PUBLIC RELEASE DATE:

1-Apr-2014

Contact: Kathy Beal kbeal@acmg.net 301-238-4582 American College of Medical Genetics

Jun Shen, PhD was honored as the 2014 recipient of the ACMG Foundation/Signature Genomics from PerkinElmer, Inc. Travel Award at the American College of Medical Genetics and Genomics (ACMG) 2014 Annual Clinical Genetics Meeting in Nashville, TN.

Dr. Shen was selected to receive the award for her platform presentation, "Clinical Validation of a Novel Combinatorial Algorithm that Predicts Pathogenicity of Human Missense Variants with High Accuracy."

Dr. Shen completed her PhD in Neurobiology at Harvard University, and completed her Postdoctoral Fellowship in Neurobiology with a focus on the inner ear at Howard Hughes Medical Institution/Harvard Medical School. Dr. Shen received her Bachelor of Arts in Biochemistry, Molecular Biology and Computer Science at Dartmouth College. She is currently an Instructor in Pathology at Brigham and Women's Hospital and Harvard Medical School and an Assistant Laboratory Director, Laboratory for Molecular Medicine, Partners HealthCare Center for Personalized Genetic Medicine.

The ACMG Foundation/Signature Genomics Travel Award is given to an ACMG Trainee member whose abstract submission was chosen as a platform presentation during the ACMG Annual Clinical Genetics Meeting. The ACMG Program Committee selects the Travel Award recipient based on scientific merit. In recognition of the selected presentation, Signature Genomics covers the travel costs for the recipient to the ACMG meeting.

"The Foundation for Genetic and Genomic Medicine is grateful to Signature Genomics for its continued generous support of the development of medical genetic researchers through this Travel Award," said Bruce R. Korf, MD, PhD FACMG, president of the ACMG Foundation for Genetic and Genomic Medicine.

"Signature Genomics is pleased to support the recognition of young researchers like Dr. Shen who are working in the field of genetics and genomics. This presentation is just one of the many outstanding presentations at the 2014 ACMG Annual Meeting," said Beth Torchia, PhD, FACMG, Technical Laboratory Director at Signature Genomics from PerkenElmer, Inc.

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2014 ACMG Foundation/Signature Genomic Labs, PerkinElmer Inc. Travel Award winner

PUBLIC RELEASE DATE:

31-Mar-2014

Contact: Kimberley Wang kimberley.wang@nus.edu.sg 65-660-11653 National University of Singapore

A team of scientists from the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore and National University Cancer Institute Singapore (NCIS), and their collaborators from the Cedars-Sinai Medical Centre, UCLA School of Medicine, demonstrated that a number of novel genetic defects are able to induce oesophageal cancer.

The research group, led by Professor H. Phillip Koeffler, Senior Principal Investigator at CSI Singapore and Deputy Director of NCIS, has conducted a successful comprehensive genomic study of oesophageal squamous carcinoma, a type of very aggressive cancer prevalent in Singapore and Southeast Asia.

This novel study was first published online in the prestigious journal Nature Genetics on 30 March 2014.

In this study, the researchers comprehensively investigated a large variety of genetic lesions which arose from oesophageal squamous carcinoma. The results showed enrichment of genetic abnormalities that affect several important cellular process and pathways in human cells, which promote the development of this malignancy. The scientists also uncovered a number of novel candidate genes that may make the cancer sensitive to chemotherapy. The researchers' findings provide a molecular basis for the comprehensive understanding of the pathophysiology of oesophageal carcinoma as well as for developing novel therapies for this deadly disease. These groundbreaking results have immediate relevance for cancer researchers, as well as for clinical oncologists who currently do not have effective therapeutic agents to treat this type of cancer.

Dr Lin Dechen, Research Fellow at CSI Singapore and first author of the research paper, noted, "Our findings are very relevant to Singapore and the region because this disease is endemic to Southeast Asia. More importantly, many potential therapeutic drugs have surfaced from our analysis, with some of them already in use for treating other types of tumours. We are more than excited to test their efficacy in oesophageal cancer."

Prof Koeffler said, "Oesophageal squamous cancer is one of most common causes of cancer-related death, and is particularly prevalent in Southeast Asia. We wanted to understand this major burden on the local public health system and to help find solutions. By completely investigating all human genes at the single nucleotide level, our current findings provide an enhanced road map for the study of the molecular basis underlying this somewhat neglected malignancy."

With the discovery of these previously unrecognised genetic defects, Prof Koeffler and his team will explore the detailed molecular mechanisms in the next phase of research. In addition, the scientists will evaluate whether some of these defects can be used in the clinic to cure this disease.

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Scientists discover a number of novel genetic defects which cause oesophageal cancer

PUBLIC RELEASE DATE:

31-Mar-2014

Contact: Robin Dutcher robin.Dutcher@hitchcock.org 603-653-9056 The Geisel School of Medicine at Dartmouth

While patients diagnosed with bladder cancer usually face a favorable prognosis, many experience recurrence after treatment. Because frequent, painful screenings are needed to identify recurrences, the ablility to identify patients at high risk of recurrent cancer could help to improve quality of life for all bladder cancer patients.

A new study published in BJU International, "Genetic polymorphisms modify bladder cancer recurrence and survival in a U.S. population-based prognostic study," suggests that certain inherited DNA sequences may affect a bladder cancer patient's prognosis. These findings may help physicians identify sub-groups of high risk bladder cancer patients who should receive more frequent screenings and agressive treatment and monitoring.

