Category Archives: Human Genetics

NEW YORK Illumina officials were muted in their response to a threat from UK regulators that could potentially kill the firm's planned $1.2 billion acquisition of Pacific Biosciences. But that was just one of the storylines running through and around the firm's conference call following the release of its third quarter financial results.

"While we're still in the process of reviewing the documents, we continue to believe this acquisition is pro-competitive and in the best interests of customers and the genomics industry," Illumina CEO Francis deSouza said.

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Illumina Reserved in Comments on PacBio Deal, Forthcoming on Qiagen Deal and New Products - GenomeWeb

The Basics

A genome refers to an organism's complete set of DNA, including all of its genes. Therefore, WGS entails determining the complete DNA sequence at a point in time. It includes the organism's chromosomal DNA as well as DNA contained in the mitochondria.

While the field of genetics refers to the study of individual genes and their roles, genomics entails study of all of an organism's genes collectively- how they affect each other and the organism.

Simply put, the process of gene expression happens through synthesis of proteins. These proteins trigger the intended change in the cells and are synthesised after the corresponding DNA is transcripted to RNA in the cells nucleus.

Such DNAs which can be transcribed into messenger RNAs are called protein-coding DNA. Protein-coding DNA sequences are the most widely studied and best understood component of the human genome.

However, protein-coding DNA consist of only a small fraction of the genome - less than two per cent - the remaining 98 per cent of human genome consists of noncoding DNA.

Noncoding DNA that dont find a function in gene expression have biological functions- like regulating structural features of the chromosomes and DNA replication.

IndiGen is basically the India-specific version of the Human Genome Project (HGP), an an international scientific research project. The latter was primarily funded by the US government and was declared complete in 2003.

The HGP was able to map close to 92.1 per cent of the human genome, leaving out difficult portions of the chromosomes like centromeres and telomeres, with high accuracy.

Why genome sequencing is important

With the exception of identical twins, all humans show significant variation in genomic DNA sequences. People of same ethnicity/race may have more commonalities. Similarly. Based on genomic commonalities, certain populations of the world may be more susceptible to certain diseases, and so on.

Director General, CSIR and Secretary, Department for Scientific & Industrial Research, Dr Shekhar C Mande said that it is important to ensure that India, with its unparalleled human diversity, is adequately represented in terms of genomic data and develops indigenous capacity to generate, maintain, analyze, utilize and communicate large-scale genome data, in a scalable manner.

The broad-based genome data and knowhow for the its analysis will help in development of technologies for clinical and biomedical applications in India.

In the future, the technology is expected to deliver cost effective genetic tests, carrier screening applications for expectant couples, enabling efficient diagnosis of heritable cancers and pharmacogenetic tests to prevent adverse drug reactions.

On the occasion, the health minister also unveiled the IndiGenome card and accompanying IndiGen mobile application that enables participants and clinicians to access clinically actionable information in their genomes. This will pave the path for personalised treatments and precision medicine.

Genome sequencing also helps in evolutionary and anthropological studies. Genome sequencing has also helped us in developing better varieties of food crops.

However, the field also raises serious ethical, social concerns. The genome of a person can offer a host of information that is unknown to himself, to those who can analyse it. During the HGP, concerns were raised that the data might be used by big companies for hiring/firing employees, insurance companies to deny insurance to certain people etc. Therefore, privacy remains a serious concern.

The genomics has also revived the old debates over racial differences. Any genetic grounding of evolutionary differences between different races can have social repercussions with certain groups using the information to justify racial discrimination or race-purity.

Genomics also raise the ethical issues regarding human interference in natural processes. As the technology develops further, scientists would be able to design humans with assorted set of good genes.

Will this lead to a new form of Eugenics where parents discard a genetically inferior embryo early on? Will the rich be able to buy 'intelligence as they can buy beauty through lip injections, plastic surgeries, implants etc? What would the concepts like hard work, merit, equality etc mean in such a world?

These are some of the hard questions we will have to figure out as we move along.

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Explained: Indias Own Human Genome Project, How It Will Aid Our Fight Against Cancer And Genetic Diseases - Swarajya

This article, written byRuanne Vent-Schmidt, University of British Columbia, originally appeared on The Conversation and has been republished here with permission:

Blind and partially sighted people no longer have to wait passively for a research breakthrough in hope of treatment options. In fact, people living with genetic eye conditions can now actively drive vision research forward by enrolling in a patient registry and getting their genes tested.

There are 2.2 billion people living with visual impairment globally. Some are living with inherited retinal diseases that are progressive and can lead to complete blindness. Up until recent years, blind and visually impaired people were told that no treatment is available. This is changing as genetic testing is paving the way for a surge of gene therapies.

My passion for vision research is personal

My doctoral dissertation at the University of British Columbia was on drug therapy for retinitis pigmentosa. This progressive, blinding eye condition is the most common type of inherited retinal disease.

In people affected by retinitis pigmentosa, the light sensing cells in their retina photoreceptors die early. Unlike skin cells that regenerate, the body does not make more photoreceptors once they are damaged.

As a vision scientist affected by retinitis pigmentosa, I am passionate about finding the truth about the disease. Why do photoreceptors die? How can we stop it? How can science and medicine help?

When I was 12 years old, I realized while at summer camp that my night vision was disappearing. In the last two decades, I lost my peripheral vision, contrast sensitivity and depth perception.

