Category Archives: Molecular Genetics

Researchers at the University of Alabama (UAB) at Birmingham report the discovery of an important role for the RSF1, or remodeling and spacing factor 1, protein in silencing genes. They also demonstrated that disrupting RSF1 expression in the embryos of African clawed frogs caused severe developmental defects in the tadpoles. This took place via a dysregulation of mesodermal cell fate specification.

The team published its paper ("Role of Remodeling and Spacing Factor 1 in Histone H2A Ubiquitination-Mediated Gene Silencing") in Proceedings of the National Academy of Sciences. Understanding how genes get turned on or off is critical for developing better therapies for diseases like cancer.

Histone H2AK119 ubiquitination (H2Aub), as mediated by Polycomb repressive complex 1 (PRC1), is a prevalent modification which has been linked to gene silencing. We report that remodeling and spacing factor 1 (RSF1), a subunit of the RSF complex, is a H2Aub-binding protein. It reads H2Aub through a previously uncharacterized ubiquitinated H2A binding (UAB) domain, write the investigators. We show that RSF1 is required both for H2Aub-target gene silencing and for maintaining stable nucleosome patterns at promoter regions.

According to Hengbin Wang, Ph.D., and colleagues, RSF1 acts on chromatin, which is not static but changes in its structure to control different physiological processes. One contributor to chromatin fluidity involves modifications of the histone proteins made by adding or removing chemical groups to the histone tails, says Dr. Wang, who notes that histones can be modified by acetylation, phosphorylation, methylation, ubiquitination, or adenosine diphosphate (ADP) ribosylation.

In the current study, Dr. Wang, an associate professor of biochemistry and molecular genetics in the UAB School of Medicine, looked at the addition of ubiquitin to the histone subunit H2A. This modification is linked to gene silencing, while removing ubiquitin from H2A leads to gene activation. Dr. Wang and colleagues discovered that RSF1 mediates the gene-silencing function of ubiquitinated H2A.

They found that RSF1 is a ubiquitinated H2A binding protein that reads ubiquitinated H2A through a previously uncharacterized and obligatory ubiquitinated H2A binding domain.

Carrying out research on human and mouse cells, the team found that the genes regulated by RSF1 overlapped greatly with those controlled by part of a complex that ubiquitinates H2A. Knocking out RSF1 in cells derepressed the genes regulated by RSF1, and this was accompanied by changes in ubiquitinated H2A chromatin organization and release of linker histone H1.

In the PNAS paper, Dr. Wang and his group suggested a model for the action of RSF1 in gene silencing.

"RSF1 binds to ubiquitinated H2A nucleosomes to establish and maintain the stable ubiquitinated H2A nucleosome pattern at promoter regions," they write. "The stable nucleosome array leads to a chromatin architecture that is refractory to further remodeling required for ubiquitinated H2A target gene activation. When RSF1 is knocked out, ubiquitinated H2A nucleosome patterns are disturbed and nucleosomes become less stable, despite the presence of ubiquitinated H2A. These ubiquitinated H2A nucleosomes are subjected to chromatin remodeling for gene activation."

Dr. Wang believes that learning more about the ubiquitinated H2A binding site may help in the discovery of other ubiquitinated histone-binding proteins.

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Gene-Silencing Finding May Lead to Better Understanding of Some ... - Genetic Engineering & Biotechnology News

A recent Duke University study sheds new light on intestinal health and disease.

The study, called Genomic Dissection of Conserved Transcriptional Regulation in Intestinal Epithelial Cells, published Tuesday in PLOS Biology journal.

Scientists identified an ancient network of genes shared between humans and other vertebrates that make up the intestine.

These results indicate that the intestines of humans and fishes share more in common than once presumed, making it possible to look into the guts of fish and other related animals to learn about the origins of human intestinal conditions, said Dr. John Rawls, the senior author of the study.

Some of the shared genes have previously been linked to diabetes, inflammatory bowel diseases and obesity. Rawls, associate professor of molecular genetics and microbiology at Dukes School of Medicine, said the researchers believe they discovered what may turn those genes on and off.

