Stories about: whole-genome sequencing

Patients’ individual genomes may affect efficacy, safety of gene editing

gene editing - truck delivering code
Subtle genetic variants in or near the gene editing target site could cause reagents to miss an address or arrive at the wrong one, researchers say.

Gene editing has begun to be tested in clinical trials, using CRISPR-Cas9, zinc finger nucleases (ZFN) and other technologies to directly edit DNA inside people’s cells. Multiple trials are in the recruiting or planning stages. But a study in PNAS this week raises a note of caution, finding that person-to-person genetic differences may undercut the efficacy of the gene editing process or, in more rare cases, cause a potentially dangerous “off target” effect.

The study adds to evidence that gene editing may need to be adapted to each patient’s genome, to ensure there aren’t variants in DNA sequence in or near the target gene that would throw off the technology.

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Mutations accumulate in our brain cells as we age. Do they explain cognitive loss?

the aging brain - do DNA mutations in neurons account for cognitive loss?

Scientists have long wondered whether somatic, or non-inherited, mutations play a role in aging and brain degeneration. But until recently, there was no good technology to test this idea.

Enter whole-genome sequencing of individual neurons. This fairly new technique has shown that our brain cells have a great deal of DNA diversity, making neurons somewhat like snowflakes. In a study published online today in Science, the same single-neuron technique provides strong evidence that our brains acquire genetic mutations over time.

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How whole-genome sequencing solved my son’s genetic mystery

Titin gene centronuclear myopathy

A longer version of this article was published in the journal Narrative Inquiry in Bioethics as part of a special issue on patients’ experiences with genetic testing.

“Negative.” “Normal.” “Fails to confirm the diagnosis of . . .” “Etiology of the patient’s disease phenotype remains unknown.”

These are words I heard repeatedly in the first 11 years of my son’s life. Even as new genes for my son’s rare muscle disorder were discovered around the world, negative or “normal” genetic test results were reported back to us 13 times.

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Decoding kidney disease, one gene at a time

blood samples chronic kidney disease
More than a third of chronic kidney diseases are caused by single mutations on single genes (Image: Graham Colm)

Part 2 of a two-part series on kidney disease. Part 1 is here.

Friedhelm Hildebrandt, MD, receives around one blood sample in the mail per day from a patient with chronic kidney disease. Over 10 years, he’s collected more than 5,000 samples from patients all over the world—in hopes of finding the genetic mutations that cause them and, ultimately, new treatments.

Consider the mutation in an 8-month-old boy from Turkey, who had fluid collection under his skin and elevated protein in his urine—signs that his kidneys were failing. Doctors identified his disease as a form of nephrotic syndrome, one of the three main types of chronic kidney disease. The disease was proving to be hard to treat: Ten weeks of steroids had produced no result, and an immunosuppressant hadn’t been effective enough to justify its harsh side effects.

Only within the last year, genetic research has revealed that more than 30 percent of childhood chronic kidney diseases—like this child’s—stem from single mutations in single genes.

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Three families, three mysteries: Results soon to come from genomic challenge

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 AJ 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.

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Cold case: Hospital DNA sequencing program open for business

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.

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Whole-genome sequencing in medicine: New knowledge, new responsibilities

(Karl-Ludwig Poggemann/Wikimedia Commons)

Recently, in the hospital cafeteria, I overheard a group of researchers discussing the upcoming availability of whole-genome sequencing to physicians. “We should devise a way to study how physicians will use this,” said one of them—underscoring the disruptive nature of the transformation that is currently happening in medicine.

The ability to immediately obtain whole-genome sequences from patients holds enormous potential for understanding and treating human disease. The list of studies reporting successful diagnosis of otherwise elusive orphan conditions is already too long to recount—more than 600 articles in PubMed as of the date of this posting—including poignant examples of advancing clinical care.

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