I worked in Dr. Orson Moritzs lab at the UBC department of ophthalmology and visual sciences, which focuses on research using tadpoles that contain known human mutations for retinitis pigmentosa to understand the disease.

I made an alarming discovery in our animal model: knowing the genetic cause of retinitis pigmentosa is vital for treatment with one class of drugs histone deacetylase inhibitors. These determine how genes are switched on or off.

A similar study in mice showed that the same drug reacted differently to variations in a single mutant gene that also causes retinitis pigmentosa.

Treating retinitis pigmentosa is like extinguishing fire. To stop a fire, you need to know whether its water-based or grease-based. If you try to use water to stop a grease fire, the damage gets worse.

Enrol in a patient registry

Blind and visually impaired people can advocate for eye health by enrolling in a patient registry. Participation in a registry benefits researchers by offering more information about the disease.

In Canada, individuals can self-refer to Fighting Blindness Canadas secure, clinical patient registry. This database is dedicated to connecting people living with retinal eye diseases to clinical trials and research.

When a gene therapy trial arises, researchers draw participants from this database. Since gene therapy aims to correct an underlying genetic mistake in DNA that causes disease, knowing the genetic cause of a disease is a criteria for most gene therapy trials.

Globally, other registries include My Retina Tracker in the United States, Target 5000 in Ireland, MyEyeSite in the United Kingdom, the Australian Inherited Retinal Disease Registry and Japan Eye Genetics Consortium. In New Zealand, Dr. Andrea Vincent has established the Genetic Eye Disease Investigation Unit. There is even a Blue Cone Monochromacy Patient Registry for one rare eye condition.

Blossoming gene therapy trials

In the last two decades, the number of gene therapy trials has blossomed. Currently, 250 genes on inherited retinal diseases have been identified. In 2017, the first gene therapy for inherited retinal disease Luxturna was approved by the United States Federal Drug Administration.

To date, there are trials for: retinitis pigmentosa; Usher syndrome, a condition that involves hearing and vision loss; achromatopsia, a disease that causes colour blindness; X-linked retinoschisis, a dystrophy that causes splitting of the retina and affects mostly in males; and age-related macular degeneration, the third-largest cause of vision loss worldwide, caused by the interplay between genetics and environment.

Enrolment in a patient registry and genetic testing advance the design of gene therapy trials. This in turn benefits blind and visually impaired people.

Research advancement is a concerted effort across the globe blind and partially sighted people should know they have the power to push it forward.

Ruanne Vent-Schmidt, PhD Candidate, Cell & Developmental Biology, University of British Columbia

This article is republished from The Conversation under a Creative Commons license. Read the original article.

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BEYOND LOCAL: How people living with genetic eye conditions can drive vision research forward - GuelphToday

News Release

Thursday, October 24, 2019

Researchers have identified 57 genetic variations ofagenestrongly associated withdeclinesinbloodoxygen levelsduring sleep. Low oxygen levels during sleep are a clinical indicator of the severity of sleep apnea, a disorder that increases the risk of heart disease, dementia, and death. The study, published today in theAmerican Journal of Human Genetics, was funded by the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health.

A persons average blood oxygen levels during sleep are hereditary, and relatively easy to measure, said study author Susan Redline, M.D., senior physician in the Division of Sleep and Circadian Disorders at Brigham and Womens Hospital, and professor at Harvard Medical School, Boston. Studying the genetic basis of this trait can help explain why some people are more susceptible to sleep disordered breathing and its related morbidities.

When we sleep, the oxygen level in our blood drops, due to interruptions in breathing. Lung and sleep disorders tend to decrease those levels further, and dangerously so. But the range of those levels during sleep varies widely between individuals and, researchers suspect, is greatly influenced by genetics.

Despite the key roleblood oxygen levelsplayin health outcomes,theinfluenceof genetics on theirvariabilityremains understudied. The current findings contribute toa betterunderstanding, particularly because researcherslookedat overnight measurementsof oxygen levels. Thoseprovide more variability than daytime levelsdue to the stressesassociated withdisordered breathing occurring during sleep.

The researchers analyzed whole genome sequence data from the NHLBIs Trans-Omics for Precision Medicine (TOPMed) program. Tostrengthenthe data,they incorporated results of family-basedlinkage analysis, a method for mapping genes that carry hereditary traits to their location in the genome. Themethod usesdata fromfamilies with several members affected by aparticulardisorder.

This study highlights theadvantage of using family data in searching for rare variants, which is often missed in genome-wide association studies, said James Kiley, Ph.D., director of the Division of Lung Diseases at NHLBI. It showed that, when guided by family linkage data, whole genome sequence analysis can identify rare variants that signal disease risks, even with a small sample. In this case, the initial discovery was done with fewer than 500 samples.

The newly identified 57 variants of the DLC1 gene were clearly associated with the fluctuation in oxygen levels during sleep. In fact, they explained almost 1% ofthevariability in the oxygen levels in European Americans, which is relatively high for complex genetic phenotypes, or traits, that are influenced by myriad variants.

Notably,51 of the 57genetic variantsinfluence and regulate human lung fibroblast cells, a type of cell producing scar tissue in the lungs, according to study author XiaofengZhu, Ph.D., professor at the Case Western Reserve University School of Medicine, Cleveland.

