could become so widely used that every infant will have it done as part of the standard newborn screen. Then, as a child grows, practitioners will be able to use the information to determine what type of pain medication to prescribe and at what level, for example.

Our focus is to bring innovation to the state, Campbell said. We want patients to be more informed when they go to the doctor and are offered these new tests. And we want to be able to offer this as a tool to doctors.

The Iowa Institute of Human Genetics is among only a dozen or so institutions nationally that offer whole exome sequencing to physicians wanting to order the test on behalf of a patient.

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University of Iowa hopes to better diagnose and treat patients

Lego Star Wars Genetic Medicine
by the Hetero-geniuses.

By: Dylon Quiros

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Lego Star Wars Genetic Medicine - Video

Irvine, CA (PRWEB) April 29, 2014

Proove Biosciences, the leader in Personalized Pain Medicine testing services, exhibited and presented clinical data on how proprietary genetic tests have been helping physicians improve patient pain treatment outcomes this weekend at The Valley Cancer Pain Foundations Third Annual Cancer Pain Conference. Proove is the only company exhibiting data on how company research and methods have been allowing doctors to utilize genetic analysis to make safer and more effective pain medication selection and dosing. At this weeks session, Proove Clinical Science Liaison, Derrick Holman, MD presented Proove research and provided medical education on the genetics of pain medicine.

As the only company presenting data on how genetic tests can improve the efficiency of pain medication and treatment, we were glad to participate in this weekends conference, stated Brian Meshkin, CEO and founder of Proove Biosciences. The Valley Cancer Pain Foundation does a wonderful job of providing an educational opportunity for pain clinicians, anesthesiologists, neurosurgeons, and hospice providers to learn about new technologies and best practices available in treating pain.

The annual conference is an industry gathering that aims to promote the most recent and relevant data and treatment options, and provide a forum to interact and discuss new and emerging evidence-based methods of improving access to and quality of care.

Proove continues to display industry leadership by publishing research showing how our unique genetic testing capabilities improve patient care. In the emerging field of pain medicine genetics, Proove is far outpacing other labs who continue to market run-of-the-mill drug metabolism genetic testing, stated Meshkin.

About Proove Biosciences Proove Biosciences is the leading Personalized Pain Medicine laboratory that provides proprietary genetic testing services to help physicians improve outcomes for patients and contain costs for insurers. With offices in Southern California and the Baltimore-Washington metropolitan area, the Company is the research leader investigating and publishing data on the genetics of pain medicine with clinical research sites across the United States. Physicians use Proove Biosciences testing to improve pain medicine selection, dosing, and evaluation of medications they prescribe. From a simple cheek swab collected in the office, Proove performs proprietary genetic tests in its CLIA-certified laboratory to identify patients at risk for misuse of prescription pain medications and evaluate their metabolism of medications. For more information, please visit http://www.proovebio.com or call toll free 855-PROOVE-BIO (855-776-6832).

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Proove Biosciences Presented Research and Data on How Genetic Testing Can Improve Pain Medicine Selection and Dosing

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Newswise Biogeographical data is useful in screening for disease risk and drug sensitivity associated with certain ethnic groups. A team of researchers, including an investigator from Childrens Hospital Los Angeles, has developed a tool to accurately identify the biogeography of worldwide individuals. Previous tools were accurate in identifying place of origin within homogeneous European populations but highly inaccurate for places with significant immigration, such as the U.S.

Tatiana Tatarinova, PhD, of The Saban Research Institute of Childrens Hospital Los Angeles, Eran Elhaik, PhD, of the University of Sheffield and colleagues developed an admixture-based Geographic Population Structure (GPS) tool that uses genetic distribution and geographical distance to determine place of origin, specifically the country, or in some cases, the village of origin. Their study will be published in the journal Nature Communications on April 29, 2014.

We were surprised by the simplicity and precision of this method, said Tatarinova, who is also an associate professor of Research Pediatrics at the Keck School of Medicine of the University of Southern California. People in a given geographical area are more likely to have similar genetics. When they also have genetic traits typically found in other, distant regions, the geographical origin of those traits is generally the closest location where those traits can be found.