Our research has uncovered aspects of intestinal biology that have been well-conserved during vertebrate evolution, suggesting they are of central importance to intestinal health, Rawls said in a news release from Duke. By doing so, we have built a foundation for mechanistic studies of intestinal biology in non-human model systems like fish and mice that would be impossible to perform in humans alone.

The use of animals in human intestinal research is nothing new. But genome-wide data generated from zebrafish, stickleback fish, mice and humans identified the extent the genes were shared among the species.

Dr. Colin Lickwar, a co-author of the study, mapped out each species activity level for all of the genes and the location of specific genetic sequences or regulatory elements that flipped those genes on and off, the university reported.

The project was supported by Duke University and the National Institutes of Health.

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Out of a fish gut study, researchers open new doors in intestinal health - Durham Herald Sun

BETHESDA, Md., Aug. 4, 2017 /PRNewswire-USNewswire/ --Madhuri Hegde, PhD, FACMG of PerkinElmer, Inc. in Waltham, MA has been elected to the ACMG Foundation for Genetic and Genomic Medicine Board of Directors, the supporting educational foundation of the American College of Medical Genetics and Genomics. The ACMG Foundation is a national nonprofit foundation dedicated to facilitating the integration of genetics and genomics into medical practice. The board members are active participants in serving as advocates for the Foundation and for advancing its policies and programs. Dr. Hegde has been elected to a 2-year renewable term starting immediately.

Dr. Hegde joined PerkinElmer in 2016 as Vice President and Chief Scientific Officer, Global Genetics Laboratory Services. She also is an Adjunct Professor of Human Genetics in the Department of Human Genetics at Emory University. Previously, Dr. Hegde was Executive Director and Chief Scientific Officer at Emory Genetics Laboratory in Atlanta, GA and Professor of Human Genetics and Pediatrics at Emory University and Assistant Professor, Department of Human Genetics and Senior Director at Baylor College of Medicine in Houston, TX.

Dr. Hegde has served on a number of Scientific Advisory Boards for patient advocacy groups including Parent Project Muscular Dystrophy, Congenital Muscular Dystrophy and Neuromuscular Disease Foundation. She was a Board member of the Association for Molecular Pathology and received the Outstanding Faculty Award from MD Anderson Cancer Center. She earned her PhD in Applied Biology from the University of Auckland in Auckland, New Zealand and completed her Postdoctoral Fellowship in Molecular Genetics at Baylor College of Medicine in Houston, TX. She also holds a Master of Science in Microbiology from the University of Mumbai in India. She has authored more than 100 peer-reviewed publications and has given more than 100 keynote and invited presentations at major national and internal conferences.

"We are delighted that Dr. Hegde has been elected to the ACMG Foundation Board of Directors. She has vast experience in genetic and genomic testing and is a longtime member of the College and supporter of both the College and the Foundation," said Bruce R. Korf, MD, PhD, FACMG, president of the ACMG Foundation.

The complete list of the ACMG Foundation board of directors is at http://www.acmgfoundation.org.

About the ACMG Foundation for Genetic and Genomic Medicine

The ACMG Foundation for Genetic and Genomic Medicine, a 501(c)(3) nonprofit organization, is a community of supporters and contributors who understand the importance of medical genetics and genomics in healthcare. Established in 1992, the ACMG Foundation for Genetic and Genomic Medicine supports the American College of Medical Genetics and Genomics' mission to "translate genes into health" by raising funds to help train the next generation of medical geneticists, to sponsor the development of practice guidelines, to promote information about medical genetics, and much more.

To learn more about the important mission and projects of the ACMG Foundation for Genetic and Genomic Medicine and how you too can support the work of the Foundation, please visit http://www.acmgfoundation.org or contact us at rel="nofollow">acmgf@acmgfoundation.org or 301-718-2014.

Contact Kathy Beal, MBA ACMG Media Relations, rel="nofollow">kbeal@acmg.net

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Helen McNeills work in developmental biology spans birth defects to cancer

Helen McNeill, PhD, has been named a BJC Investigator at Washington University School of Medicine in St. Louis. She is the first researcher named as part of the new BJC Investigators Program.