This is important becauseMendelian Randomization analysis, a statistical approach for testing causal relationship between an exposure and an outcome, shows a potential causal relationship between how the DLC1 gene modifies fibroblasts cells andthechanges in oxygen levels during sleep, he said.

Thisrelationship,Kileyadded,suggests thata shared molecular pathway, or a common mechanism,may beinfluencing a persons susceptibility to the lack of oxygen caused by sleep disordered breathingand other lung illnesses such as emphysema.

The project was jointly led by Zhu and Redline, who also directs the National Sleep Research Resource, supported by NHLBI.

About theNational Heart, Lung, and Blood Institute (NHLBI): NHLBI is the global leader in conducting and supporting research in heart, lung, and blood diseases and sleep disorders that advances scientific knowledge, improves public health, and saves lives. For more information, visithttps://www.nhlbi.nih.gov.

About the National Institutes of Health (NIH):NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

NIHTurning Discovery Into Health

Sequencing analysis at 8p23 identifies multiple rare variants in DLC1 associated with sleep related oxyhemoglobin saturation level.

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Researchers identify genetic variations linked to oxygen drops during sleep - National Institutes of Health

SAN DIEGO, Oct. 24, 2019 (GLOBE NEWSWIRE) -- Bionano Genomics, Inc. (NASDAQ: BNGO), a life sciences instrumentation company that develops and markets Saphyr, a platform for ultra-sensitive and ultra-specific structural variation detection in genome analysis, today announced the key takeaways from presentations given between October 15-19 by scientists from top institutes and diagnostic companies at the American Society of Human Genetics (ASHG) Annual Meeting and at Bionanos satellite educational event in Houston, TX.

At ASHG and at the satellite education event held prior to the conference and organized by Bionano, clinicians and researchers using the Saphyr system to analyze samples from patients with genetic diseases and cancer presented a series of new findings and validation results that support the adoption of Saphyr as a complement to next-generation sequencing for variant discovery and as a replacement for traditional cytogenetic methods in variant detection for clinical applications.

Alka Chaubey, Ph.D., Head of Cytogenomics at PerkinElmer Genomics summarized the validation of Saphyr technology by PerkinElmer that enabled the development of PerkinElmers assay for Facioscapulohumeral Dystrophy (FSHD), which PerkinElmer and the University of Iowa developed based on the Bionano EnFocus FSHD Analysis tool. Dr. Chaubey presented 100% concordance between the assay and known disease state for publicly available cell lines, and 100% reproducibility among all runs and all FSHD patient samples at multiple test sites and with multiple operators.

Joe Devaney, Ph.D., Associate Director of R&D of diagnostic company GeneDx presented a Saphyr validation study for the detection of the disease-causing variants in FSHD and repeat expansion disorders such as Mytonic Dystrophy 1 and 2. For the 40 samples genotyped for the contraction causing FSHD and the 36 samples genotyped for CNBP gene expansion that causes Mytonic Dystrophy 2, the results generated with Saphyr had a sensitivity, specificity and Positive Predictive Value of 100%.

Dr. Gokce Toruner from the MD Anderson Cancer Center demonstrated 100% concordance between data generated with Saphyr and structural variant data generated with gold standard cytogenetic methods in five bone marrow specimens with hematological malignancies. All previously identified cytogenetic abnormalities detected by karyotyping, FISH or microarray analysis were detected by Saphyr. In addition, several novel structural and copy number changes were detected.

Professor Mark Ebbert from the Mayo Clinic used Saphyr to resolve challenging genomic regions implicated in neurodegenerative diseases on 31 brain samples collected post-mortem from patients with ALS, Parkinsons disease, and Alzheimers disease. One of the causes of ALS is an expansion of a repeat in a gene called C9orf72. While no technology commonly used today for genome analysis has been capable of spanning and measuring the larger repeat expansions of this gene, Dr. Ebbert was able to use the Saphyr system to size a range of expansions from a single brain biopsy, demonstrating a full continuum of mosaicism. In patients with Parkinsons disease, Saphyr resolved the structure of an inverted triplication of an associated gene. In patients with Alzheimers disease, Saphyr detected structural variants in CR1, an important gene with a repeat structure that cannot be fully analyzed with next-generation sequencing, and detected inversions in the Tau gene that protect against the disease.

Frances High, MD., Ph.D., from Massachusetts General Hospital for Children at Harvard University presented results of a study on 19 samples from patients with Congenital Diaphragmatic Hernia (CDH), a common and severe structural birth defect that leads to malformation for the developing lungs. Using data from the Saphyr system, Dr. Highs team confirmed all high-confidence structural variants that were detected by cytogenetic methods, provided additional higher-resolution detail and elucidated the structure of several, and identified novel likely causative variants. Dr. High announced an upcoming larger study of 50 patient-parent trios, or 150 samples total, to identify novel structural variants that are causative for this disease.

Professor Jennifer Mulle from Emory University School of Medicine used the Saphyr system to study a genetic syndrome characterized by intellectual disability, autism and a 40-fold increased risk for schizophrenia. She identified a high degree of previously undocumented structural variation in the disease region, identified a new gene previously not known to be involved in the disease, and was able to develop a new hypothesis about the disease mechanism from the data generated by Saphyr.