"The genetic markers that we found could potentially be useful for individually tailoring surveillance and treatment of bladder cancer patients," said principal investigator Angeline S. Andrew, PhD, Assistant Professor of Community and Family Medicine and the Geisel School of Medicine at Dartmouth and a member of the Norris Cotton Cancer Center.

Andrew and her colleagues analyzed the genes of 563 patients to identify genetic variants that modified time to bladder cancer recurrence and patient survival. The investigators isolated DNA from immune cells circulating in the blood, and then examined the genes involved in major biological processes linked to cancer, including cell death, proliferation, DNA repair, hormone regulation, immune surveillance, and cellular metabolism. After diagnosis, patients were followed over time to ascertain recurrence and survival status. Patients were followed for a median of 5.4 years, and half of patients experienced at least one recurrence.

The team found that patients with a variant form of the aldehyde dehydrogenase 2 (ALDH2) gene were more likely to experience bladder cancer recurrence shortly after treatment. This gene encodes an enzyme involved in alcohol metabolism. Time to recurrence was also shorter for patients who had a variation in the vascular cellular adhesion molecule 1 (VCAM1) gene and were treated with immunotherapy. VCAM1 encodes a glycoprotein involved in the development of lymphoid tissues. Patients who had non-invasive tumors and a single variant allele in the DNA repair gene XRCC4 tended to live longer than patients who did not have the variant.

"Our present data suggest novel associations between genetic variations (SNPs) and bladder cancer recurrence that merit future investigation," said Andrew. "Prognostic variations will help us to identify sub-groups of bladder cancer patients at high risk of tumor recurrence and progression so that they can receive more personalized bladder cancer surveillance and treatment."

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Certain genetic variants may identify patients at higher risk of bladder cancer recurrence

Heart valve defects are a common cause of death in newborns. Scientists at the University of Bonn and the caesar research center have discovered "Creld1" is a key gene for the development of heart valves in mice. The researchers were able to show that a similar Creld1 gene found in humans functions via the same signaling pathway as in the mouse. This discovery is an important step forward in the molecular understanding of the pathogenesis of heart valve defects. The findings have been published in the journal "Developmental Cell."

Atrioventricular septal defect (AVSD) is a congenital heart defect in which the heart valves and cardiac septum are malformed. Children with Down's syndrome are particularly affected. Without surgical interventions, mortality in the first months of life is high. "Even in adults, unidentified valve defects occur in about six percent of patients with heart disease," says Prof. Dr. Michael Hoch, Executive Director of the Life & Medical Sciences (LIMES) Institute of the University of Bonn.

For years, there have been indications that changes in the so-called Creld1 gene (Cysteine-Rich with EGF-Like Domains 1) increase the pathogenic risk of AVSD. However, the exact molecular connection between the gene and the disease was previously unknown. A research team from the LIMES Institute and the caesar research center in Bonn has now shown, in a mouse model, that Creld1 plays a crucial role in heart development. Researchers at the University of Bonn switched off the Creld1 gene in mice: "We discovered that the precursor cells of the heart valves and the cardiac septum could no longer develop correctly," reports Dr. Elvira Mass from the LIMES Institute. This was an important indication that Creld1 is required at a very early stage for the development of the heart.

In embryonic development, the heart develops as the first organ

"In the embryonic stage, the heart develops as the very first organ. It pumps blood through the vascular system and is essential for supplying other organs of the body with oxygen and nutrients," reports the cooperation partner, Dr. Dagmar Wachten who directs the Minerva research group "Molecular Physiology" at the caesar research center and is engaged in research involving cardiac development. The research team discovered that the Creld1 gene controls the development of heart valves via the so-called calcineurin NFAT signaling pathway. The heart valve defects in mice lacking the Creld1 gene ultimately led to insufficient oxygen supply to the body, causing the mouse embryo to cease development after approximately eleven days.

Potential starting point for improving diagnostic measures

The research team anticipates that the findings can be carried over to patients. With regard to cardiac development, mice and humans are very similar and the Creld1 gene and the calcineurin/NFAT signaling pathway likewise function analogously in both species. "Our results contribute to a better understanding of the molecular basis of heart development and, in the medium-term, to improved diagnosis of unidentified heart valve diseases," explains Prof. Hoch. Interestingly, the calcineurin/NFAT signaling pathway is not only active in the heart but also in immune cells. In transplant medicine, it has to be suppressed over the long-term by drugs such as cyclosporine A so that transplanted organs are not rejected. "Within the scope of the ImmunoSensation Excellence Cluster, we are currently investigating the mechanism of action of Creld1 in immune cells," says Prof. Hoch, who is convinced that it will also be of importance in transplant medicine in the future.

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

Originally posted here:

Genetic cause of heart valve defects revealed

IRVINE, CA and FULTON, MD (PRWEB) March 31, 2014

Proove Biosciences, the leading personalized pain medicine laboratory, is proud to announce its membership in the Personalized Medicine Coalition, a unique organization created to advance personalized medicine as a viable solution to the challenges of healthcare safety, efficiency, and cost.

Proove Biosciences leads the industry in scientifically driven genetic pain medicine research, and has presented findings on how genetic analysis can help physicians make more informed and efficient decisions on pain treatments. Over the last three years the companys genetic testing services have helped physicians analyze patients risk profile for developing prescription narcotic dependencies, as well as which medications will be most effective in treating their pain.