Helen McNeill, PhD, has been named a BJC Investigator at Washington University School of Medicine in St. Louis. She is the first researcher named as part of the new BJC Investigators Program, which aims to recruit scientists who bring innovative approaches to major biological quandaries and whose discoveries stand to inform new ways of understanding disease and developing treatments.

McNeill, the first of 10 expected BJC Investigators, is currently a professor in the Institute of Medical Science and the Department of Molecular Genetics, both at the University of Toronto. She is also a senior investigator at the Lunenfeld-Tanenbaum Research Institute, part of the Sinai Health System in Toronto. Her appointment as a BJC Investigator and a professor of developmental biology at Washington University begins Jan. 1, 2018.

We are excited to begin the BJC Investigators Program with the appointment of Dr. Helen McNeill, an international leader in the field of developmental biology, said David H. Perlmutter, MD, executive vice chancellor for medical affairs and dean of the School of Medicine. We sought candidates who had already indelibly changed their fields, whose discoveries will result in new and fundamental shifts in scientific thinking and whose laboratories will become a nidus for additional innovative work across Washington University. Helens scientific accomplishments, her high standards of excellence and ability to collaborate across disciplines make her a perfect fit.

The program is designed to specifically focus on basic science and is inspired by the Howard Hughes Medical Institutes philosophy of investing in people with exceptional creative talent. It plans to bring 10 renowned researchers to Washington University School of Medicine and the life sciences ecosystem of St. Louis.

We are very excited about the BJC Investigators Program at Washington University School of Medicine, said Steven H. Lipstein, CEO of BJC HealthCare. This program represents another joint effort between BJC and Washington University to help keep the schools biomedical research at the forefront of discovery. Pioneering research here in St. Louis offers our best hope for finding solutions to societys greatest medical challenges.

McNeills work is focused on understanding the processes that govern how cells make contact and work together to form the broader architecture of whole tissues, both during development and adulthood. Her work spanning studies of fruit flies, mice and human genetic data has relevance for understanding birth defects, cancer and diseases of specific organs, such as the kidney and lungs.

McNeill earned a bachelors degree in biology from the Ramapo College of New Jersey in 1985, followed by a doctorate in molecular and cellular physiology from Stanford University in 1993. She continued research at Stanford with a postdoctoral fellowship in fruit fly genetics. McNeill later led the Developmental Patterning Laboratory at the London Research Institute, a part of the Imperial Cancer Research Fund of the United Kingdom. She joined the faculty of the University of Toronto in 2005, where she has directed the Collaborative Program in Developmental Biology and earned numerous recognitions for her research, including the Petro-Canada Young Innovator Award and the Lloyd S.D. Fogler, QC, Award of Excellence for her research in cancer biology. Last year, she was awarded a Canada Tier 1 Research Chair, a position in which a scientist is recognized by peers as a world leader in his or her field.

I am delighted that Dr. McNeill will be joining us at Washington University, said Lilianna Solnica-Krezel, PhD, the Alan A. and Edith L. Wolff Professor of Developmental Biology and head of the Department of Developmental Biology. She is a leader in the field and among the most original and creative investigators of pathways that are vital for the regulation of tissue structure and growth. The pathways she studies are among the least understood cellular pathways, with implications for a variety of birth defects and other diseases, including cancer.

Specifically, McNeill studies molecules that govern how cells make contact and communicate with one another. Called giant cadherins for their large size, these molecules play important roles in controlling the size of organs and in orchestrating how cells assemble themselves into complex tissues at precise times and with specific patterns and orientations. Her work also has implicated these molecules in cellular metabolism and the function of mitochondria, molecular powerhouses that manufacture a cells fuel supply. According to McNeills research, disruption of the giant cadherins can interfere with early embryonic development leading to, for example, neural tube defects that cause spina bifida or defects in the development of the kidney and urinary tract. Her work has identified cadherins as a culprit in congenital kidney diseases such as cystic kidney disease.

I am excited and honored to be joining Washington University School of Medicine as a BJC Investigator, McNeill said. Supporting research in the basic sciences is so important in making new discoveries and pushing the boundaries of what is known about human health and development. I thank the School of Medicine and BJC HealthCare for their commitment to supporting basic biomedical science in my own lab and in the labs of my fellow investigators.