Professors Eric Vilain and Hayk Barseghyan from the George Washington University and Childrens National Medical Center presented a number of cases from the Undiagnosed Diseases Network, patients with Disorders of Sex Development, Gitelmans Syndrome, FSHD and Beckwith-Wiedeman syndrome where Bionano was able to provide a molecular diagnosis, identify new likely causative genes, or identify structural variants affecting known or expected disease genes.

Other talks included those by Professor Claudia Carvalho of Baylor College of Medicine, who used data from the Saphyr system to analyze repeat-mediated inversions, which are complex genomic structures that are hard or impossible to resolve with other molecular methods but can predispose to genetic disease; Tina Graves-Lindsay from the McDonnell Genome Institute at Washington University, who corrected structural errors in the official human reference genomes with data generated with Saphyr; and Amir Trabelsi, CEO of Genoox, who announced the new release of a software pipeline that now automatically validates, annotates and classifies Bionano translocation calls from whole genome sequence data.

Erik Holmlin, Ph.D., CEO of Bionano, commented, The quality of the studies presented and wide variety of applications for Saphyr in genetic disease and cancer research is continuing to increase. Data generated by the Saphyr system are answering difficult questions in complex genetic diseases that have been historically very challenging according to each of the presenters who described their experiences with Saphyr. The validation studies for FSHD, repeat expansion disorders and hematological malignancies are setting the stage for Saphyr to become a routine tool in research and clinical settings. We are grateful to all our customers and collaborators for their inspiration and for their work in showing what Saphyr can do.

More information about Bionano Genomics is available at http://www.bionanogenomics.com.

About Bionano GenomicsBionano is a life sciences instrumentation company in the genome analysis space. Bionano develops and markets the Saphyr system, a platform for ultra-sensitive and ultra-specific structural variation detection that enables researchers and clinicians to accelerate the search for new diagnostics and therapeutic targets and to drive the adoption of digital cytogenetics, which is designed to be a more systematic, streamlined and industrialized form of traditional cytogenetics. The Saphyr system comprises an instrument, chip consumables, reagents and a suite of data analysis tools.

Forward-Looking StatementsThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as may, will, expect, plan, anticipate, estimate, intend and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) convey uncertainty of future events or outcomes and are intended to identify these forward-looking statements. Forward-looking statements include statements regarding our intentions, beliefs, projections, outlook, analyses or current expectations concerning, including among other things, adoption of Saphyr as a routine tool in research and clinical settings and the effectiveness and utility of the Saphyr system in such settings. Each of these forward-looking statements involves risks and uncertainties. Actual results or developments may differ materially from those projected or implied in these forward-looking statements. Factors that may cause such a difference include the risks that our sales, revenue, expense and other financial guidance may not be as expected, as well as risks and uncertainties associated with general market conditions; changes in the competitive landscape and the introduction of competitive products; changes in our strategic and commercial plans; our ability to obtain sufficient financing to fund our strategic plans and commercialization efforts; the ability of key clinical studies to demonstrate the effectiveness of our products; the loss of key members of management and our commercial team; and the risks and uncertainties associated with our business and financial condition in general, including the risks and uncertainties described in our filings with the Securities and Exchange Commission, including, without limitation, our Annual Report on Form 10-K for the year ended December 31, 2018 and in other filings subsequently made by us with the Securities and Exchange Commission. All forward-looking statements contained in this press release speak only as of the date on which they were made and are based on management's assumptions and estimates as of such date. We do not undertake any obligation to publicly update any forward-looking statements, whether as a result of the receipt of new information, the occurrence of future events or otherwise.

Contacts

Company Contact:Mike Ward, CFOBionano Genomics, Inc. +1 (858) 888-7600mward@bionanogenomics.com

Investor Relations Contact:Ashley R. RobinsonLifeSci Advisors, LLC+1 (617) 775-5956arr@lifesciadvisors.com

Media Contact:Kirsten ThomasThe Ruth Group+1 (508) 280-6592kthomas@theruthgroup.com

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Takeaways from ASHG 2019 in Houston: Users of Bionano's Saphyr System Presented Validation Results for FSHD, Repeat Expansion Disorders and Digital...

Using artificial Intelligence and health-encounter data from 933 people with familial hypercholesterolemia and 83,000 without it, researchers say they have developed a model for more precisely screening for the condition that leads to high LDL cholesterol levels and elevated risk for heart disease. By some estimates,1.3 million Americans have undiagnosed familial hypercholesterolemia, an inherited genetic condition.

Its fair to say that we think based on all of this data, precision screening for FH is now a reality,saidDaniel J. Rader, MD,one of the study authors and chair of the department of genetics and chief of the division of translational medicine and human genetics at the University of Pennsylvania Perelman School of Medicine, said during a presentation this week.

Rader and his colleagues reported their resultsin the Lancet Digital Health this week and also presented thematan FH Foundation meeting. The foundation and Amgen, Sanofi, and Regeneron paid for the study.

When the researchers applied their model to a national database of 170 million patients, it flagged 1.3 million as possibly having familial hypercholesterolemia. When experts reviewed a small subset of those flagged people, they found that 87% were candidates for further evaluation and possible diagnosis andtreatment.

The researchers used the same process to sift through a smaller database of 173,000 patients at a number ofhealth care systems. The experts said 77% of a small subset of thoseflagged patients would bein the "should be evaluated" group.

