Category Archives: Genetic Medicine

What is a genetic disease? How is it defined?

A genetic disease is any disease that is caused by an abnormality in an individual's genome, the person's entire genetic makeup. The abnormality can range from minuscule to major -- from a discrete mutation in a single base in the DNA of a single gene to a gross chromosome abnormality involving the addition or subtraction of an entire chromosome or set of chromosomes. Some genetic disorders are inherited from the parents, while other genetic diseases are caused by acquired changes or mutations in a preexisting gene or group of genes. Mutations can occur either randomly or due to some environmental exposure.

What are the types of genetic inheritance?

There are a number of different types of genetic inheritance including:

Single gene genetic inheritance

Single gene inheritance, also called Mendelian or monogenetic inheritance. This type of inheritance is caused by changes or mutations that occur in the DNA sequence of a single gene. There are more than 6,000 known single-gene disorders, which occur in about 1 out of every 200 births. These disorders are known as monogenetic disorders (disorders of a single gene).

Some examples of monogenetic disorders include:

Single-gene disorders are inherited in recognizable patterns: autosomal dominant, autosomal recessive, and X-linked.

Multifactorial genetic inheritance

Multifactorial inheritance, which is also called complex or polygenic inheritance. Multifactorial inheritance disorders are caused by a combination of environmental factors and mutations in multiple genes. For example, different genes that influence breast cancer susceptibility have been found on chromosomes 6, 11, 13, 14, 15, 17, and 22. Some common chronic diseases are multifactorial disorders.

Examples of multifactorial inheritance include:

Multifactorial inheritance also is associated with heritable traits such as fingerprint patterns, height, eye color, and skin color.

Chromosome abnormalities

Chromosomes, distinct structures made up of DNA and protein, are located in the nucleus of each cell. Because chromosomes are the carriers of the genetic material, abnormalities in chromosome number or structure can result in disease. Abnormalities in chromosomes typically occur due to a problem with cell division.

For example, Down syndrome (sometimes referred to as "Down's syndrome") or trisomy 21 is a common disorder that occurs when a person has three copies of chromosome 21. There are many other chromosome abnormalities including:

Diseases may also occur because of chromosomal translocation in which portions of two chromosomes are exchanged.

Mitochondrial genetic inheritance

This type of genetic disorder is caused by mutations in the non-nuclear DNA of mitochondria. Mitochondria are small round or rod-like organelles that are involved in cellular respiration and found in the cytoplasm of plant and animal cells. Each mitochondrion may contain 5 to 10 circular pieces of DNA. Since egg cells, but not sperm cells, keep their mitochondria during fertilization, mitochondrial DNA is always inherited from the female parent.

Examples of mitochondrial disease include:

What is the human genome?

The human genome is the entire "treasury of human inheritance." The sequence of the human genome obtained by the Human Genome Project, completed in April 2003, provides the first holistic view of our genetic heritage. The 46 human chromosomes (22 pairs of autosomal chromosomes and 2 sex chromosomes) between them house almost 3 billion base pairs of DNA that contains about 20,500 protein-coding genes. The coding regions make up less than 5% of the genome (the function of all the remaining DNA is not clear) and some chromosomes have a higher density of genes than others.

Most genetic diseases are the direct result of a mutation in one gene. However, one of the most difficult problems ahead is to further elucidate how genes contribute to diseases that have a complex pattern of inheritance, such as in the cases of diabetes, asthma, cancer, and mental illness. In all these cases, no one gene has the yes/no power to say whether a person will develop the disease or not. It is likely that more than one mutation is required before the disease is manifest, and a number of genes may each make a subtle contribution to a person's susceptibility to a disease; genes may also affect how a person reacts to environmental factors.

Medically Reviewed on 3/23/2018

References

National Human Genome Research Institute.<http://www.genome.gov>

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List of Genetic Diseases - Types, Symptoms, Causes ...

Precision medicine is gaining steamas consumers and healthcare organizations get up to speed with what promises to be a new paradigm in wellness care delivery. Consider the genetic testing startup 23andMe, which just landed $250 million in funding this past September. That financing brings the total capital raised by the company to $491 million as the kits become more popular.

And just this week, both Google and Microsoft participated in a $58 million funding round into precision medicine upstart DNAnexus and its cloud-based platform for machine learning and the sharing of biomedical and genomics data.

With this sort of momentum industry-wide, another startup, Genome Medical, has just launched programs designed to enable employer groups to offer genetic services and physician-guided genetic testing to their employees through its national network of clinical genetic experts. Employees can consult independently with Genome Medical providers includingtelemedicine consultations to ensure confidentiality and privacy of employee health information.