We are tremendously excited to be a member of the Personalized Medicine Coalition, and contribute towards the advancement of realizing personal medicines life-changing potential, stated Proove Biosciences founder and CEO, Brian Meshkin. As a member of PMC, we are looking forward to collaborating and working along side industry leaders to shape, promote, and foster new mediums that will strengthen personalized medicines market viability through policy initiatives and public support.

Proove Founder and CEO Brian Meshkin has also been appointed to both the Science Policy and Public Policy committees of the Personalized Medicine Coalition. Brian brings extensive background conducting scientific research in the field of personalized medicine, having developed the worlds largest practice-based evidence (PBE) database of personalized pain medicine and being an author on over 15 publications in peer-reviewed medical journals. His first publication was in Mutation Research in 2005 outlining the proofs of principle in pharmacogenetics and laying out, for the first time, a pharmacoeconomic model for demonstrating the benefits of personalized medicine testing. Additionally, Brian has a background in public policy, having recently served as an elected official in the State of Maryland and having successfully lobbied as a citizen for various pieces of legislation. Currently, he serves on the Board of Education of Howard County, Maryland.

About The Personalized Medicine Coalition The Personalized Medicine Coalition (PMC) was launched in 2004 to educate the public and policymakers, and to promote new ways of thinking about health care. Today, PMC represents a broad spectrum of more than 225 innovator, academic, industry, patient, provider and payer communities, as we seek to advance the understanding and adoption of personalized medicine concepts and products for the benefit of patients.

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 Is Now a Member of The Personalized Medicine Coalition

Released: 3/25/2014 4:05 PM EDT Source Newsroom: Mayo Clinic Contact Information

Available for logged-in reporters only

http://newsnetwork.mayoclinic.org/discussion/implications-of-patient-genomic-sequencing-at-acmg

Newswise ROCHESTER, Minn. Researchers from the Mayo Clinic Center for Individualized Medicine will present results of three different studies evaluating implications and feasibility of genome sequencing at the ACMG Annual Clinical Genetics Meeting this week in Nashville, Tenn. Presenters are available for interviews at the conference or remote interviews by telephone. To schedule an interview, please contact Sam Smith, Mayo Clinic public affairs specialist, at 507-284-5005 or newsbureau@mayo.edu.

Richard Sharp, Ph.D., director of the Bioethics Program in the Mayo Clinic Center for Individualized Medicine, also will participate on Saturday, March 30, in a panel discussion entitled Duty to Recontact in the Genomics Era: Interdisciplinary Perspectives and Open Forum. Duty to Recontact addresses providers obligations to patients who have undergone previous genetic testing, given the growing complexities of genetic/genomic medicine and the potential for new findings in old tests. Dr. Sharp is an advisor to the National Institutes of Health, the Institute of Medicine and the Environmental Protection Agency. He can discuss the ethical, legal and social implications of integrating genomics technologies into patient care.

The Mayo Clinic Center for Individualized Medicine presentations include:

Patients Views on Incidental Findings from Clinical Exome Sequencing (platform oral presentation) The Individualized Medicine Clinic offers whole exome sequencing for patients with advanced cancers and difficult diagnoses. Among the difficult questions clinicians and patients wrestle with is, How much information is too much? Researchers interviewed 44 patients of the Individualized Medicine Clinic about what they would and wouldnt want to know from next-generation sequencing. Findings demonstrate that patient perspectives of risks and benefits of knowing genomic information are personal and contextual. As one participant stated, I think this is the Individual Medicine program for a reason. Everything has to be on a case-by-case basis. Whole Exome Sequencing of Ten Scientists: Evaluation of Process and Outcomes (poster presentation) As genome sequencing technologies advance at a breakneck pace, patients will increasingly expect to have their whole exome and eventually their whole genome embedded in their records, just like family histories and medication lists. In an attempt to understand the difficulties and limitations of whole exome sequencing in routine care, 10 genetics scientists underwent sequencing and genomic counseling. Pharmacogenomic Information in the EMR: Perspectives of Biobank Participants Invited to Participate in a Proof of Concept PGx Study (poster presentation) The debate is just getting started over who will have access to genomic information and how that information will (or wont) be protected. Researchers asked 900 participants in a pilot pharmacogenomics study their understanding and concerns about a pilot program embedding their personal genomic information into patient electronic medical records. From this sampling of participants in the Mayo Clinic Biobank, the largest concern was whether insurance companies could have access to genomic information.

About Mayo Clinic Recognizing 150 years of serving humanity in 2014, Mayo Clinic is a nonprofit worldwide leader in medical care, research and education for people from all walks of life. For more information, visit 150years.mayoclinic.org, http://www.mayoclinic.org and newsnetwork.mayoclinic.org.

About the Mayo Clinic Center for Individualized Medicine The Mayo Clinic Center for Individualized Medicine is home to the Individualized Medicine Clinic, which uses patients own genetic codes to provide new hope for people with advanced cancers and difficult diagnoses. The center discovers and integrates the latest in genomic, molecular and clinical sciences into personalized care for each Mayo Clinic patient. Visit http://mayoresearch.mayo.edu/center-for-individualized-medicine for more information.