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Study Shows Promise of 'Precision Screening' for Familial Hypercholesterolemia - Managed Care magazine

Were in a new era of biotech, Alfred Sandrock, Biogens head of research and development and chief medical officer, said of both developments in a telephone interview. We have better drug targets validated by human genetics.

Many questions remain, particularly about Biogens stunning reversal. Still, the news involving two of the states biggest biotechs raised the hopes of families anddoctors desperate for drugs to treat the diseases.

Biogens announcement on Tuesday was the bigger bombshell. The firm has been working for years on the experimental drug aducanumab for Alzheimers. That form of dementia afflicts more than 5 million Americans, and no drugs significantly slow its ravages.

The hunt for an effective treatment has eluded some of the worlds biggest drug companies. According to an industry report, there were 146 failed attempts to develop medicines to treat and potentially prevent Alzheimers in the past two decades and only four new drugs approved to treat symptoms.

On March 21, Biogen said it was abandoning tests on aducanumab based on the recommendations of an independent monitoring board entrusted to protect patients in the study.

Biogen and its Japanese partner Eisai said they halted two late-stage clinical trials after concluding that the compound was unlikely to benefit patients.

The news sent Biogen stock into a free fall, and the company lost a staggering $18 billion the day of the announcement. With the setback, Biogen joined the long list of drug firms that had struck out on Alzheimers treatments.

It also appeared to mark the demise of a series of experimental Alzheimers drugs that targeted a protein in the brain called beta amyloid, all of which had failed.

But Michel Vounatsos, Biogens CEO, and Sandrock said the aducanumab story didnt end in March.

Biogen, in consultation with a team from the FDA, conducted a new analysis of a larger data set from the late-stage clinical trials that were halted, they said. The new analysis included additional data that became available after the prior analysis showed the study had no chance of success.

The new data showed that aducanumab was pharmacologically and clinically active in higher doses in reducing brain amyloid and in reducing clinical decline. Sandrock said the earlier data contained only about half the patients who had enrolled in the clinical trial and focused on people who had received smaller doses.

We didnt quite appreciate how important it was to get to a very high dose, he said.

On Monday, a dozen Biogen scientists and statisticians and two representatives of Eisai met for two hours with eight FDA neurology officials at the agencys Maryland headquarters, said Sandrock, who attended.

We shared with them the entire data set, and we were told it was reasonable to submit an application for approval of aducanumab, Sandrock said. Biogen expects to make the submission early next year.

Several analysts expressed deep skepticism that the FDA will OK the drug despite the new analysis.

Brian Skorney, an analyst with Baird, issued a report headlined If You Torture the Data Long Enough, It Will Confess to Anything.

Biogens decision to file for regulatory for aducanumab in Alzheimers, after halting the study for futility, is understandable given the addressable market, he wrote. However we do not share theirenthusiasm for the interpretation of the results and believe approval would rely on regulators with minimal capacity for critical analysis.

PiperJaffray analysts said in another report that aducanumabs return from the dead was a complete shocker and that they werent sure what to make of the drugs prospects.

However, Dr. Brent Forester, chief of geriatric psychiatry at McLean Hospital and a principal investigator in the aducanumab trial at his hospital, was delighted by the news.

Forester said six patients with early symptoms of Alzheimers received the drug. While its difficult to say whether it worked, he said, the patients seemed stable.

There was never any indication that Biogen would pull the plug because it wasnt working, he said.

Debbie Rosenkrantz, a 66-year-old retired clinical social worker in Cambridge, said she took the medicine in the trial for about eight months. She felt it halted the decline in her memory.

I actually felt like it was working, and then to be told that it wasnt working was kind of disappointing to me, she said. This was a nice turnaround.

The revival of aducanumab Tuesday sent Biogens stock up, and it closed up more than 26 percent on the Nasdaq. That helped the firm recoup some of the billions of dollars in value it lost when Biogen said it had pulled the plug on the compound.

Mondays announcement about Vertexs cystic fibrosis drug approval was widely expected but the speed of the government ruling caught the industry by surprise. The FDA had set a goal of deciding whether to approve the drug by March 2020.

Vertex already has three cystic fibrosis drugs on the market. Trikafta, the new combination drug, is expected to benefit up to 90 percent of the 27,000 CF patients in the country, according to the FDA.

The FDAs acting commissioner, Ned Sharpless, said after the drug won approval that the agency has been striving to speed the development of therapies for complex diseases.

Like Vertexs other drugs for cystic fibrosis, Trikafta has a jaw-dropping list price: $311,000 a year.

Joseph J. ODonnell, a Boston corporate tycoon whose son, Joey, died of cystic fibrosis in 1986 at the age of 12, was stunned to learn about the approval while on vacation.

ODonnell has helped to raise hundreds of millions of dollars for the nonprofit Cystic Fibrosis Foundation, much of which has gone to Vertex for research.

He said he and his wife, Kathy, were on a cruise ship near Athens on Monday night when they heard the news in a phone call from their daughter, Kate ODonnell.

The ODonnells celebrated over dinner with six other couples with whom they took the cruise, all of them contributors to the fund.

I knew this was going to happen sooner or later because all the results [of clinical trials] were so consistently good, ODonnell, 75, said in a phone interview. But I never dreamed it would happen before the first of the year.