Using a database of worldwide populations, the investigators developed a dataset of reference populations that are genetically diverse and have been geographically localized for centuries. With the GPS tool, the investigators were able to take unknown samples, identify the proportions of admixture--meaning, genetic characteristics specific to certain ethnic groups that were combined because of events like migration or invasion--and then calculate the distance to the nearest known population that shares the same admixture signature, in order to identify place of origin.

GPS was found to be both sensitive and specific. For example, in admixed populations such as Kuwaitis, it identified the countries of origin (Saudi Arabia and Iran), not just their current location. In the case of Sardinians, it placed a quarter of them within their villages. We expect the incredible abilities of GPS to become useful in forensics, allowing us to help lost people find their way home, says Elhaik.

According to the researchers, in ethnically diverse regions like the U.S., where many people know only a few generations of their descendants, this kind of screening has important medical implications. Discovery of a certain genotype might indicate the potential for a genetic disease and suggest that diagnostic testing be done. Also, as scientists learn more about personalized medicine, there is evidence that specific genotypes respond differently to medicationsmaking this information potentially useful when selecting the most effective therapy and appropriate dosing. The investigators are currently designing a study to correlate pharmacokinetics, the time course of drug metabolism, with genotype.

Genetic diseases are not the only driving force behind the development of GPS, according to Tatarinova. With a growing interest in the field of genealogy, more and more individuals are seeking information on their ancestral roots. Tatarinova has developed the website http://www.prosapia.org to allow anyone who previously obtained a DNA genotype to use the GPS tool to find their country or even village of origin.

About Childrens Hospital Los Angeles Children's Hospital Los Angeles has been named the best childrens hospital in California and among the top five in the nation for clinical excellence with its selection to the prestigious US News & World Report Honor Roll. Childrens Hospital is home to The Saban Research Institute, one of the largest and most productive pediatric research facilities in the United States, is one of America's premier teaching hospitals and has been affiliated with the Keck School of Medicine of the University of Southern California since 1932.

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Genealogy and Biogeography Meet Personalized Medicine

A study published today in Nature Genetics has revealed mutations that could have a major impact on the future diagnosis and treatment of many human diseases. Through an international collaboration, researchers at the Montreal Heart Institute (MHI) were able to identify a dozen mutations in the human genome that are involved in significant changes in complete blood counts and that explain the onset of sometimes severe biological disorders.

The number of red and white blood cells and platelets in the blood is an important clinical marker, as it helps doctors detect many hematological diseases and other diseases. Doctors can also monitor this marker to determine the effectiveness of therapy for certain pathologies.

"Complete blood counts are a complex human trait, as the number of cells in the blood is controlled by our environment and the combined expression of many genes in our DNA," explained Dr. Guillaume Lettre, a study co-author, an MHI researcher, and an Associate Professor at the Faculty of Medicine at Universit de Montral.

In collaboration with their colleagues at the University of Washington in Seattle and the University of Greifswald in Germany, these MHI researchers analyzed the DNA of 6,796 people who donated specimens to the MHI Biobank by looking specifically at segments of DNA directly involved in protein function in the body. They specifically identified a significant mutation in the gene that encodes erythropoietin, a hormone that controls the production of red blood cells. "Subjects who carry this mutation in their DNA have reduced hemoglobin levels and a 70% greater chance of developing anemia," explained Dr. Lettre. The scientists also identified a mutation in the JAK2 gene, which is responsible for a 50% increase in platelet counts and, in certain cases, for the onset of bone marrow diseases that can lead to leukemia. Dr. Jean-Claude Tardif, Director of the MHI Research Centre, Full Professor at the Faculty of Medicine at Universit de Montral, and a study co-author, added that "after reviewing pre-existing clinical data from the MHI Biobank, we observed that these donors also had a higher risk of having a stroke during their lifetime."

Dr. Lettre believes that these findings are very encouraging, as they suggest that the experimental approach used in the study can be applied to other human diseases. "Thanks to the existing genetic data and wealth of other clinical information available from the MHI Biobank, we will be able to identify other rare genetic variations that may impact the risk of cardiovascular disease and open the door to the development of new therapies."