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Implications of Patient Genomic Sequencing at ACMG

Lead researcher Dr Peter Taylor, from the University of Cardiff's School of Medicine, said: "If other studies confirm our finding then there may be benefit in carrying out a genetic test for this gene variant in addition to the standard neonatal thyroid screening, which would identify children most at risk of developing low IQ.

Around 4 per cent of the population have the gene variant coupled with a lower than normal thyroid hormone levels.

The finding could mean that up to 2.5 million people in Britain could be suffering from the effects of low IQ which might have been treatable.

The new research focused on an enzyme called deiodonase-2 which is involved in processing thyroid hormones within cells.

A mutation in the gene coding for the enzyme had already been associated with other health problems including diabetes and high blood pressure.

In the new study, scientists from the universities of Cardiff and Bristol looked at genetic data on 3,123 children under the age of seven who also had their IQ tested.

Those with thyroid hormone levels at the bottom of the normal range who also possessed the deiodonase-2 variant were four times more likely to have an IQ under 85.

Children with lower thyroid hormone levels alone were not at greater risk of low IQ.

The findings were presented at the Society for Endocrinology's British Endocrine Societies (BES) conference in Liverpool.

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Genetic test could show which babies will have low IQ

PUBLIC RELEASE DATE:

21-Mar-2014

Contact: John Ascenzi ascenzi@email.chop.edu 267-426-6055 Children's Hospital of Philadelphia

Long before next-generation sequencing technology ushered in today's data-intensive era of human genome information, clinicians have been taking family histories by jotting down pedigrees: hand-drawn diagrams recording how diseases may recur across generations, and offering clues to inheritance patterns.

Now healthcare providers can create those diagrams digitally on an iPad screen with a few finger taps, during a face-to-face encounter with an individual and his or her family. Users can store the pedigrees in a standardized format, make corrections flexibly as they gather new information, and export the diagrams so they can be used in other applications such as electronic medical records.

"Instead of storing a pedigree on a piece of paper in a physical file, we can capture the information with an easy-to-use interface that produces accessible data," said Jeff Miller, lead analyst at the Center for Biomedical Informatics (CBMi) at The Children's Hospital of Philadelphia. Miller led the CBMi team that developed the Proband app, which made its debut today on the iTunes App StoreSM. Genetic counselors, clinical genetics specialists and others can download the app for a limited-time introductory price of $1.99.

Designed for use as a data collection tool during a genetic counseling interview or in similarly interactive settings, Proband uses a simple, gesture-based interface to make drawing pedigrees as efficient as drawing on paper. Users can quickly create even the most complex family pedigrees simply and easily using standard nomenclature and symbols. "We designed this app for ease of use with options appearing as you need them," said Miller. "Our goal is to make those features contextually relevant, and not to overwhelm the user."

Mindy Li, M.D., a clinical genetics fellow at CHOP, is one of those who helped test the app, providing critiques and feedback to the CBMi development team. "One strength for me as a clinician is being able to set the device on my lap while I conduct an interviewit's a better interaction than if I had to turn toward a computer screen and input the information," she said.

A suggestion of hers that was incorporated, said Li, was to allow for careful spacing and alignment, to make it clear which individuals belong to each generation: "Alignment is importantyou have to see children in their correct generation." An auto-alignment button on the app screen helps to straighten that out. She added, "As health technology in general is moving toward electronic data, it's important to have pedigrees easy to read and easy to integrate." Compared to reviewing traditional hand-drawn pedigrees, she doesn't have to decipher someone else's handwriting or idiosyncratic abbreviations.

Miller and other team members are presenting Proband at the annual meeting of the American College of Medical Genetics and Genomics, March 28 in Nashville.

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With a few finger taps, draw genetic pedigrees at point of care with new app

Grace Wilsey was born with NGLY1 deficiency, which is caused by two mutations in the NGLY1 gene.

STORY HIGHLIGHTS

(CNN) -- What do you do when your baby lies limp in your arms, staring blankly into the distance while never crying?

What do you do when tests show signs of liver damage and your baby's seizures won't stop, but doctors can't tell you what's wrong or how to fix it?

Thanks to the Human Genome Project, which was completed in 2003, identifying new genetic mutations has gotten easier and cheaper. But geneticists often struggle to find patients who share these rare DNA quirks. Studying multiple patients with the same gene mutations and similar symptoms is crucial to identifying a new genetic disorder.

That's why a paper published Thursday in the journal Genetics in Medicine is so remarkable.

The paper identifies NGLY1 deficiency as an inherited genetic disorder, caused by mutations in the NGLY1 gene. The researchers have confirmed eight patients with these mutations who share several symptoms, including developmental delays, abnormal tear production and liver disease.

And they credit an "Internet blog" with bringing the patients and scientists together.

Grace's genome

Grace Wilsey's parents knew something was wrong right away. Their newborn daughter was lethargic. Her eyes seemed hollow and unfocused. She refused to eat. Doctors at the hospital ran multiple tests, but couldn't come up with a diagnosis.

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New disorder: Kids who don't cry

Home > News > health-news

Washington, March 21 : Researchers have reported a defined genetic defect that causes a subset of irritable bowel syndrome (IBS).

Researchers found that patients with a subset of IBS have a specific genetic defect, a mutation of the SCN5A gene. This defect causes patients to have a disruption in bowel function, by affecting the Nav1.5 channel, a sodium channel in the gastrointestinal smooth muscle and pacemaker cells.