Jonathan Saltzman can be reached at jsaltzman@globe.com

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In the span of 16 hours, two giant biotech developments - The Boston Globe

Our understanding of post-traumatic stress disorder (PTSD), until now, is that it is a mental health disorder that occurs as a consequence of exposure to extreme, life-threatening stress, and/or serious injury. This exposure, by definition, is requisite for the development of PTSD, but not all those who face trauma necessarily develop it the individual susceptibility to PTSD varies widely. Since the turn of the century, scientists have been trying to find evidence for genetic influence on PTSD risk, with the last decade witnessing concerted efforts to identify specific DNA variants that can influence ones genetic susceptibility to develop PTSD.

New research, findings of which were published in Nature Communications, has, for the first time, identified a clear biological pathway for the mental health disorder, despite a section of science still viewing it as an entirely social construction. In the largest and most diverse genetic study of PTSD to date, scientists from the University of California, San Diego, School of Medicine and more than 130 additional institutions have concluded that genetics do, in fact, play a role in determining whether or not a person will develop PTSD, similar to the biological pathways of depression and other forms of mental illness.

Our long-term goal is to develop tools that might help clinicians predict who is at greatest risk for PTSD and personalize their treatment approaches. We cant always protect people from trauma. But we can treat them in the best ways possible, at the best time, Dr. Caroline Nievergelt, the studys first author, associate professor of psychiatry at UC San Diego School of Medicine and associate director of neuroscience in the Center of Excellence for Stress and Mental Health at the Veterans Affairs San Diego Healthcare System, said in a press release.

In collaboration with the Psychiatric Genomics Consortiums PTSD working group and Cohen Veterans Bioscience, a non-profit organization dedicated to accelerating PTSD and traumatic brain injury research, the studys authors built a 12-country network of more than 200 researchers, assembling data and DNA samples from more than 20,000 people with PTSD and 170,000 control subjects (those who did not develop PTSD following trauma).

At more than 200,000 people, the latest studys sample size is 10 times larger than the firstPsychiatric Genomics Consortium PTSD study, published in 2017, and includes both civilians and members of the military. The release notes the cohort is also the most ancestrally diverse for any psychiatric genetics study to date, with more than 23,000 people with PTSD of European ancestry and more than 4,000 of African ancestry.

Related on The Swaddle:

Researchers Find Genetic Hotspot Behind Autism

Putting this large database through statistical analyses, the studys authors measured the effect of gene variants at millions of different points on chromosomes across the human genomes on someones chances of developing PTSD.

According to the findings, PTSDs heritability the level of influence genetics has on the variability of PTSD risk among people is between 5% and 20%. Scientists found that, like other psychiatric disorders and several human traits, the risk of developing PTSD following trauma is a highly polygenic trait. This means there exist thousands of genes at different loci on different chromosomes that make tiny contributions to the disorder and when expressed together, add up to the heritable trait. Scientists have found gene variants at six loci that were strongly associated with PTSD risk.

Three of the six loci were specific to certain ancestral backgrounds two European and one African and three were only detected in men. The six loci hint that inflammatory and immune mechanisms may be involved in the disorder, which is consistent with findings from previous studies, the release summarises.

Further exploring the relatively nascent belief in science that many psychiatric disorders and behavioral traits have important molecular similarities at DNA-level, the study also analyzed genetic correlations between PTSD and 235 other disorders behaviors and physical traits. They found a significant overlap with 21, including depression, schizophrenia, insomnia, asthma, and coronary artery disease. Additionally, a Parkinsons disease gene involved in dopamine regulation was also found to be associated with PTSD. Similar to other mental disorders, the genetic contribution to PTSD correlates with that for many other traits. Further research is needed to determine what this means whether some of the same genes that influence risk for PTSD also influence risk for other diseases like, for example, depression, Karestan Koenen, a senior author of the study and associate member of the Stanley Center for Psychiatric Research at MIT and Harvard University, and a professor of psychiatric epidemiology in the Harvard T.H. Chan School of Public Health, said in the release.

Koenen adds: Based on these findings, we can say with certainty that there is just as much of a genetic component to PTSD risk as major depression and other mental illnesses. Our limited ability to study the living human brain and uncover the biological roots of PTSD has contributed to the lack of treatments and the stigma around this debilitating condition. Genetics helps us make new discoveries, find opportunities for new therapies, and counter that stigma.

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Study: The Likelihood of Developing PTSD Following Trauma Is Party Determined by Genetics - The Swaddle

Researchers discovered that these signatures of DNA mutations are also present in healthy and diseased liver, and that it is the accumulation of changes from these signatures that ultimately leads to serious health problems.

The study, published this week in Nature, is the largest study of the differences in genetic changes between healthy and diseased liver tissue, with a view to better understanding how liver disease and hepatocellular carcinoma (HCC) develop. These discoveries advance the possibility of one day using genomic data to predict the future risk of cancer in people suffering from chronic liver disease.

Chronic liver disease, which refers to conditions including cirrhosis, fatty liver disease and cancer, has risen by 400 per cent in the UK since 1970 to become the biggest cause of death among 35-49 year olds. The commonest causes in the UK are excessive alcohol intake and obesity. In 2016/17, almost 15,000 deaths were caused by liver disease in the UK*.