With more than 5,000 inherited genetic disorders and only about 6,000 practicing genetic experts in the United States, finding and accessing the right professional can be a challenge, and wait times for an appointment can be long. Further, research shows that non-genetic specialist doctors have an order error rate for genetic testing that is three times the error rate of genetic specialists, according to Genome Medical.

"Many individuals have a family history suggestive of an inherited condition such as cancer or heart disease, but lack guidance from their own providers about how to evaluate these risks," said Robert Green, MD, a medical geneticist at Harvard Medical School and co-founder of Genome Medical. "Employer programs that provide their employees with confidential access to independent genetics experts can help these individuals and their families benefit from evaluation and testing that meet established recommendations.

Genome Medical now offers employer groups four genetic programs. The first is genetic medical services. Genome Medical can help identify individuals at risk for an inherited disease or condition who would qualify for genetic testing under current medical guidelines and insurance coverage. Services include genetic counseling, genetic test ordering when indicated, simplified sample collection, medical case management and referrals as needed.

Proactive health programs, meanwhile, offer preemptive genetic screening for actionable genetic conditions to help individuals learn of genetic risks and take appropriate action. The program includes: detection of changes in genes associated with inheritable cancers, cardiovascular diseases and blood disorders; how genes affect response to anesthesia and other medications; and carrier testing for family planning and reproductive health.

The companys Genetics Resource Center offers a national network of genetic experts to employees. Using interactive tools, real-time chat services and a telehealth platform, individuals can ask questions and explore options across the full spectrum of genetic topics and conditions.

And the second opinion program provides a resource for employees to get an expert opinion on any genetic-related diagnosis or treatment plan. Genome Medicals network includes physicians across multiple specialties at top medical institutions who can provide expert second opinions.

"Recent studies suggest that many patients who meet guidelines for genetic testing are not receiving appropriate genetic services," said Lisa Alderson, co-founder and CEO of Genome Medical. "Genome Medical employer programs can help accelerate access to the standard of care in genetics by providing another avenue to identify individuals for whom a genetic test might be beneficial. Employees gain access to information that helps them be proactive about their health, and having healthier employees is in the interest of all employers."

Twitter:@SiwickiHealthITEmail the writer: bill.siwicki@himssmedia.com

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With precision medicine heating up, Genome Medical ...

Even though cancers may be found in the same part of the body and look similar under the microscope, we now understand that they can be quite different. That difference often appears in how that tumor type responds to therapy. Increasingly, that variation in response to treatment can reflect the changes that are found in the DNA of the tumor. Thats why Moffitt Cancer Center looks at every patients cancer as unique. We start with a precise diagnosis that tries to identify the specific DNA alternations in the tumor and then create an individualized treatment plan that has the best chance of beating your cancer. Our team approach ensures a full range of specialists are collaborating to look at your cancer from every perspective.

The ultimate goal of personalized medicine at Moffitt is to create and share new, targeted treatments that will improve outcomes, cure disease, extend survivorship and improve quality of life for patients regardless of where they live. This is accomplished through existing clinical programs as well as ongoing research into how best to develop the right diagnosis and treatment plan for each individual.

Our efforts include:

DeBartolo Family Personalized Medicine InstituteThe DeBartolo Family Personalized Medicine Institute provides the hub for personalized care and research at Moffitt. Created by a generous donation from the DeBartolo Family Foundation, the DFPMI was created in 2012 to revolutionize the discovery, delivery and effectiveness of cancer care on an international scale.

Department of Individualized Cancer ManagementThe Department of Individualized Cancer Management includes five high impact and clinically oriented departments under the leadership of Dr. Howard McLeod: Adolescent & Young Adult, Gene Home, Genetic Risk Assessment Service, Personalized Cancer Medicine and the Senior Adult Oncology Program. The Personalized Cancer Medicine department is comprised of the Personalized Medicine Clinical Service (PMCS) and Clinical Genomics Action Committee (CGAC). PMCS and CGAC were developed as pathways for direct clinical translation of results from genomic testing. PMCS provides consultation and interpretation of the tumor genetic sequencing results for Moffitt patients and serves as a resource to Moffitt Physicians for input and advice regarding personalized medicine. CGAC serves as Moffitts unique molecular tumor board and includes a diverse team with expertise from various disciplines. Dr. McLeod, a renowned expert on the role of genetics on the individuals response to cancer therapies, is the Medical Director for the DeBartolo Family Personalized Medicine Institute.