Gianrico Farrugia, M.D., a study author, Mayo Clinic gastroenterologist and director of the Mayo Clinic Center for Individualized Medicine, said that this gives them hope that from only treating symptoms of the disease, they can work to find disease-modifying agents, which is where they really want to be to affect long-term treatment of IBS.

Researchers studied the sodium channel of 584 people with IBS and 1,380 control subjects. The analysis demonstrated that a defect in the SCN5A gene was found in 2.2 percent of IBS patients. The results were confirmed in a genome-wide association study and replicated in 1,745 patients in four independent cohorts of patients with IBS and control subjects.

The research has been published in the journal Gastroenterology.

--ANI (Posted on 22-03-2014)

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Genetic clue to irritable bowel syndrome found

Grace Wilsey was born with NGLY1 deficiency, which is caused by two mutations in the NGLY1 gene.

STORY HIGHLIGHTS

(CNN) -- What do you do when your baby lies limp in your arms, staring blankly into the distance while never crying?

What do you do when tests show signs of liver damage and your baby's seizures won't stop, but doctors can't tell you what's wrong or how to fix it?

Thanks to the Human Genome Project, which was completed in 2003, identifying new genetic mutations has gotten easier and cheaper. But geneticists often struggle to find patients who share these rare DNA quirks. Studying multiple patients with the same gene mutations and similar symptoms is crucial to identifying a new genetic disorder.

That's why a paper published Thursday in the journal Genetics in Medicine is so remarkable.

The paper identifies NGLY1 deficiency as an inherited genetic disorder, caused by mutations in the NGLY1 gene. The researchers have confirmed eight patients with these mutations who share several symptoms, including developmental delays, abnormal tear production and liver disease.

And they credit an "Internet blog" with bringing the patients and scientists together.

Grace's genome

Grace Wilsey's parents knew something was wrong right away. Their newborn daughter was lethargic. Her eyes seemed hollow and unfocused. She refused to eat. Doctors at the hospital ran multiple tests, but couldn't come up with a diagnosis.

Original post:

Kids who don't cry: A genetic disorder

Grace Wilsey was born with NGLY1 deficiency, which is caused by two mutations in the NGLY1 gene.

STORY HIGHLIGHTS

(CNN) -- What do you do when your baby lies limp in your arms, staring blankly into the distance while never crying?

What do you do when tests show signs of liver damage and your baby's seizures won't stop, but doctors can't tell you what's wrong or how to fix it?

Thanks to the Human Genome Project, which was completed in 2003, identifying new genetic mutations has gotten easier and cheaper. But geneticists often struggle to find patients who share these rare DNA quirks. Studying multiple patients with the same gene mutations and similar symptoms is crucial to identifying a new genetic disorder.

That's why a paper published Thursday in the journal Genetics in Medicine is so remarkable.

The paper identifies NGLY1 deficiency as an inherited genetic disorder, caused by mutations in the NGLY1 gene. The researchers have confirmed eight patients with these mutations who share several symptoms, including developmental delays, abnormal tear production and liver disease.

And they credit an "Internet blog" with bringing the patients and scientists together.

Grace's genome

Grace Wilsey's parents knew something was wrong right away. Their newborn daughter was lethargic. Her eyes seemed hollow and unfocused. She refused to eat. Doctors at the hospital ran multiple tests, but couldn't come up with a diagnosis.

The rest is here:

Kids who don't cry: New genetic disorder discovered

PUBLIC RELEASE DATE:

20-Mar-2014

Contact: Erin Digitale digitale@stanford.edu 650-724-9175 Stanford University Medical Center

STANFORD, Calif. Scientists and parents have worked together to identify a new genetic disease that causes neurologic, muscle, eye and liver problems in children. The discovery was unusually fast thanks to a combination of modern gene-sequencing techniques, social media and old-fashioned detective work.

One important clue was that affected children cry without making tears.

The new disease, called NGLY1 deficiency, is described in a paper that will be published online March 20 in Genetics in Medicine, the journal of the American College of Medical Genetics and Genomics. The paper describes eight children with mutations in the gene coding for N-glycanase 1, an enzyme that recycles defective products from a cellular assembly line. Children who lack this enzyme have varying degrees of movement disorders, including a characteristic combination of muscle contractions that causes abnormal tremulous movements. They also have developmental delays and liver problems. The gene defect is so rare that until recently, finding eight affected individuals would have taken several years; instead, the children were found in a matter of months.

"This represents a complete change in the way we're going about clinical medicine," said Gregory Enns, MB, ChB, associate professor of genetics in pediatrics at the Stanford University School of Medicine and co-lead author of the new paper. Gene-sequencing tools have sped the translation of findings between clinical and lab settings; in addition, scientists around the globe and lay people are contributing to the discovery process.

"This is happening so quickly because of the integration of the families with the researchers, and because so many people are coming at this from so many angles," said Enns, who is also a geneticist at Lucile Packard Children's Hospital Stanford and Stanford Children's Health. Other co-authors of the paper come from 12 research institutions across the United States, Canada, Germany and the United Kingdom.

"The relief of finally getting a diagnosis is just life-changing," said Kristen Wilsey, mother of Grace Wilsey, 4, who was the second American patient, and among the first few in the world, to be identified with NGLY1 deficiency. Grace's diagnosis was a pivotal moment not just for her San Francisco Bay Area family but also for defining the new disease, since the comparison of multiple patients allowed researchers to confirm that the disease existed.

