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genomics

direct-to-consumer genetic testingLast November, the U.S. Food and Drug Administration issued a “cease and desist” order to 23andMe, a major purveyor of direct-to-consumer (DTC) genetic testing. In its letter to the company—issued after three prior warnings—the FDA reiterated its view that 23andMe’s Personal Genome Service (PGS) constitutes a medical device requiring further premarket evaluation:

FDA is concerned about the public health consequences of inaccurate results from the PGS device…we still do not have any assurance that the firm has analytically or clinically validated the PGS for its intended uses.

The FDA’s order, based on potential rather than actual medical harm, has generated a great deal of controversy. In a recent critique published in Nature, Robert Green, MD, MPH, of the Partners HealthCare Center for Personalized Genetic Medicine, and Nita Farahany, PhD, JD, of the Duke Institute for Genome Sciences and Policy, argued against regulating DTC genomic interpretation services as medical devices:

… doing so could put FDA regulations in greater tension with the First Amendment of the US Constitution, which protects the rights of individuals to receive information, and of ‘commercial speech’ ….the agency should avoid restricting consumer genomic testing unless faced with empirical evidence of harm. Full story »

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cancer genomicsIn 2012, Boston Children’s Hospital held the international CLARITY Challenge—an invitation to interpret genomic sequence data from three children with rare diseases and provide a meaningful, actionable report for clinicians and families. (Click for more background on the children, findings and winners.)

The full proceedings, published March 25 in Genome Biology, concluded that while the technical approaches were markedly similar from center to center, the costs, efficiency and scalability were not. Most variable, and most in need of future work, was the quality of the clinical reporting and patient consenting process. The exercise also underscored the need for medical expertise to bring meaning to the genomic data.

That was CLARITY 1. CLARITY 2, focusing on cancer genomics in children, promises to be exponentially more complex. Full story »

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The Sylvian fissure (via BodyParts3D/Wikimedia Commons)

The Sylvian fissure (via BodyParts3D/Wikimedia Commons)

Five people with an unusual pattern of brain folds have afforded a glimpse into how the human brain may have evolved its language capabilities.

How the human brain develops its hills and valleys—expanding its surface area and computational capacity—has been difficult to study. Mice, the staple of scientific research, lack folds in their brains.

Christopher Walsh, MD, PhD, head of the Division of Genetics and Genomics at Boston Children’s Hospital, runs a brain development and genetics clinic and has spent 25 years studying people in whom the brain formation process goes awry. Some brains are too small (microcephaly). Some have folds, or gyri, that are too broad and thick (pachygyria). Some are smooth, lacking folds altogether (lissencephaly). And some have an abnormally large number of small, thin folds—known as polymicrogyria.

In 2005, studying people with polymicrogyria, Walsh and colleagues identified a mutation in a gene known as GPR56, a clue that this gene helps drive the formation of folds in the cortex of the human brain.

In a study published in today’s issue of Science, Walsh and his colleagues focused on five people whose brain MRIs showed polymicrogyria, but just in one location—near a large, deep furrow known as the Sylvian fissure, which includes the brain’s primary language area. Full story »

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Girl looking in microscope-ShutterstockSince our “trends” posts at the top of the year are among our most viewed, Vector took time out this summer to take an interim snapshot of pediatric medicine’s cutting edge. Here we present, in no particular order, our first five picks. Check back next Friday for Part 2. If you want more, there’s still time to register for our National Pediatric Innovation Summit + Awards (September 26-27). The posts will also appear as an article in the fall issue of Children’s Hospitals Today magazine.

1. Digital health apps 2.0

The electronic revolution in health care continues. According to recent surveys, more than 90 percent of physicians have smartphones and more than 60 percent are using tablet devices like iPads for professional purposes. Dr. Eric Topol and others think these digital tools are the future of medicine.

Mobile apps keep proliferating, adding more and more features: high-quality image capture, voice-to-text capabilities and gaming techniques to motivate adherence, as well as sensors that gather physiologic data, like glucose levels and heart rate. Consumers are tracking and sharing data themselves, saving time in the clinic and helping physicians monitor their symptoms. Through the much-hyped Google Glass, it won’t be long before doctors can seamlessly call up patient data, look up a drug dosage and get decision support during a clinical visit without using a hand-held device.

One limiting factor in this “Wild West” scenario is the FDA’s ability to keep up with digital advances from a regulatory standpoint. Full story »

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Whole-exome sequencing reveals a gene mutation that comes into play only if inherited from the father.

Whole-exome sequencing reveals a gene mutation that comes into play only if inherited from the father.

For a small subset of boys and girls who undergo early puberty, there’s now a specific explanation. New genetic research, involving whole-exome sequencing, has identified four novel heterozygous mutations in a gene known as MKRN3. Interestingly, while precocious puberty is more common in girls, all 15 affected children in the study inherited the mutations from their fathers.