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The above story is based on materials provided by Montreal Heart Institute. Note: Materials may be edited for content and length.

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Genetic mutations involved in human blood diseases identified

Three Texas universities are joining together to create ahome for environmental investigators, funding infrastructure needs with a $4.4 million grant from the National Institutes of Health,funding the first-ever hub for researchers looking for connections between genetic traits and environmental health factors.

UH, Texas A&M University and Baylor College of Medicine are teaming up to create thecenter, named by the National Institutes of Health as the newest national Center of Excellence in Environmental Health Science. It will be led by research team leader Cheryl Lyn Walker, director of the Texas A&M Health Science Center Institute of Biosciences and Technology andCollege ofVeterinary Medicine & Biomedical Sciences.

In addition to the $4.4 million NIH grant, researchers will be using their own existing grants and seeking additional grants to do their work, said Jeannie Kever, senior media relations specialist at UH.

As reported by the Eagle, this center is a cross-institutional initiative to promote integrated environmental health research and translate research advances into practices that can improve human health.

The grant will pay for the centers infrastructure needs and provide $250,000 in seed grants through a pilot program, officials said in a press release.

This is a game-changer, Walker said in a press release. We knew it needed to be an intercollegiate effort.

The Texas A&M Health Science Center is leading the centers development with collaboration from AgriLife Research, the Bush School of Government and Public Service,the Collegeof Education and Human Development, the College of Medicine, the College of Veterinary Medicine & Biomedical Sciences and the Dwight Look College of Engineering. That network is expanded with help from the Baylor College of Medicine and University of Houston researchers in the Texas Medical Center.

This is a great opportunity for major Texas institutions to address the environmental health issues of Texas, said Melissa Bondy, professor in the National Cancer Institute-designated Dan L. DuncanCancer Centerat the Baylor College of Medicine and associate director of the new center, in a UH press release.

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UH helps create hub for environmental experts

A newly identified genetic disorder associated with degeneration of the central and peripheral nervous systems in humans, along with the genetic cause, is reported in the April 24, 2014 issue of Cell.

The findings were generated by two independent but collaborative scientific teams, one based primarily at Baylor College of Medicine and the Austrian Academy of Sciences, the other at the University of California, San Diego School of Medicine, the Academic Medical Center (AMC) in the Netherlands and the Yale University School of Medicine.

By performing DNA sequencing of more than 4,000 families affected by neurological problems, the two research teams independently discovered that a disease marked by reduced brain size and sensory and motor defects is caused by a mutation in a gene called CLP1, which is known to regulate tRNA metabolism in cells. Insights into this rare disorder, the researchers said, may have important implications for the future treatment of more common neurological conditions.

"What we found particularly striking, when considering the two studies together, is that this is not a condition that we would have been able to separate from other similar disorders based purely on patient symptoms or clinical features," said Joseph G. Gleeson, MD, Howard Hughes Medical Institute investigator, professor in the UC San Diego departments of Neurosciences and Pediatrics and at Rady Children's Hospital-San Diego, a research affiliate of UC San Diego. "Once we had the gene spotted in these total of seven families, then we could see the common features. It is the opposite way that doctors have defined diseases, but represents a transformation in the way that medicine is practiced."

Each child tested was affected by undiagnosed neurological problems. All of the children were discovered to carry a mutation in the CLP1 gene and displayed the same symptoms, such as brain malformations, intellectual disabilities, seizures and sensory and motor defects. A similar pattern emerged in both studies, one led by Gleeson, with Murat Gunel, MD, of the Yale University School of Medicine and Frank Baas, PhD, of the Academic Medical Center in the Netherlands, and the other by Josef Penninger and Javier Martinez of the Austrian Academy of Sciences, teamed with James R. Lupski, MD, PhD, of the Baylor College of Medicine.

"Knowing fundamental pathways that regulate the degeneration of neurons should allow us to define new pathways that, when modulated, might help us to protect motor neurons from dying, such as in Lou Gehrig's disease," said Penninger, scientific director of the Institute of Molecular Biotechnology of the Austrian Academy of Sciences.