The enzyme that is missing in NGLY1-deficiency patients is normally found in cells throughout the body. N-glycanase 1 helps break down incorrectly shaped proteins so their components can be reused. The new research confirmed that children with a defective NGLY1 gene do not make the N-glycanase enzyme. The researchers also observed that the children's liver biopsies contained an amorphous substance, which they suspected was an accumulation of protein that did not get recycled.

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Scientists, parents join forces to identify new genetic disease in children

PUBLIC RELEASE DATE:

20-Mar-2014

Contact: Shawna Williams shawna@jhmi.edu 410-955-8236 Johns Hopkins Medicine

Many diseases have their origins in either the genome or in reversible chemical changes to DNA known as the epigenome. Now, results of a new study from Johns Hopkins scientists show a connection between these two "maps." The findings, reported March 20 on the website of the American Journal of Human Genetics, could help disease trackers find patterns in those overlays that could offer clues to the causes of and possible treatments for complex genetic conditions, including many cancers and metabolic disorders.

"By showing the connections between genetic variants and epigenetic information, we're providing epidemiologists with a road map," says Andy Feinberg, M.D., M.P.H., a Gilman Scholar, the King Fahd Professor of Medicine and the director of the Center for Epigenetics in the Institute for Basic Biomedical Sciences at the Johns Hopkins University School of Medicine. "Epigenetic tags show how disease-causing genetic variants might affect distant genes that in turn contribute to the disease."

Feinberg says it has long been known that individual genetic variants in sections of DNA that don't contain blueprints for proteins (once thought of as "junk DNA") seem to alter the quantity of proteins produced far afield. That phenomenon has made it very hard for researchers to pinpoint the source of some genetic diseases or targets for their treatment. This study, Feinberg says, shows that these genetic variants may be acting on distant protein-forming genes by influencing epigenetic tags, or chemical add-ons, atop the DNA.

Feinberg; co-leader Dani Fallin, Ph.D., professor and chair of the Department of Mental Health at the Bloomberg School of Public Health and director of the Wendy Klag Center for Autism and Developmental Disabilities; and their team analyzed genetic data from hundreds of healthy participants in three studies to first figure out what a normal epigenetic pattern looks like. Although it's now common to compare the genomes of healthy and sick populations to identify predispositions for diseases, it has not been possible to compare epigenomes this way. The researchers zoomed in on one type of epigenetic change, the attachment of a chemical tag called a methyl group to a particular site on DNA. Known as methylation, these tags affect whether genes produce any protein, and if so, how much.

The team then looked for the relationship between the resulting epigenetic data and genetic data. Human genetic code is marked by telltale blocks of DNA that children tend to inherit from their parents in unbroken chunks called haplotypes. One of these blocks is often fingered as a suspect when a genetic disease arises. However, since the blocks are comprised of hundreds of thousands of "letters" of DNA code, researchers are not often able to identify the culprit mutation, or the protein-forming genes it affects, which may lie somewhere else in the block.

Epigenetic signatures like methylation patterns also occur in blocks, which the team dubbed "GeMes," for methylation blocks controlled by genes. The researchers found that the GeMes overlapped with the long genetic blocks but were much shorter.

That led them to suspect that the protein-coding genes turned on or off by those tags must be at the root of the disease associated with a particular genetic variant found elsewhere in the block.

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New tool pinpoints genetic sources of disease

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Newswise A non-invasive test that includes detection of the genetic abnormalities related to cancer could significantly improve the effectiveness of colon cancer screening, according to research published by a team of scientists including David Ransohoff, MD, professor of medicine at the UNC School of Medicine and UNC Lineberger Comprehensive Cancer Center member. The large-scale, cross-sectional study was published online today in The New England Journal of Medicine.

The study compared two different types of tests used for screening colorectal cancer: a non-invasive, multitarget stool test that includes DNA markers related to colon cancer along with a test that detects stool blood, versus a commercial fecal immunochemical test (FIT). While the FIT test detects hidden blood in the stool, a potential signal for cancer, the multitarget test also includes genetic mutations in the stool that are related to cancer. In the study of nearly 10,000 participants, the DNA test detected 92 percent of colon cancer, significantly more cancers compared to the 72 percent for the FIT test in asymptomatic participants at average risk for colorectal cancer.

The results from this study could impact screening rates, which remain frustratingly low in the U.S. despite the evidence of their effectiveness.

Detection of 92 percent of colon cancer is extremely high for a non-invasive test, so that a negative test result means that no further evaluation, like colonoscopy, is needed at that time, said Ransohoff. Having such a sensitive, non-invasive option could have an important effect on screening rates for colorectal cancer.

While the DNA test appears to be more sensitive than the FIT test, it did produce more false positive results, which would lead to colonoscopy. Further, the study did not address the question of how frequently non-invasive testing might be needed. Colorectal cancer is the third leading cause of cancer-related deaths in the United States and is expected to cause over 50,000 deaths in 2014, according to the American Cancer Society.

In addition to the University of North Carolina, additional institutions involved in the study include Indiana University School of Medicine, Icahn School of Medicine at Mount Sinai, Kaiser Permanente Medical Center, and the Boston Biostatistics Research Foundation. The study was funded by Exact Sciences.

