Stories about: genomics

Gene discovery: When you’re the only patient with the disease

Gene Discovery Core rare diseaseVector took a moment this morning at the Boston Children’s Hospital Global Pediatric Innovation Summit + Awards to catch up with the Gene Discovery Core at the Manton Center for Orphan Disease Research. Its exhibition table doesn’t have fancy mannequins or flashy screens, but this team is rocking genetics and genomics, one patient at a time.

The usual methods for finding disease-causing genes don’t work for many patients who walk in the doors of Boston Children’s, or who mail in samples from all over the world. They may be one of just a handful of patients in the world with their condition—which may not even have a name yet.

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“Deep sequencing” finds hidden causes of brain disorders

brain malformations sequencing mosaicism
New methods can find a mutation that strikes just 1 in 10 cells.

It’s become clear that our DNA is far from identical from cell to cell and that disease-causing mutations can happen in some of our cells and not others, arising at some point after we’re conceived. These so-called somatic mutations—affecting just a percentage of cells—are subtle and easy to overlook, even with next-generation genomic sequencing. And they could be more important in neurologic and psychiatric disorders than we thought.

“There are two kinds of somatic mutations that get missed,” says Christopher Walsh, MD, PhD, chief of Genetics and Genomics at Boston Children’s Hospital. “One is mutations that are limited to specific tissues: If we do a blood test, but the mutation is only in the brain, we won’t find it. Other mutations may be in all tissues but in only a fraction of the cells—a mosaic pattern. These could be detectable through a blood test in the clinic but aren’t common enough to be easily detectable.”

That’s where deep sequencing comes in. Reporting last month in The New England Journal of Medicine, Walsh and postdoctoral fellow Saumya Jamuar, MD, used the technique in 158 patients with brain malformations of unknown genetic cause, some from Walsh’s clinic, who had symptoms such as seizures, intellectual disability and speech and language impairments.

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Solving medical mysteries: The Undiagnosed Disease Network

Emmie was lucky enough to be diagnosed before age 3, but many families face a much longer journey.
Emmie Mendes was lucky enough to be diagnosed before age 3, but many families face a much longer journey.

At first, Corrie and Adam Mendes thought their daughter Emmie had an inner ear problem. She was late with several early milestones, including walking, and when she did walk, she often lost her balance. The family pediatrician sent them to a neurologist, who ordered a brain MRI and diagnosed her with pachygyria, a rare condition in which the brain is smoother than normal, lacking its usual number of folds.

Additionally, Emmie’s ventricles, the fluid-filled cushions around the brain, looked enlarged, so the neurologist recommended brain surgery to install a shunt to drain off fluid. He advised Corrie and Adam that Emmie’s life expectancy would be greatly reduced.

As Corrie recounts on her blog, Emmie’s Story, she went online and came across the research laboratory of Christopher Walsh, MD, PhD, at Boston Children’s Hospital. The lab does research on brain malformations and has an affiliated Brain Development and Genetics Clinic that can provide medical care.

After Walsh’s team reviewed Emmie’s MRI scan, genetic counselor Brenda Barry invited the family up from Florida.

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Direct-to-consumer genetic testing: a case of potential harm

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.

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The challenge of cancer genomics: Embarking on CLARITY 2

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.

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Five people, one mutation and the evolution of human language

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.

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10 trends to watch in pediatric medicine: Part 1

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.

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Dads to blame? Genetic research reveals cause for precocious puberty

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.

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Biomarkers for all

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.

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Personal genomics takes flight as hospitals join forces with industry

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.

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