The CLP1 protein plays an important role in generating mature, functional molecules called transfer RNAs (tRNAs), which shuttle amino acids to cellular subunits called ribosomes for assembly into proteins. Mutations affecting molecules involved in producing tRNAs have been implicated in human neurological disorders, such as pontocerebellar hypoplasia (PCH), a currently incurable neurodegenerative disease affecting children. Although CLP1 mutations have been linked to neuronal death and motor defects in mice, the role of CLP1 in human disease was not known until now.

These scientists performed DNA sequencing on children with neurological problems. Seven out of the more than 4,000 families studied shared an identical CLP1 mutation, which was associated with motor defects, speech impairments, seizures, brain atrophy and neuronal death.

Bass at the AMC said the neurological condition represents a new form of PCH. "Identification of yet another genetic cause for this neurodegenerative disorder will allow for better genetic testing and counseling to families with an affected child," he said.

In a published paper last year, Gleeson and colleagues identified a different gene mutation for a particularly severe form of PCH, and reported early evidence that a nutritional supplement might one day be able to prevent or reverse the condition.

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New genetic brain disorder in humans discovered

PUBLIC RELEASE DATE:

24-Apr-2014

Contact: Sid Dinsay sid.dinsay@mountsinai.org 212-241-9200 The Mount Sinai Hospital / Mount Sinai School of Medicine

A substantial proportion of risk for developing autism spectrum disorders (ASD), resides in genes that are part of specific, interconnected biological pathways, according to researchers from the Icahn School of Medicine at Mount Sinai, who conducted a broad study of almost 2,500 families in the United States and throughout the world. The study, titled "Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders," was first published online in the American Journal of Human Genetics on April 24.

ASD affects about one percent of the population in the United States and is characterized by impairments in social interaction and communication, as well as by repetitive and restricted behaviors. ASD ranges from mild to severe levels of impairment, with cognitive function among individuals from above average to intellectual disability.

Previously, ASD has been shown to be highly inheritable, and genomic studies have revealed that that there are various sources of risk for ASD, including large abnormalities in whole chromosomes, deletions or duplications in sections of DNA called copy number variants (CNVs), and even changes of single nucleotides (SNVs) within a gene; genes contain instructions to produce proteins that have various functions in the cell.

The researchers reported numerous CNVs affecting genes, and found that these genes are part of similar cellular pathways involved in brain development, synapse function and chromatin regulation. Individuals with ASD carried more of these CNVs than individuals in the control group, and some of them were inherited while others were only present in offspring with ASD.

An earlier study, results of which were first published in 2010, highlighted a subset of these findings within a cohort of approximately 1,000 families in the U.S. and Europe; this larger study has expanded that cohort to nearly 2,500 families, each comprising "trios" of two parents and one child. By further aggregating CNVs and SNVs (the latter identified in other studies), Mount Sinai researchers discovered many additional genes and pathways involved in ASD.

"We hope that these new findings will help group individuals with ASD based upon their genetic causes and lead to earlier diagnosis, and smarter, more focused therapies and interventions for autism spectrum disorders," said first author Dalila Pinto, PhD, Assistant Professor of Psychiatry, and Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai. Dr. Pinto is a Seaver Foundation Faculty Fellow, and a member of the Mindich Child Health & Development Institute, the Icahn Institute for Genomics and Multiscale Biology, and the Friedman Brain Institute at the Icahn School of Medicine at Mount Sinai; other Mount Sinai researchers on this study include Mafalda Barbosa, Graduate Student in Psychiatry; Xiao Xu, PhD, Postdoctoral Fellow in Psychiatry; Alexander Kolevzon, MD, Clinical Director of the Seaver Autism Center and Associate Professor of Psychiatry and Pediatrics; and Joseph D. Buxbaum, PhD, Director of the Seaver Autism Center, Vice Chair for Research in Psychiatry, and Professor of Psychiatry, Neuroscience, and Genetics and Genomic Sciences.