Washington University School of Medicines 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked seventh in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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First of 10 expected BJC Investigators named - Washington University School of Medicine in St. Louis

A medical technologist at CombiMatrix examines live tissue looking for fetal cells to analyze. (File Photo)

From left, medical technologists Lilybeth Wilkens, Meg Purayil, and Catherine Marte work on live samples of tissue at CombiMatrix, a genetic testing lab in Irvine. (File Photo)

Catherine Marte works on live samples of tissue at CombiMatrix, a genetic testing lab in Irvine. (File Photo)

Chief Executive Mark McDonough stands in the lobby of his company, CombiMatrix Corp., in Irvine. The company hopes its testing method will be used to analyze cases of women whove had multiple miscarriages. (File Photo)

Irvine-based CombiMatrix Corp. has agreed to be acquired in an all-stock merger by San Francisco-based Invitae Corp. for $33 million.

The deal between two genetic biotech firms is subject to approval by CombiMatrixs stockholders and regulatory agencies.

CombiMatrix is a molecular diagnostics company that studies theremains of lost pregnancies, extracting DNA that is analyzed to uncover genetic abnormalities that can help explain why the women who gave the samples have had multiple miscarriages. It also does pre-implantation genetic diagnostics and screening, prenatal diagnosis andDNA-based testing forgenetic abnormalities.

In 2014, the companys chief executive, a former Navy navigator, told the Register the companys methods would soon become the standards for analyzing pregnancy loss and prenatal testing.

Merging with Invitae, which also specializes in genetic material and hereditary disorders, should expand the scope of CombiMatrixs reach.

By coming together with Invitae, we believe we can synergistically combine their scale, technology and expertise with the CombiMatrix product offering, human capital and sales channels to achieve even greater success in the future for the company and our shareholders, Mark McDonough, president and chief executive officer of CombiMatrix, said in a statement.

CombiMatrix will be a wholly-owned subsidiary of Invitae, according to documents filed with the Securities and Exchange Commission.

The company declined to provide any information not found in SEC documents, such as potential job impacts or executive changes.

For many people, preparing to have a child is their introduction to the power of genetics to inform health decisions, Sean George, chief executive officer of Invitae, said in a statement. The combination of Invitae and CombiMatrix will expand our ability to provide actionable answers to the complex questions that can arise when starting a family.

Testing has become more common as women have babies later in life. In 2016, theaverage age when women have their first child was 28. In 1970, it was 24.6, according to the CDC.

McDonough, in 2014, said he saw a market of up to $200 million a year for so called microarray prenatal testing and a$330 million marketfor recurrent pregnancy loss.

CombiMatrixspun off of Newport Beach-basedAcacia Research Corp. in 2007. It got its start supplyinglaboratories conducting microarray tests with biotech tools before founding a genetic testing lab.

In 2010, it moved to Irvine from Seattle.

Invitaeon Monday said it is also acquiring Cambridge, Mass.-based Good Start Genetics, another pregnancy-related molecular diagnostics company that specializes in preimplantation and carrier screening.

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A fundraising page set up in memory of Nottingham's official Maid Marian will support a range of cancer and end of life charities.

Dr Sally Pollard died on Friday, June 16, aged just 39 after losing her battle with breast cancer.

Sally was a lecturer and researcher in human molecular genetics at The University of Nottingham.

She was diagnosed with the disease in July 2015 after she started noticing changes in her breasts. She visited her local GP and specialists confirmed the devastating news that it had spread to her bones and liver.

Sally and her husband Tim Pollard - the city's official Robin Hood - received help from a number of charities, including Macmillan Cancer Support, during her fight against the disease.

As a 'thank you' for that support, Tim set up a Go Fund Me page to raise money for Macmillian Cancer Support, the Red Cross, Nottingham City Hospital's Hayward House Specialist Palliative Care Unit, Nottingham and Treetops Hospices and Maggie's Nottingham on Friday (June 30).

Tim asked loved ones to donate to the Sally Pollard's Thank You Fund instead of having flowers at Sally's funeral, and by Sunday (July 2) afternoon 985 had already been raised.

The 53-year-old, who lives in Beeston, is overwhelmed by the "brilliant" support.