Precocious puberty—the development of secondary sexual characteristics before 8 years in girls and 9 years in boys—has been associated with short stature, long-term health risks and an increase in conduct and behavioral disorders during adolescence. Physiologically, there are two types: central and peripheral. Central, the more common form, occurs when the pituitary gland, which controls puberty development, is activated too early.

“While a great deal of genetic studies have focused on the overall genetic contribution to pubertal timing, far less research has been conducted to find specific genetic causes of central precocious puberty,” says Andrew Dauber, MD, MMSc, of the Division of Endocrinology at Boston Children’s Hospital, who co-authored the study, published online this week by The New England Journal of Medicine. Full story »

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Biomarkers for all

by Tom Ulrich on February 5, 2013

Just about any measurable molecule that changes with health and disease could be a biomarker. (David Guo's Master/Flickr)

Your doctor has a lot of tools to detect, diagnose and monitor disease: x-rays, MRIs, angiography, blood tests, biopsies…the list goes on.

What would be great would be the ability to test for disease in a way where there’s no or low pain (not invasive) and lots of gain (actionable data about the disease process itself, its progression and the success of treatment).

That’s where biomarkers come in. Full story »

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A new spinoff business will make large-scale genomic diagnostics a reality in medical practice (Image: Rosendahl)

Genomic sequencing and molecular diagnostics are becoming a global business. At the recent American Society of Human Genetics meeting, dazzling technologies for reading genetic code were on display—promising faster, cheaper, sleeker.

Nevertheless, it’s become clear that the ability to determine someone’s DNA or RNA sequence doesn’t automatically translate into useful diagnostics or even actionable information. In fact, the findings are often confusing and hard to interpret, even by physicians.

That’s where academic-industry partnerships can flourish—tapping the deep expertise of medical research centers to bring clinical meaning to sequencing findings. Yesterday, Boston Children’s Hospital and Life Technologies Corp. announced a new venture with a great list of ingredients: fast, accurate, scalable sequencing technology—Life’s Ion Proton® Sequencer—but also research and clinical experience in rare and genetic diseases, bioinformatics expertise to handle the big data, and the medical and counseling expertise to create meaning from the results. Full story »

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It’s been more than a decade since the Human Genome Project cracked our genetic code. DNA sequencing is getting cheaper and cheaper. So why isn’t it being used every day in medicine?

The truth is that while we have the technology to blow apart a patient’s DNA and piece it back together, letter by letter, and compare it with normal “reference” DNA, doctors don’t really know what to do with this information. How much of it is really relevant or useful? Should they be giving it back to patients and their families, and how?

Handled badly, the information could do more harm than good. “We don’t want to scare patients for no reason, or for the wrong reason,” says Isaac Kohane, MD, PhD, who chairs the Children’s Hospital Informatics Program.

Seeking a set of best practices for safe, clinically useful genomic sequencing, Boston Children’s Hospital took a crowd-sourcing approach. Full story »

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Liam Burns died 12 days after birth from an unexplained set of heart defects. His parents hope the CLARITY challenge will provide a meaningful explanation.

One extended family has a range of unexplained heart defects—sometimes a hole in the heart, sometimes an arrhythmia. One child, Liam Burns, died days after birth from an underdeveloped heart, a narrowed artery to the lungs and an electrical block. Yet other family members have little more than a heart murmur. All of the defects are on the right side of the heart.

Another family’s son, 11-year-old Adam Foye, has unexplained muscle weakness and fatigue. He can walk only short distances and needs a ventilator at night to support his breathing.

These families—and a third that chose to remain anonymous—decided to submit their DNA to a challenge sponsored by Boston Children’s Hospital called CLARITY. Not only have their complete genomes been sequenced, but 30 teams all over the world—from biotech startups to the National Institutes of Health—were given access to the sequences and set loose to come up with “best practices” for interpreting the results. Two dozen turned in submissions, now being evaluated by a panel of judges. Full story »

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Mary Elizabeth Stone and her son John, with genetic counselor Meghan Connolly and Pankaj Agrawal, principal investigator of the Gene Discovery Core. (Courtesy ME Stone)

Sequencing a patient’s genome to figure out the exact source of his or her disease isn’t standard operating procedure — yet. But falling sequencing costs and a growing number of successes are starting to bring this approach into the mainstream, helping patients and families while advancing a broader understanding of their diseases.

The Stone family is a case in point. When John and Warren Stone were born, their parents were envisioning life raising identical twins, when suddenly everything changed. On their second day of life, the twins started to have seizures with stiffening of their arms and legs; more alarmingly, they would stop breathing from time to time, requiring a ventilator to help them breathe. Further work-up revealed that both John and Warren were having persistent seizures consistent with Ohtahara syndrome, a rare, debilitating seizure disorder.

Warren died a few weeks later, and the family transferred John’s care to Boston Children’s Hospital. An extensive clinical and genetic work-up here and at several other hospitals involved in his care — including sequencing all the genes known to cause Ohtahara syndrome – identified no cause for John’s unique seizures. Full story »

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