###

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Genetic alterations in shared biological pathways as major risk factor for ASD

CHICAGO (Reuters) - International teams of researchers using advanced gene sequencing technology have uncovered a single genetic mutation responsible for a rare brain disorder that may have stricken families in Turkey for some 400 years.

The discovery of this genetic disorder, reported in two papers in the journal Cell, demonstrates the growing power of new tools to uncover the causes of diseases that previously stumped doctors.

Besides bringing relief to affected families, who can now go through prenatal genetic testing in order to have children without the disorder, the discovery helps lend insight into more common neurodegenerative disorders, such as ALS, also known as Lou Gehrig's disease, the researchers said.

The reports come from two independent teams of scientists, one led by researchers at Baylor College of Medicine and the Austrian Academy of Sciences, and the other by Yale University, the University of California, San Diego, and the Academic Medical Center in the Netherlands.

Both focused on families in Eastern Turkey where marriage between close relatives, such as first cousins, is common. Geneticists call these consanguineous marriages.

In this population, the researchers focused specifically on families whose children had unexplained neurological disorders that likely resulted from genetic defects.

Both teams identified a new neurological disorder arising from a single genetic variant called CLP1. Children born with this disorder inherit two defective copies of this gene, which plays a critical role in the health of nerve cells.

Babies with the disorder have small and malformed brains, they develop progressive muscle weakness, they do not speak and they are increasingly prone to seizures.

Dr Ender Karaca, a post-doctoral associate in the department of molecular and human genetics at Baylor, first encountered the disorder in 2006 and 2007 during his residency training as a clinical geneticist in Turkey.

"We followed them for years," said Karaca, a lead author on one of the papers. Karaca said he and his colleagues performed some basic genetic tests on the families but to no avail.

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Researchers discover that two defective copies of a single gene cause rare brain disorder

PUBLIC RELEASE DATE:

24-Apr-2014

Contact: Scott LaFee slafee@ucsd.edu 619-543-6163 University of California - San Diego

A newly identified genetic disorder associated with degeneration of the central and peripheral nervous systems in humans, along with the genetic cause, is reported in the April 24, 2014 issue of Cell.

The findings were generated by two independent but collaborative scientific teams, one based primarily at Baylor College of Medicine and the Austrian Academy of Sciences, the other at the University of California, San Diego School of Medicine, the Academic Medical Center (AMC) in the Netherlands and the Yale University School of Medicine.

By performing DNA sequencing of more than 4,000 families affected by neurological problems, the two research teams independently discovered that a disease marked by reduced brain size and sensory and motor defects is caused by a mutation in a gene called CLP1, which is known to regulate tRNA metabolism in cells. Insights into this rare disorder, the researchers said, may have important implications for the future treatment of more common neurological conditions.

"What we found particularly striking, when considering the two studies together, is that this is not a condition that we would have been able to separate from other similar disorders based purely on patient symptoms or clinical features", said Joseph G. Gleeson, MD, Howard Hughes Medical Institute investigator, professor in the UC San Diego departments of Neurosciences and Pediatrics and at Rady Children's Hospital-San Diego, a research affiliate of UC San Diego. "Once we had the gene spotted in these total of seven families, then we could see the common features. It is the opposite way that doctors have defined diseases, but represents a transformation in the way that medicine is practiced."

Each child tested was affected by undiagnosed neurological problems. All of the children were discovered to carry a mutation in the CLP1 gene and displayed the same symptoms, such as brain malformations, intellectual disabilities, seizures and sensory and motor defects. A similar pattern emerged in both studies, one led by Gleeson, with Murat Gunel, MD, of the Yale University School of Medicine and Frank Baas, PhD, of the Academic Medical Center in the Netherlands, and the other by Josef Penninger and Javier Martinez of the Austrian Academy of Sciences, teamed with James R. Lupski, MD, PhD, of the Baylor College of Medicine.

"Knowing fundamental pathways that regulate the degeneration of neurons should allow us to define new pathways that, when modulated, might help us to protect motor neurons from dying, such as in Lou Gehrig's disease," said Penninger, scientific director of the Institute of Molecular Biotechnology of the Austrian Academy of Sciences.