He said: "The help that Sal got was second to none. It was lovely care from all of the organisations involved.

"She really wanted to stay at home if possible and thankfully, with the help of the Red Cross and both of the Nottingham hospices - especially our Macmillan nurse, who was just brilliant - we managed.

"When the time came, she was at home surrounded by everybody that loved her and that meant everything to her - that's a simple thing but it's an important thing. If we can raise some money to help someone have a bit of extra care and help from the people that helped us that's brilliant."

Sally's funeral will be held in private but Tim will be celebrating her life with family and friends at the Nottingham Riverside Festival, which was "always Sal's favourite".

The three-day festival, held on Victoria Embankment, starts on Friday, August 4, which would have been Sally's 40th birthday.

Tim said: "This year would have been her 40th birthday. We're turning Riverside into 'Sal Fest' so that anybody who knows or loves Sal can come down and make it a big celebration."

Last month, Tim told The Post that a tree will be planted over Sally's final resting place.

It will be called 'Mummy's Tree' and will be a place that Tim and the couple's three-year-old daughter Scarlett can visit regularly.

You can find the Sally Pollard's Thank You Fund page here.

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Fundraising page set up in memory of Nottingham's Maid Marian - Nottingham Post

Dogs outnumbered students at the University of Otago yesterday.

Pooches ranging from pugs to boisterous Labradors had their mouths swabbed for DNA on the Dunedin campus grounds as part of a project to gather information on the connection between canine behaviour and genetics.

A large bag of treats proved enough to keep most of the dogs under control - although Yiwen Zheng could not stop her dog Huahua from eating the swab.

The dog gathering signalled the start of a Genetics Society of Australasia conference in conjunction with the New Zealand Society for Biochemistry and Molecular Biology which will draw about 250 delegates to the University of Otago this week.

Darwin Dogs project leader Dr Elinor Karlsson said she expected New Zealand dogs would have different characteristics from the thousands of dogs which had been tested by the citizen-led project in America since it started in 2015.

''New Zealand will have a lot stronger working dog origins. A lot of dogs were bought over here for sheep herding, and at the same time when the Europeans showed up there were already dogs here, so you have the dogs Maori had and presumably those genetics are still in the New Zealand dog population.''

Athleticism, determination and curiosity were obvious traits in the Dunedin dogs, as more than a few slipped their leads to make new canine friends.

While it was too early to conclude the genetic basis of a dog's behaviour, the study had revealed an interesting connection between dogs and humans, Dr Karlsson said.

''I think you can ask any dog owner this, and they probably agree, but it turns out that people and dogs just aren't as different sometimes as we like to think.''

The presentation and treatment of obsessive compulsive disorder (OCD) in humans and canines was one example.

''When comparing dogs with OCD with ones that didn't have it, we found that the genes we were honing in on were in the same kind of pathways in the brain as what we saw when we looked at people with OCD.''

Like humans, when a dog developed OCD it would perform a normal behaviour too often, and the condition was treated with the same drugs in humans and dogs, Dr Karlsson said.

University of Otago department of geology lecturers Dr Christina Riesselman and Dr Chris Moy hoped the project would offer some answers on the behaviour of their golden retriever Arlo.

Arlo made more of a meow than a bark and favoured a particular ''security blanket'', Dr Riesselman said.

Conference organiser and University of Otago centre for genetics Prof Peter Dearden said he hoped to find out the breed of his dog Barkley, who looked like a ''lab crossed with a pony''.

Dr Karlsson opened the conference with a talk about the Darwin Dogs project last night.

The health and histories of New Zealand populations using evolutionary genomics, conservation and genetics and molecular research will be among the other topics discussed at the conference.

margot.taylor@odt.co.nz

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Dogs have their day at conference - Otago Daily Times

Greenwood Genetic Center (GGC) recently recognized Kasia Ellsworth, PhD, and Catie Spellicy, PhD upon their completion of laboratory fellowships in Clinical Molecular Genetics and Genomics.