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Genetic, Non-Invasive Test Could Improve Colon Cancer Screening

PUBLIC RELEASE DATE:

19-Mar-2014

Contact: Katy Jones katy_jones@unc.edu 919-962-3405 University of North Carolina Health Care

A non-invasive test that includes detection of the genetic abnormalities related to cancer could significantly improve the effectiveness of colon cancer screening, according to research published by a team of scientists including David Ransohoff, MD, professor of medicine at the UNC School of Medicine and UNC Lineberger Comprehensive Cancer Center member. The large-scale, cross-sectional study was published online today in The New England Journal of Medicine.

The study compared two different types of tests used for screening colorectal cancer: a non-invasive, multitarget stool test that includes DNA markers related to colon cancer along with a test that detects stool blood, versus a commercial fecal immunochemical test (FIT). While the FIT test detects hidden blood in the stool, a potential signal for cancer, the multitarget test also includes genetic mutations in the stool that are related to cancer. In the study of nearly 10,000 participants, the DNA test detected 92 percent of colon cancer, significantly more cancers compared to the 72 percent for the FIT test in asymptomatic participants at average risk for colorectal cancer.

The results from this study could impact screening rates, which remain frustratingly low in the U.S. despite the evidence of their effectiveness.

"Detection of 92 percent of colon cancer is extremely high for a non-invasive test, so that a negative test result means that no further evaluation, like colonoscopy, is needed at that time," said Ransohoff. "Having such a sensitive, non-invasive option could have an important effect on screening rates for colorectal cancer."

While the DNA test appears to be more sensitive than the FIT test, it did produce more false positive results, which would lead to colonoscopy. Further, the study did not address the question of how frequently non-invasive testing might be needed.

Colorectal cancer is the third leading cause of cancer-related deaths in the United States and is expected to cause over 50,000 deaths in 2014, according to the American Cancer Society.

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Newswise NEW YORK (March 19, 2014) New research shows an alternative DNA test offers clinically relevant genetic information to identify why a miscarriage may have occurred years earlier. Researchers were able to identify chromosomal variants and abnormalities in nearly 50 percent of the samples. This first-of-its-kind study was conducted by researchers from Montefiore Medical Center and the Albert Einstein College of Medicine of Yeshiva University. The results were published in the March issue of Reproductive Biology and Endocrinology.

The technique used in this study, called rescue karyotyping, allows physicians to obtain important genetic information from tissue that had not been tested at the time of the miscarriage. As part of standard hospital protocol, tissue from miscarriages is embedded in paraffin for archival use and the karyotyping test is performed on DNA extracted from this tissue.

In this retrospective study of 20 samples from 17 women, genetic testing was successfully performed on 16 samples that had been archived for as long as four years. Of those samples, eight showed chromosomal variants and abnormalities. This is an important alternative when conventional karyotyping is not available or cannot be used for a specific sample.

Given the ease of obtaining results, even if a delay in testing occurs, this new test may provide a useful technique to gain a better understanding as to why miscarriage occurs in some women, said Zev Williams, M.D., Ph.D., director, Program for Early and Recurrent Pregnancy Loss (PEARL), Montefiore and Einstein, assistant professor of obstetrics & gynecology and womens health and of genetics at Einstein, and corresponding author of the study. I have seen women in tears because testing was not done at the time of the miscarriage and they feared they would never learn why it happened. Now we are able to go back and often get the answers we need.

One in five pregnancies ends in miscarriage, with the vast majority occurring in the first trimester. Recurrent miscarriage, which is defined as two or more miscarriages, occurs in up to 5 percent of couples attempting to conceive. Led by Dr. Williams, PEARL is comprised of a team of expert physicians, scientists, genetic counselors, nurses, technicians and staff members who work together to help these women maintain their pregnancies.

Montefiore and Einstein have worked together to develop an innovative model based on research, which allows us to develop novel diagnostic and treatment options and, in parallel, to quickly bring new advances to the clinic, said Dr. Williams. This represents a new and emerging model in medicine where the lab and clinic are brought closer in order to speed the pace of discovery and treatment.

Most miscarriages are caused by an abnormal number of chromosomes in the embryo, accounting for up to 75 percent of first trimester losses, continued Dr. Williams. This new test can help guide future treatment options but, importantly, can also help alleviate some of the guilt and self-blame often associated with unexplained miscarriage and can close a door or a painful chapter in a womans and couples life.

Dr. Williams is a board certified obstetrician gynecologist with specialty training in reproductive endocrinology and infertility. He received his M.D. and Ph.D. degrees from the Mount Sinai School of Medicine and trained in Obstetrics and Gynecology at Harvard Medical Schools Brigham and Womens Hospital and the Massachusetts General Hospital. Dr. Williams completed a fellowship in Reproductive Endocrinology and Infertility at Weill-Cornell Medical Center.

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Miscarriage Clues Identified in New DNA Test According to Researchers at Montefiore and Einstein

"A Decade Later, Genetic Map Yields Few New Cures," said a New York Times headline in June 2010. It declared the failure of the $3 billion Human Genome Project and claimed that medicine had seen none of the benefits that President Bill Clinton had promised in announcing the first draft of the human-genome sequence in 2000. According to the article, geneticists were "almost back to square one in knowing where to look for the roots of common disease."

The New York Times judged the project too soon.

The cost of sequencing a human genome had fallen from about $100 million in 2001 to $30,000 when the article was written; today, it can be done for nearly $1,000. And the promise is coming true.