The CLP1 protein plays an important role in generating mature, functional molecules called transfer RNAs (tRNAs), which shuttle amino acids to cellular subunits called ribosomes for assembly into proteins. Mutations affecting molecules involved in producing tRNAs have been implicated in human neurological disorders, such as pontocerebellar hypoplasia (PCH), a currently incurable neurodegenerative disease affecting children. Although CLP1 mutations have been linked to neuronal death and motor defects in mice, the role of CLP1 in human disease was not known until now.

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Researchers discover new genetic brain disorder in humans

PUBLIC RELEASE DATE:

24-Apr-2014

Contact: Bill Hathaway william.hathaway@yale.edu 203-432-1322 Yale University

An international team of researchers have identified a previously unknown neurodegenerative disorder and discovered it is caused by a single mutation in one individual born during the Ottoman Empire in Turkey about 16 generations ago.

The genetic cause of the rare disorder was discovered during a massive analysis of the individual genomes of thousands of Turkish children suffering from neurological disorders.

"The more we learn about basic mechanisms behind rare forms of neuro-degeneration, the more novel insights we can gain into more common diseases such as Alzheimer's or Lou Gehrig's Disease," said Murat Gunel, the Nixdorff-German Professor of Neurosurgery, and professor of genetics and neurobiology at Yale.

Gunel is a senior co-author of one of two papers published in the April 24 issue of the journal Cell that document the devastating effects of a mutation in the CLP1 gene. Gunel and colleagues at Yale Center for Mendelian Genomics along with Joseph Gleeson's group at University of California-San Diego compared DNA sequencing results of more than 2,000 children from different families with neurodevelopmental disorders. In four apparently unrelated families, they identified the exact same mutation in the CLP1 gene. Working with the Frank Bass group from the Netherlands, the researchers also studied how CLP1 mutations interfered with the transfer of information encoded within genes to cells' protein-making machinery.

The discovery of the identical mutation in seemingly unrelated families originally from eastern Turkey suggested an ancestral mutation, dating back several generations, noted the researchers.

Affected children suffer from intellectual disability, seizures, and delayed or absent mental and motor development, and their imaging studies show atrophy affecting the cerebral cortex, cerebellum, and the brain stem.

The second Cell paper by researchers from Baylor School of Medicine and Austria also found the identical founder mutation in CLP1 in another 11 children from an additional five families originally from eastern Turkey.

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Genetic legacy from the Ottoman Empire: Single mutation causes rare brain disorder

Research assistant Natalie Thomas pulls a slice of a cancerous tumor for analysis at the Anschutz Medical Campus. (Andy Cross, The Denver Post)

Ellen Smith received a death sentence for her advanced lung cancer five years ago, but it was commuted by a revolution in human genetics, drug therapies and clinical approaches unfolding at the University of Colorado Hospital.

The advances have saved her life, by her reckoning, four times.

The accelerating speed of DNA sequencing, drug development and data analysis has led UCHealth, the University of Colorado Medical School and Children's Hospital Colorado to join in an effort to fundamentally change the way they care for patients.

The partnership will invest more than $63 million over the next five years to create a new division, adding clinicians, genetic counselors, researchers and advanced practice nurses and also expanding a DNA bank and advanced data warehouse. It's called the Center for Personalized Medicine and Biomedical Informatics.

The pioneering field of personalized medicine uses molecular analysis to determine a patient's predisposition to developing certain diseases and to deliver tailored medical treatment.

"There is no doubt in my mind that this will change how we treat disease, how we teach our students, how physicians work, how we raise our kids and how we conduct public health policy," Dr. David Schwartz, chair of the CU Department of Medicine, said of the center.

The DNA bank, Schwartz said, probably will require a year of discussion with physicians, academicians, lawyers, ethicists and patient advocates about what it really means to secure patients' genetic blueprints and how they should be used.

While the center will be based on the Anschutz Medical Campus in Aurora, it will serve UCHealth's five hospitals and Children's Hospital. The DNA bank would sequence and analyze samples from around the region.