Dr. Ellsworth earned a PhD in Molecular Pharmacology and Experimental Therapeutics from Mayo Clinic College of Medicine in Rochester, Minnesota. After finishing a Clinical Biochemical Genetics fellowship at GGC in 2016, she remained at the Center to complete a second fellowship in Clinical Molecular Genetics and Genomics. Dr. Ellsworth has joined GGCs DNA Diagnostic Laboratory as a Clinical Molecular Specialist.

Dr. Spellicy earned a PhD in Human and Molecular Genetics at the University of Texas Health Science Center in Houston (UTHSCH). Prior to enrolling in GGCs program, she also completed two postdoctoral fellowships, the first studying neural tube defects, also at UTHSCH, and the second at Baylor College of Medicine where she studied the genetics of addiction. In July, she will join Mission Fullerton Genetics Laboratory in Asheville, NC as a Clinical Molecular Geneticist.

GGCs two-year fellowships include intensive training in laboratory technologies, clinical genetics and diagnostic laboratory management. GGC is one of only 44 sites in the US and the only program in SC offering this post-graduate genetics training programs in all specialty areas.

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Since GGCs program began in 1989, nearly 40 fellows and residents have completed the training and have gone on to practice medical genetics or lead diagnostic laboratories.

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GGC Graduates Two from Medical Genetics Training Program - Index-Journal

San Francisco Classical Voice

The Passions of Nazneen Rahman San Francisco Classical Voice She completed her degree in medicine at Oxford University in 1991, undertook training as a resident in Oxford and London, and earned a Ph.D. in Molecular Genetics in 1999. Today, she is Professor Rahman, age 50, head of the Division of Genetics and ...

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The Passions of Nazneen Rahman - San Francisco Classical Voice

Whole genome sequencing involves the analysis of all three billion pairs of letters in an individuals DNA and has been hailed as a technology that will usher in a new era of predicting and preventing disease.

However, the use of genome sequencing in healthy individuals is controversial because no one fully understands how many patients carry variants that put them at risk for rare genetic conditions and how theyand their doctorswill respond to learning about these risks.

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In a new paper published June 26 in the Annals of Internal Medicine by investigators at Harvard Medical School and Brigham and Womens Hospital, along with collaborators at Baylor College of Medicine, report the results of the four-year, NIH-funded MedSeq Project, the first-ever randomized trial conducted to examine the impact of whole genome sequencing in healthy primary care patients.

In the MedSeq Project, 100 healthy individuals and their primary care physicians were enrolled and randomized so that half of the patients received whole genome sequencing and half did not.

Nearly 5,000 genes associated with rare genetic conditions were expertly analyzed in each sequenced patient, and co-investigators from many different disciplines, including clinical genetics, molecular genetics, primary care, ethicsand law, were involved in analyzing the results.

Researchers found that among the 50 healthy primary care patients who were randomized to receive genome sequencing, 11 (22 percent) carried genetic variants predicted to cause previously undiagnosed rare disease.

Two of these patients were then noted to have signs or symptoms of the underlying conditions, including one patient who had variants causing an eye disease called fundus albipunctatus, which impairs night vision.

This patient knew he had difficulty seeing in low-light conditions but had not considered the possibility that his visual problems had a genetic cause.

Another patient was found to have a genetic variant associated with variegate porphyria, which finally explained the patients and family members mysterious rashes and sun sensitivity.

The other nine participants had no evidence of the genetic diseases for which they were predicted to be at risk. For example, two patients had variants that have been associated with heart rhythm abnormalities, but their cardiology workups were normal. It is possible, but not at all certain, that they could develop heart problems in the future.

Sequencing healthy individuals will inevitably reveal new findings for that individual, only some of which will have actual health implications, said lead author Jason Vassy,an HMS assistant professor of medicine at Brigham and Womens and primary care physician at the VA Boston Healthcare System.

This study provides some reassuring evidence that primary care providers can be trained to manage their patients sequencing results appropriately, and that patients who receive their results are not likely to experience anxiety connected to those results. Continued research on the outcomes of sequencing will be needed before the routine use of genome sequencing in the primary care of generally healthy adults can be medically justified, Vassy said.

Primary care physicians received six hours of training at the beginning of the study regarding how to interpret a specially designed, one-page genome testing report summarizing the laboratory analysis.