Total Cancer CareMoffitt Cancer Center's Total Cancer Care initiative is an ambitious research partnership between patients, doctors and researchers to improve all aspects of cancer prevention and care. Patients participate by donating information and tissue. Researchers use the information to learn about all issues related to cancer and how care can be improved. Physicians use the information to better educate and care for patients.

Clinical PathwaysMoffitts clinical pathways are a model for providing evidence-based, consensus-driven, cost-effective cancer care. Each of the 51 disease-specific pathways that Moffitt has developed offers a detailed road map for physicians to provide state-of-the-art cancer care. The pathways demonstrate how to integrate evidence-based medicine with available technology to standardize, benchmark, measure and improve cancer care.

Molecular Diagnostics LaboratoryThe Morsani Molecular Diagnostics Laboratory is revolutionizing cancer diagnostics by using the most advanced genetic testing tools available to improve the precision in the patient care we provide. Studies show as many as 30 percent of initial cancer diagnoses are revised to indicate a different type of cancer. This lab seeks to reduce that number by developing clinical biomarkers that can help identify the right drug for a particular patient or determine if a specific clinical trial is a good match for a patient with a certain tumor gene mutation.

ORIENThe Oncology Research Information Exchange Network (ORIEN) is a unique research partnership among North Americas top cancer centers that recognizes collaboration and access to data as the key to cancer discovery. Through ORIEN, founders Moffitt and The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute in Columbus leverage multiple data sources and match patients to targeted treatments. Partners have access to one of the worlds largest clinically annotated cancer tissue repositories and data from more than 100,000 patients who have consented to the donation for research.

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Personalized Medicine | Moffitt

Yoav Gilad, PhD

Chief, Section of Genetic Medicine

University of ChicagoDepartment of Medicine

The Section of Genetic Medicine was created over 10 years ago to both build research infrastructure in genetics within the Department of Medicine and to focus translational efforts related to genetics. As a result, the Section of Genetic Medicine is shaping the future of precision medicine with very active and successful research programs focused on the quantitative genetics, systems biology and genomics, and bioinformatics and computational biology. The Section provides extremely valuable collaborations with investigators in the Department of Medicine who are seeking to develop new and more powerful ways to identify genetic risk factors for common, complex disorders with almost immediate clinical application.

The Section of Genetic Medicine continues to shape the future of personalized medicine with successful research programs focused on the quantitative genetic and genomic science. The Section provides extremely valuable collaborations with investigators in the Department of Medicine who are seeking to develop new and more powerful ways to identify genetic risk factors for common, complex disorders with almost immediate clinical application.

The Section of Genetic Medicine conducts impactful investigations focused on quantitative genetics, systems biology and genomics, bioinformatics and computational biology. Some highlights from the past year include:

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Genetic Medicine - University of Chicago - Department of ...

Posted by Ardent Editor on July 23rd, 2007

One of the most promising uses for genetic modification being eyed in the future is on the field of medicine. There are a number of advances already being done in the field of genetic modification that may be able to allow researchers to someday be able to develop a wide range of medicines that will be able to treat a variety of diseases that current medicines may not be able to.

There are many ways that genetic modification can be used in the development of new medicines in the future. One of them is in the production of some human therapeutic proteins which is used to treat a variety of diseases.

Current methods of producing these valuable human proteins are through human cell cultures but that can be very costly. Human proteins can also be purified from the blood, but the process always has the risk of contamination with diseases such as Hepatitis C and the dreaded AIDS. With genetic modification, these human proteins can be produced in the milk of transgenic animals such as sheep, cattle and goats. This way, human proteins can be produced in higher volumes at less cost.

Genetic modification can also be used in producing so-called nutriceuticals. Through this genetic modification can be used in producing milk from genetically modified animals in order to improve its nutritional qualities that may be needed by some special consumers such as those people who have an immune response to ordinary milk or are lactose intolerant. That is just one of the many uses that genetic modification may be able to help the field of medicine in trying to improve the quality of life.

Other ways of using genetic modification in the field of medicine concern organ transplants. In is a known fact to day that organ transplants are not that readily available since supply for healthy organs such as kidneys and hearts are so very scarce considering the demand for it. With the help of genetic modification, the demand for additional organs for possible transplants may be answered.

Genetic modification may be able to fill up the shortfall of human organs for transplants by using transgenic pigs in order to provide the supply of vital organs ideal for human transplants. The pigs can be genetically modified by adding a specific human protein that will be able to coat pig tissues and prevent the immediate rejection of the transplanted organs into humans.