The benefits of personalized medicine have been evident for several years in cancer treatment, said Dr. Dan Theodorescu, director of the CU Cancer Center. It's why the center's survival rates are significantly better for certain types of cancers than the average national outcomes, he said. The new center will bring these kinds of lifesaving therapies to all disease fronts while providing more laboratory and analytical power to evaluate cancer DNA, he said.

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CU system resets health care with $63M personalized medicine division

PUBLIC RELEASE DATE:

17-Apr-2014

Contact: Jane C. Figueiredo janefigu@usc.edu PLOS

A common genetic variant that affects one in three people appears to significantly increase the risk of colorectal cancer from the consumption of processed meat, according to study published today in PLOS Genetics. The study of over 18,000 people from the U.S., Canada, Australia and Europe represents the first large-scale genome-wide analysis of genetic variants and dietary patterns that may help explain more of the risk factors for colorectal cancer. Dr Jane Figueiredo at the Keck School of Medicine of the University of Southern California, explained that eating processed meat is associated with an increased risk of colorectal cancer and for about a third of the general population who carry this genetic variant, the risk of eating processed meat is even higher compared to those who do not. "Our results, if replicated by other studies, may provide us with a greater understanding of the biology into colorectal carcinogenesis," said Dr Ulrike Peters of the Fred Hutchinson Cancer Research Center's Public Health Sciences Division.

The study population totaled 9,287 patients with colorectal cancer and a control group of 9,117 individuals without cancer, all participants in 10 observational studies that were pooled in the largest meta-analysis sponsored by the National Institutes of Health-funded Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and Colorectal Cancer Family Registry. Scientists systematically searched 2.7 million variants to identify those that are associated with the consumption of meat, fiber, fruits and vegetables. A significant interaction between the genetic variant rs4143094 and processed meat consumption was detected. This variant is located on the same chromosome 10 region that includes GATA3, a transcription factor gene previously linked to several forms of cancer. The transcription factor encoded by this gene plays a role in the immune system. Dr Figueiredo hypothesized that the genetic locus found to interact with processed meat may have interesting biological significance given its location in the genome, but further functional analyses are required.

Colorectal cancer is a multi-factorial disease attributed to both genetic causes and lifestyle factors; including diet. About 30 known genetic susceptibility alleles for colorectal cancer have been pinpointed throughout the genome. How specific foods affect the activities of genes has not been established but represents an important area of research for prevention. "The possibility that genetic variants may modify an individual's risk for disease based on diet has not been thoroughly investigated but represents an important new insight into disease development," said Dr Li Hsu, the lead statistician on the study. "Diet is a modifiable risk factor for colorectal cancer. Our study is the first to understand whether some individuals are at higher or lower risk based on their genomic profile. This information can help us better understand the biology and maybe in the future lead to targeted prevention strategies," said Dr Figueiredo.

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New gene variant found increases the risk of colorectal cancer from eating processed meat

PUBLIC RELEASE DATE:

17-Apr-2014

Contact: Helen Dodson helen.dodson@yale.edu 203-436-3984 Yale University

New Haven, Conn. Researchers from Yale School of Medicine and Celera Diagnostics have confirmed the significance of a genetic variant that substantially increases the risk of a frequently fatal thoracic aortic dissection or full rupture. The study appears online in PLOS ONE.

Thoracic aortic aneurysms, or bulges in the artery wall, can develop without pain or other symptoms. If they lead to a tear dissection or full rupture, the patient will often die without immediate treatment. Therefore, better identification of patients at risk for aortic aneurysm and dissection is considered essential.

The research team, following up on a previous genome-wide association study by researchers at Baylor College of Medicine, investigated genetic variations in a protein called FBN-1, which is essential for a strong arterial wall. After studying hundreds of patients at Yale, they confirmed what was found in the Baylor study: that one variation, known as rs2118181, put patients at significantly increased risk of aortic tear and rupture.

"Although surgical therapy is remarkable and effective, it is incumbent on us to move to a higher genetic level of understanding of these diseases," said senior author John Elefteriades, M.D., the William W. L. Glenn Professor of Surgery (Section of Cardiac Surgery) at Yale School of Medicine, and director of the Aortic Institute at Yale-New Haven Hospital. "Such studies represent important steps along that path."