Consultation with genetic specialists was available, but not required. Primary care physicians then used their own judgment about what to do with the information, and researchers monitored the interactions for safety and tracked medical, behavioral and economic outcomes.

The researchers noted that they analyzed variants from nearly 5,000 genes associated with rare genetic diseases. These included single genes causing a significantly higher risk for rare disorders than the low-risk variants for common disorders reported by direct-to-consumer genetic testing companies. No prior study has ever examined healthy individuals for pathogenic (high-risk) variants in so many rare disease genes.

We were surprised to see how many ostensibly healthy individuals are carrying a risk variant for a rare genetic disease, said Heidi Rehm, HMS associate professor of pathology at Brigham and Women's anddirector of the Laboratory for Molecular Medicine at Brigham and Women's.

We found that about one-fifth of this sample population carried pathogenic variants, and this suggests that the potential burden of rare disease risk throughout our general population could be far higher than previously suspected,said Rehm, a co-investigator on the study who directed the genome analysis.However, the penetrance, or likelihood that persons carrying one of these variants will eventually develop the disease, is not fully known.

Additionally, investigators compared the two arms of the studyand found that patients who received genome sequencing results did not show higher levels of anxiety. They did, however, undergo a greater number of medical tests and incurred an average of $350 more in health care expenses in the six months following disclosure of their results. The economic differences were not statistically significant with the small sample size in this study.

Because participants in the MedSeq Project were randomized, we could carefully examine levels of anxiety or distress in those who received genetic risk information and compare it to those who did not, said Amy McGuire,director of the Center for Medical Ethics and Health Policy at Baylor College of Medicine.

While many patients chose not to participate in the study out of concerns about what they might learn, or with fears of future insurance discrimination, those who did participate evinced no increase in distress, even when they learned they were carrying risk variants for untreatable conditions, saidMcGuire, who supervised the ethical and legal components of the MedSeq Project.

There has also been great concern in the medical community about whether primary care physicians can appropriately manage these complicated findings. But when a panel of expert geneticists reviewed how well the primary care physicians managed the patients with possible genetic risk variants, the experts determined that only two of the 11 cases were managed inappropriately and that no harm had come to these patients.

MedSeq Project investigators note that the studys findings should be interpreted with caution because of the small sample size and because the study was conducted at an academic medical center where neither the patients nor the primary care physicians are representative of the general population. They also stressed that carrying a genetic risk marker does not mean that patients have or will definitely get the disease in question. Critical questions remain about whether discovering such risk markers in healthy individuals will actually provide health benefits, or will generate unnecessary testing and subsequent procedures that could do more harm than good.

Integrating genome sequencing and other -omics technologies into the day-to-day practice of medicine is an extraordinarily exciting prospect with the potential to anticipate and prevent diseases throughout an individuals lifetime, said senior author Robert C. Green, HMSprofessor of medicineat Brigham and Womens Hospital,associate member of the Broad Institute of Harvard and MITandleader ofthe MedSeq Project. But we will need additionalrigorously designed and well-controlled outcomes studies like the MedSeq Project with larger sample sizes and with outcomes collected over longer periods of time to demonstrate the full potential of genomic medicine.

The MedSeq Project is one of the sites in the Clinical Sequencing Exploratory Research Consortium and was funded by the National Human Genome Research Institute, part of the National Institutes of Health.

The Genomes2People Research Program at Brigham and Womens Hospital, the Broad Institute and Harvard Medical School conducts empirical research in translational genomics and health outcomes. NIH-funded research within G2P seeks to understand the medical, behavioral and economic impact of using genetic risk information to inform future standards. The REVEAL Study has conducted several randomized clinical trials examining the impact of disclosing genetic risk for a frightening disease. The Impact of Personal Genomics (PGen) Study examined the impact of direct-to-consumer genetic testing on over 1,000 consumers of two different companies. The MedSeq Project has conducted the first randomized clinical trial to measure the impact of whole genome sequencing on the practice of medicine. The BabySeq Project is recruiting families of both healthy and sick newborns into a randomized clinical trial where half will have their babys genome sequenced. Green directs the Program.

Adapted from a Brigham and Women's news release.

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Genetic Testing for the Healthy - Harvard Medical School (registration)