Although genetic modification may have a bright future ahead, concerns still may overshadow its continuous development. There may still be ethical questions that may be brought up in the future concerning the practice of genetic modification. And such questions already have been brought up in genetically modified foods.

And such questions may still require answers that may help assure the public that the use of genetic modification in uplifting the human quality of life is sound as well as safe enough. Public acceptance will readily follow once such questions have been satisfactorily answered.

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Genetic Modification in Medicine | gm.org

The field of genetics has long been an object of global fascination, beginning with Mendels pea plant experiments in the 19th century and peaking when the human genome was sequenced (albeit not completely) in 2003. But epigenetics as the next level up from genetics is still mysterious to most. Efforts are already underway to make this next leap in our therapeutic understanding of DNA to unlock the potential of epigenetics.

Genetics has gone mainstream and people get really excited about it, but when I tell people I work on epigenetics, I have to explain what I do, laughed Dr. Jason Mellad, CEO of Cambridge Epigenetix.

While there has been much excitement as epigenetics advances with the development of diagnostics, therapeutic applications are still in their infancy. Historically, epigenetic discovery has been expensive, the right tools havent existed to do it, and interpreting the data has been challenging, he explained.

Mellad and his company are working to change that by establishing themselves in diagnostics to lay the groundwork for more diverse applications. Initially, we sold kits to academic researchers so that they could examine how certain enzymes regulate interpretation of the genetic code, he explained to me in an interview after ON Helix. We started there to prove ourselves and enable discovery; now we are harnessing the power of epigenetics in diagnostics and thereby laying the foundation for new therapeutics.

Cambridge Epigenetix was spun out of its eponymous university to address a challenge a colleague lobbed at Sir Shankar Balasubramanian, Professor of Medicinal Chemistry at the University of Cambridge. Professor Balasubramanian co-invented the sequencing-by-synthesis platform at the heart of Solexa, which was subsequently snapped up by DNA sequencing giant Illumina.

As Mellad recounted, the colleague noticed that a particular epigenetic enzyme, TET2, is highly mutated in acute myeloid leukemia and produces a new DNA modification called 5-hydroxymethylcytosine (5hmC). Balasubramanianwondered, could this modification be detected by sequencing and used as a novel diagnostic epigenetic biomarker?

A DNA methyltransferase, DNMT3, which transfers methyl groups in DNA to regulate gene expression and activity. Such an enzyme could serve as a target for epigenetic medicine.

Balasubramanian and his PhD student, Michael Booth, took on the challenge and developed a selective chemical oxidation methodology that made it possible to accurately and quantitatively sequence 5hmC and other methylated variants of the DNA base cytosine for the first time. On the heels of its 2012 publication in Science, Cambridge Epigenetix was born with this methodology as its foundational platform.

The following year, Mellad was recruited for business development as Employee #3. We were still camped out in the lab at that point, he told me. But it soon built up steam: After its first fundraising round in 2014, the company went on to raise a $21M (18M) Series B led by none other than Google Ventures (GV). GV was excited by the tech and the team, but they also saw the potential and long-term vision, said Mellad.

So what was this promise that Google saw in epigenetics? Big companies seem to be rushing to jump on board: AstraZeneca has already launched its own exploration of the field with MRC Technology, now known as LifeArc. Could epigenetics be the next generation of genetic medicine?

Though the field still feels brand new, there are a handful of epigenetic drugs already on the market. These drugs are largely histone deacetylase (HDAC) inhibitors targeted at T cell lymphomas; the most recent approval went to Belinostat, which was developed by a formerly Copenhagen-based company known as TopoTarget, now part of the French Onxeo.

Epigenetics has taken a particularly strong hold in the cancer niche. As scientists from Harvard Medical School and the Broad Institute discussed in a Science review last July, recent cancer genome projects [have] unexpectedly highlighted the role of epigenetic alterations in cancer development and suggested that these changes are responsible for the so-called hallmarks of cancer.

Unfortunately, HDAC inhibitors seem to have limited use in this arena. A pair of Italian researchers concluded in the British Journal of Cancer that they are effective on a small set of [cancer] patients with selected hematological diseases, but their use as a monotherapy has not been satisfactory. The efficacy of these drugs has been marred by individual sensitivities to them that are difficult to untangle such that patient stratification is not an option.

A German company, 4SC, has taken heed of such findings, combining its lead candidate resminostat with Bayers kinase inhibitor, Nexavar (sorafenib). In January, 4SC was able to show that its HDAC in tandem with this first-line liver cancer treatment reducedthe risk of death and extended patient survival from 5.1 months to 13.7 months.