There has been a 162 per cent increase in cases of liver cancer in the UK since the 1990s, with around 5,900 new cases every year, and by 2035 the number of cases is predicted to rise by 38 per cent (from 2014 levels)**. The most common type of primary liver cancer is called hepatocellular carcinoma (HCC)***. HCC is rare in people with a normal liver, but commonly develops in people with chronic liver disease.

DNA mutations**** play a prominent role in many forms of cancer and can be caused by a large number of factors, including genetic factors and things we are exposed to during life such as chemicals found in food or the environment. Liver cancer arises from the effects of particular types of DNA damage, which cause specific signatures of mutations.

The common genetic events and patterns of DNA mutation associated with liver cancers were previously known, but it was unknown in what order these events occur, or why some people with chronic liver disease develop cancer but others develop failure of the liver to perform its normal function.

The new study is the most comprehensive use of genomic analysis to compare normal liver tissue with tissue affected by chronic liver disease, providing researchers with an unprecedented level of detail on how the accumulation of DNA mutations over time leads to liver disease and cancer.

Tissue samples from five normal and nine cirrhotic livers were collected by Addenbrookes hospital in Cambridge*****. From these samples, scientists at the Wellcome Sanger Institute created 482 whole genome sequences so the DNA of the tissues could be analysed.

The team observed a substantial increase in the number of mutations in chronic liver disease compared to normal liver. Cirrhotic liver tissue contained around twice the number of mutations as healthy liver and HCC tumour tissue had an even higher numbers of mutations. The variety in the type of mutations in diseased and cancerous tissue was also much greater than healthy liver, with mutations causing more damage to the overall integrity of the DNA.

Only a few mutations associated with HCC were discovered in the chronically diseased liver, suggesting that the increased risk of liver cancer arises because the substantial DNA damage seen in liver disease promotes the emergence of cells with the potential to eventually become cancers.

The study also highlighted the way our environment can influence the patterns of DNA damage in the liver. For example, 10-20 per cent of DNA mutations in samples from one patient indicated exposure to a toxin produced by Aspergillus moulds. These moulds often contaminate crops and are prevalent in arable farmers, which was the occupation of the patient.

The researchers say that many things can cause DNA mutations associated with cancer, particularly in the liver because it processes many of the chemicals that we are exposed to in our diet and the environment. As such, the richest diversity of DNA mutations are found in liver cancer.

Dr Matthew Hoare, a lead author of the study from the Cancer Research UK Cambridge Institute, said: Its incredibly compelling to be able to show how liver disease affects the DNA in our livers. We knew there was a link between chronic liver disease and liver cancer, so it was unexpected to find so few cancer-causing mutations among the DNA damage in liver disease. The next step will be to look for common patterns within this damage that might help us predict who is at a higher risk of cancer.

People with chronic liver disease have a higher risk of HCC, but it is not clear why this cancer occurs in some of these people and not in others. For now the exact cause of HCC remains unknown, but understanding that the processes involved in chronic liver disease are the same as those involved in HCC opens up the possibility of one day being able to predict an individuals risk of liver cancer.

Dr Peter Campbell, a lead author of the study and Senior Group Leader at the Wellcome Sanger Institute, said: Whats interesting about the findings of this study is that we have been able to observe how excessive alcohol intake and obesity are linked to DNA mutations in chronic liver disease as well as liver cancer. Though it is early days, we can start thinking about ways to predict a persons risk of liver cancer from the number and types of mutations in their DNA.

Image: Cirrhosis_ Nephron, Wikimedia Commons

*The British Liver Trust has information on liver disease and the rise in incidence https://britishlivertrust.org.uk/about-us/media-centre/statistics/

**For statistics on liver cancer in the UK, see the Cancer Research UK website https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/liver-cancer

***HCC is more common in people with cirrhosis, a form of chronic liver disease where scarring forms as a result of damage to the liver. This can be caused by excess alcohol consumption, hepatitis B or hepatitis C. Cancer Research UK has more information on HCC and other liver cancers https://www.cancerresearchuk.org/about-cancer/liver-cancer/types

****DNA mutations are changes to a single letter of a persons genetic code and occur naturally as we go through life. Many mutations do not significantly alter how our body functions or are repaired by our bodies before they can interfere with our health. But when a large number of mutations occur, it increases the chances of something going wrong. The Genetics Home Reference website has a library of information on genetics and health https://ghr.nlm.nih.gov/primer#mutationsanddisorders

******Patients recruited at Addenbrookes Hospital, Cambridge gave written informed consent with approval of the Local Research Ethics Committee (16/NI/0196). All tissue samples were snap-frozen in liquid nitrogen and stored at -80C in the Human Research Tissue Bank of the Cambridge University Hospitals NHS Foundation Trust.

Publication:

Simon F Brunner, Nicola D Roberts and Luke A Wylie et al. (2019). Somatic mutations and clonal dynamics in healthy and cirrhotic human liver. Nature. DOI: 10.1038/s41586-019-1670-9

Funding:

This work was supported by Wellcome and a Cancer Research UK Grand Challenge Award. The Cambridge Human Research Tissue Bank is supported by the NIHR Cambridge Biomedical Research Centre.