Hardly a week passes without the announcement of a major scientific breakthrough in genomics. The March 6 edition of The New England Journal of Medicine detailed how human cells can be genetically engineered to make them resistant to the virus that causes AIDS. A week earlier, the journal published a finding that analyzing fetal DNA in a pregnant woman's blood was a more accurate -- and less intrusive -- way of screening for Down syndrome and other chromosomal disorders than methods such as ultrasound imaging and blood tests.

Genome analysis is already being used to guide the treatment of cancers of the brain and the breast. Eric Green, director of the National Human Genome Research Institute, explains that cancer is essentially a genomic disease: "Instead of classifying cancers by the tissue where they are first detected -- colon, breast or brain, doctors are beginning to categorize cancer by its genomic characteristics and select treatments based on the signature of different mutations. This approach promises to treat patients with the most effective medicines while minimizing undesirable side effects, especially when chemotherapy is unlikely to help."

Green says that the end of the Human Genome Project was the starting point on the path to genomic medicine. He predicts that before long, doctors will tailor treatment for many diseases on the basis of an individual's genomic information.

The early triumphs are being seen with rare inherited diseases -- which together afflict more than 25 million Americans. Genomic strategies, driven by the plummeting cost of genome sequencing, have led to the identification of the genomic defects for more than 5,000 of the inherited diseases caused by mutations in a protein-encoding gene. An intense four-year, more than $400 million, research program, the Centers for Mendelian Genomics, is working to find the genomic cause of the remaining 2,000 to 4,000 rare genetic diseases.

We may be predisposed to certain diseases because of our genes, but it is not only genes that determine our health. It is also our lifestyle, habits and environment. These may cause genes to be switched on and off and even altered. There is also still a lot to be understood about what was once-called "junk DNA" -- which is now known to contain important control mechanisms over the bits we recognize as genes. And then there is the microbiome -- an ecosystem of microorganisms that live on and in the human body. So a lot more data are needed and much more research and analysis still needs to be done.

The good news is that other technologies are also rapidly progressing that will facilitate this. With the cost of genome sequencing dropping to affordable levels, genome data soon will be available for millions of people. Additionally, our smartphones are capturing information about our lifestyle and habits, location and activity levels. Wearable medical devices, which many companies are developing, will record vital signs such as temperature, blood oxygenation and heart rhythm. When you combine these data, you gain the ability to rapidly analyze the correlation between our genome, habits and disease -- exactly what is needed to develop individualized treatments for disease.

This is the same type of data analysis that is done of social media streams and shopping and online-browsing data by Silicon Valley start-ups and marketers.In other words, we human beings have become data and software -- and entrepreneurs can now do the work of pharmaceutical companies and medical research labs.

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Vivek Wadhwa: The triumph of genomic medicine is just beginning

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Washington, March 14 : Scientists have linked autism and intellectual disability in newborn males with genetic changes that could result from harmful environmental factors, a study said.

An analysis of 100 million US medical records said that autism and intellectual disability rates are correlated at the county level with incidence of genital malformations in newborn males, an indicator of possible congenital exposure to harmful environmental factors such as pesticides.

Autism rates - after adjustment for gender, ethnic, socioeconomic and geopolitical factors - jump by 283 percent for every one percent increase in frequency of malformations in a county.

The intellectual disability rates increase 94 percent.

Slight increases in autism and intellectual disability rates are also seen in wealthier and more urban counties.

The study, published by scientists from the University of Chicago March 13 in PLOS Computational Biology, confirmed the dramatic effect of diagnostic standards, reported Science Daily.

Incidence rates for autism and intellectual disability on a per-person basis decrease by roughly 99 percent in states with stronger regulations on diagnosis of these disorders.

"Autism appears to be strongly correlated with rate of congenital malformations of the genitals in males across the country," said study author Andrey Rzhetsky, Ph.D, professor of genetic medicine and human genetics at the University of Chicago.

"This gives an indicator of environmental load and the effect is surprisingly strong."

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Environmental factors linked to autism, intellectual disability

12 March 2014

Genetic markers provide unprecedented primate link in human evolution

Genetics provide stunning new answers to the question of human evolution, according to Auckland cancer researcher, Dr Graeme Finlay.

Genetic markers that are used to follow the development of populations of cells have exactly the same character as those that track the development of species, says Dr Finlay who has just published a book on genetics and human evolution.

His book, Human Evolution: Genes, Genealogies and Phylogenies, was published by Cambridge University Press late last year.

Dr Finlay is senior lecturer in Scientific Pathology at the Department of Molecular Medicine and Pathology, and an Honorary Senior Research Fellow at the Auckland Cancer Society Research Centre, in the University of Auckland.

Controversy over human evolution remains widespread, but the human genome project and genetic sequencing of many other species has provided myriad precise and unambiguous genetic markers that establish our evolutionary relationships with other mammals, says Dr Finlay.

This book identifies and explains these identifiable, rare and complex markers including endogenous retroviruses, genome-modifying transposable elements, gene-disabling mutations, segmental duplications and gene-enabling mutations.

These new genetic tools also provide fascinating insights into when and how many features of human biology arose: from aspects of placental structure, vitamin C dependence and trichromatic vision, to tendencies to gout, cardiovascular disease and cancer.

The book brings together a decade's worth of research and ties it together to provide an overwhelming argument for the mammalian ancestry of the human species.

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Genetic markers provide primate link in human evolution