The hallmarks of cancer (Source)

Carlos Buesa, Founder and CEO of Oryzon Therapeutics, is optimistic about the rise of a new generation of epigenetic treatments that his company is leading. Weve seen very recently that the second generation of epigenetic modulators could be druggable in a selective manner overcoming the problems that the old-fashioned HDAC inhibitors have gone through, he told me at BIO Europe Spring earlier this year.

His Barcelona-based company, founded in 2000, is leading the charge in this direction. Its lead candidate ORY-1001 just cleared Phase I for acute leukemia and is under investigation in small cell lung cancer. It inhibits lysine specific demethylase 1 (LSD1), which in 2004 became the first histone demethylase to be discovered of approximately 30 thus far described.

LSD1 is thought to play a role in epigenetic reprogramming during cell proliferation among other biological processes, making it an attractive target for potential cancer therapies. We know now that its key to hematopoietic differentiation in normal progenitors, and we know that in some cancers its responsible for the differentiation blockade, as in some leukemias, Buesa said.

The role of epigenetics in cancer (Source)

Oryzon presented its Phase I/IIa results at the American Society for Hematology conference last fall: ORY-1001 proved itself to be safe and likely effective, on top of indicating a number of useful biomarkers to monitor patient responses. We were the first company to ever present [clinical] results with such an inhibitor, Buesa told me proudly. More recently, 4SC launched a program to develop an LSD1 inhibitor, 4SC-202, but it has yet to enter the clinic.

For the Oryzon, much has been riding on the success of ORY-1001: Having been shown to provoke the differentiation of cancer cells accompanied by a preliminary clinical response, it now serves as the companys proof of concept.

Even though Roche abandoned the biotech when it reprioritized its portfolio, Oryzon is pressing on, so far alone. Were seeing now that this is opening a door for a personalized approach, and its giving us information about diseases that have an underlying epigenetic component, said Buesa, explaining the companys determination to move ahead.

Though approved epigenetic drugs are limited to oncology, applications to other indications are also receiving attention. A recent mouse study published by the American Society for Microbiology in mBio suggested they might work as antivirals that would be effective against Herpes Simplex Virus, while an investigation into the treatment of HIV/AIDS is still at an early stage. Various neurodegenerative diseases are also topics of interest.

In order to build a foundation for the development of such a wide range of therapeutics, Cambridge Epigenetix plans to continue its technology and diagnostic development programs to illuminate epigenetic signatures that improve our understanding of biology to develop better therapeutics, said Mellad. Whats important is to first understand the biology.

Thats the sticking point for epigenetics at the moment: as reflected in the global scarcity of biotechs in the space, its still such new territory with a largely unknown extent that effective therapeutics may be an overreach.

As an intermediate step, Cambridge Epigenetix hopes that its diagnostic assays will become standard screening practice before treatment decisions, since, as he argues, the epigenetic versions are more effective than their genetic counterparts. Were developing a companion diagnostic strategy to be used from day one to get the best efficacy and patient outcomes, Mellad told me. Genetic sequencing is informative, but epigenetics is better for monitoring and predicting responses [to treatments].

Such an addition is already an important dimension of checkpoint inhibitor regimens as pharmas like Bristol-Meyers Squibb and Merck compete to dominate the niche. BMS was quick to knock the necessary genetic test for its rivals candidate, Keytruda, as cumbersome, while its own comparatively easy drug, Opdivo, maintainednearly a half billion-dollar sales lead in the first half of 2016.

The tide turned in May this year when the FDA approved Keytruda for solid tumors with a specific genetic signature. For the first time in history, cancer was classified not by location but by the genetic mutation believed to be at its root.

Keytrudas biomarker approval changed how people see diagnostics like the ones were working on,Mellad continued, hailing the FDA decision as a milestone for not just cancer genetics but epigenetics as well. And, Mellad said, this grown-up version of genetics could be even more useful, since epigenetics provides a more nuanced view of responses to therapeutics as a mirror of the bodys dynamic response to its environment.

More and more companies are jumping on board, making epigenetics increasingly mainstream versus a niche, remarked Mellad. As personalized medicine takes hold and such drugs become more successful in the treatment of diseases like cancer, epigenetics may soon capture the public imagination following in the footsteps of its predecessor.

Images via petarg, Leigh Prather, ESB Professional / shutterstock.com

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The Next Generation of Genetic Medicine: A Review of Epigenetics - Labiotech.eu (blog)