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Accumulation of DNA mutations found in healthy liver leads to disease - Cambridge Network

HOUSTON, Oct. 17, 2019 /PRNewswire/ -- Researchers fromInvitae Corporation (NYSE: NVTA), a leading medical genetics company, are presenting data showing the increasing utility of genetic information at the American Society of Human Genetics (ASHG) annual meeting this week, ranging from comprehensive screening for cancer patients, to appropriate clinical follow up for women using non-invasive prenatal screening, to the limitations of direct to consumer genetic screening health reports.

The company's research includes three platform presentations and multiple poster sessions, many performed in collaboration with leading academic researchers. Among the data presented is a study evaluating the utility of combined germline testing and tumor profiling (somatic testing) in cancer patients. Germline and somatic testing are increasingly used in precision treatment of people with cancer, although frequently are ordered separately in clinical practice. Data presented at the meeting shows a substantial number of patients with medically significant variants in hereditary cancer syndrome genes in their tumor profile carry the same variant in their germline, thereby establishing a previously unknown risk of hereditary cancer and suggesting the value of combined or concurrent testing to inform precision medicine approaches.

"The research we are presenting at this year's ASHG meeting provides meaningful insight into both the science and practice of genetics, helping identify how we as clinicians can better use deep genetic insights to help a wide array of patients, whether they are cancer patients, women having a child or healthy adults seeking to better understand their risk of disease," said Robert Nussbaum, M.D., chief medical officer of Invitae. "We are proud and grateful to be able to join our colleagues from across genetic medicine in meaningful conversations that push genetic medicine forward."

Following are research from the company and collaborators to be presented at the meeting:

Wednesday, October 16:

Poster presentation #819W | 2:00 3:00 pm Germline testing in colorectal cancer: Increased yield and precision therapy implications of comprehensive multigene panels. Presented by Shan Yang, PhD. Invitae.

Poster presentation #2427W | 2:00 3:00 pm Harmonizing tumor sequencing with germline genetic testing: identification of at-risk individuals for hereditary cancer disorders. Presented by Daniel Pineda-Alvarez, MD, FACMG, Invitae.

Poster presentation #606W | 3:00 4:00 pm A comprehensive evaluation of the importance of prenatal diagnostic testing in the era of increased utilization of non-invasive prenatal screening. Presented by Jenna Guiltinan, MS, LCGC, Invitae.

Thursday, October 17:

Platform presentation #235 | 5:00 pm, Room 370A, Level 3 Limitations of direct-to-consumer genetic screening for hereditary breast, ovarian and colorectal cancer risk. Presented by: Edward Esplin, MD, PhD, FACMG, FACP, Invitae.

Poster presentation #763T | 2:00 3:00 pm In-depth dissection of APC pathogenic variants: Spectrum of more than 400 pathogenic variants, challenges of variant interpretation, and new observations in a large clinical laboratory testing cohort. Presented by: Hio Chung Kang, PhD, Invitae.

Poster presentation #1399T | 2:00 3:00 pm Prediction of lethality and severity of osteogenesis imperfecta variants in the triple-helix regions of COL1A1 and COL1A2. Presented by: Vikas Pejaver, PhD, University of Washington.

Friday, October 18:

Platform presentation #264 | 9:00 am, Room 361D, Level 3 Million Veteran Program Return Of Actionable Results - Familial Hypercholesterolemia (MVP-ROAR-FH) Study: Considerations for variant return to mega-biobank participants. Presented by Jason Vassy, MD, MPH, VA, Boston Healthcare System.

Platform presentation #265 | 9:15 am, Room 361D, Level 3 Comprehensive secondary findings analysis of parental samples submitted for exome evaluation yields a high positive rate. Presented by Eden Haverfield, DPhil, FACMG, Invitae.

Poster presentation #698F | 2:00 3:00 pm Reporting of variants in genes with limited, disputed, or no evidence for a Mendelian condition among GenomeConnect participants. Presented by: Juliann Savatt, MS, LGC, Geisinger.

About InvitaeInvitae Corporation(NYSE: NVTA)is a leading medical genetics company, whose mission is to bring comprehensive genetic information into mainstream medicine to improve healthcare for billions of people. Invitae's goal is to aggregate the world's genetic tests into a single service with higher quality, faster turnaround time, and lower prices. For more information, visit the company's website atinvitae.com.

Safe Harbor StatementsThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including statements relating to the increasing utility of genetic information; the utility of combined germline and somatic testing; and the benefits of the company's research. Forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially, and reported results should not be considered as an indication of future performance. These risks and uncertainties include, but are not limited to: the applicability of clinical results to actual outcomes; the company's history of losses; the company's ability to compete; the company's failure to manage growth effectively; the company's need to scale its infrastructure in advance of demand for its tests and to increase demand for its tests; the company's ability to use rapidly changing genetic data to interpret test results accurately and consistently; security breaches, loss of data and other disruptions; laws and regulations applicable to the company's business; and the other risks set forth in the company's filings with the Securities and Exchange Commission, including the risks set forth in the company's Quarterly Report on Form 10-Q for the quarter ended June 30, 2019. These forward-looking statements speak only as of the date hereof, and Invitae Corporation disclaims any obligation to update these forward-looking statements.

Contact:Laura D'Angelopr@invitae.com(628) 213-3283

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Research presented by Invitae at the American Society of Human Genetics Meeting Pushes Science and Practice of Genetics Forward - P&T Community