The researchers hope their confirmation of the earlier study may help lead to better clinical care of patients who may be at high risk of this fatal condition. "Patients with this mutation may merit earlier surgical therapy, before aortic dissection has a chance to occur," Elefteriades says. Yale cardiothoracic surgeons will now begin assessing this gene in clinical patients with aneurysm disease.

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The Yale-New Haven Hospital Aortic Institute opens April 22. It will specialize in clinical care, basic science, and clinical research in aortic disease.

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Gene variant raises risk for aortic tear and rupture

University of Missouri researchers have previously shown that a genetic pre-disposition to be more or less motivated to exercise exists. In a new study, Frank Booth, a professor in the MU College of Veterinary Medicine, has found a potential link between the genetic pre-disposition for high levels of exercise motivation and the speed at which mental maturation occurs.

For his study, Booth selectively bred rats that exhibited traits of either extreme activity or extreme laziness. Booth then put the rats in cages with running wheels and measured how much each rat willingly ran on their wheels during a six-day period. He then bred the top 26 runners with each other and bred the 26 rats that ran the least with each other. They repeated this process through 10 generations and found that the line of running rats chose to run 10 times more than the line of "lazy" rats.

Booth studied the brains of the rats and found much higher levels of neural maturation in the brains of the active rats than in the brains of the lazy rats.

"We looked at the part of the brain known as the 'grand central station,' or the hub where the brain is constantly sending and receiving signals," Booth said. "We found a big difference between the amount of molecules present in the brains of active rats compared to the brains of lazy rats. This suggests that the active rats were experiencing faster development of neural pathways than the lazy rats."

Booth says these findings may suggest a link between the genes responsible for exercise motivation and the genes responsible for mental development. He also says this research hints that exercising at a young age could help develop more neural pathways for motivation to be physically active.

"This study illustrates a potentially important link between exercise and the development of these neural pathways," Booth said. "Ultimately, this could show the benefits of exercise for mental development in humans, especially young children with constantly growing brains."

Booth's study, "Nucleus accumbens neuronal maturation differences in young rats bred for low versus high voluntary running behavior," was published in the Journal of Physiology.

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The above story is based on materials provided by University of Missouri-Columbia. Note: Materials may be edited for content and length.

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Genetic pre-disposition toward exercise, mental development may be linked

PUBLIC RELEASE DATE:

15-Apr-2014

Contact: Nathan Hurst hurstn@missouri.edu 573-882-6217 University of Missouri-Columbia

COLUMBIA, Mo. University of Missouri researchers have previously shown that a genetic pre-disposition to be more or less motivated to exercise exists. In a new study, Frank Booth, a professor in the MU College of Veterinary Medicine, has found a potential link between the genetic pre-disposition for high levels of exercise motivation and the speed at which mental maturation occurs.

For his study, Booth selectively bred rats that exhibited traits of either extreme activity or extreme laziness. Booth then put the rats in cages with running wheels and measured how much each rat willingly ran on their wheels during a six-day period. He then bred the top 26 runners with each other and bred the 26 rats that ran the least with each other. They repeated this process through 10 generations and found that the line of running rats chose to run 10 times more than the line of "lazy" rats.

Booth studied the brains of the rats and found much higher levels of neural maturation in the brains of the active rats than in the brains of the lazy rats.

"We looked at the part of the brain known as the 'grand central station,' or the hub where the brain is constantly sending and receiving signals," Booth said. "We found a big difference between the amount of molecules present in the brains of active rats compared to the brains of lazy rats. This suggests that the active rats were experiencing faster development of neural pathways than the lazy rats."

Booth says these findings may suggest a link between the genes responsible for exercise motivation and the genes responsible for mental development. He also says this research hints that exercising at a young age could help develop more neural pathways for motivation to be physically active.

"This study illustrates a potentially important link between exercise and the development of these neural pathways," Booth said. "Ultimately, this could show the benefits of exercise for mental development in humans, especially young children with constantly growing brains."

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Genetic pre-disposition toward exercise and mental development may be linked