New insight into how brain cells die in Alzheimer's and FTD

(Epi)genetic hallucinations induced by loss of LSD1 resemble Alzheimer's. Another surprise: LSD1 aggregates in Alzheimer's brain, looking like Tau Read more

2B4: potential immune target for sepsis survival

Emory immunologists have identified a potential target for treatments aimed at reducing mortality in sepsis, an often deadly reaction to Read more

EHR data superior for studying sepsis

Analysis of EHR data says sepsis rates and mortality have been holding steady, contrary to what is suggested by after-the-fact Read more

whole exome sequencing

New pediatric digestive/liver disease gene identified by international team

In a study published this month in Hepatology, a multinational team of researchers describes a newly identified cause of congenital diarrhea and liver disease in children.

The rare disorder is characterized by significant diarrhea beginning soon after birth, low serum levels of fat-soluble vitamins and evidence of liver disease. Despite continued symptoms, with medical support, the children grow and develop normally, at least to the age of 12.

From left to right: Mutaz Sultan, Orly Elpeleg and Paul Dawson, representing three collaborating institutions.

Researchers from Emory University School of Medicine and Children’s Healthcare of Atlanta, working with colleagues from Makassed Hospital, Al-Quds University and Hadassah Medical Center, Hebrew University of Jerusalem studied a family with two children from the Palestinian territories who suffer from the disorder.

The team found that both children had inherited a mutation in a gene responsible for the transport of bile acids, which facilitate the digestion and absorption of dietary fats and fat-soluble vitamins. Although mutations had been identified in other genes important for the recycling of bile acids, this is the first report in humans of disease-associated defects in this gene, called Organic Solute Transporter-beta (SLC51B).

Almost 20 years ago, pediatric GI & hepatology researcher Paul Dawson, PhD, and colleagues identified mutations in another bile acid transporter gene (ASBT; SLC10A2) that caused congenital bile acid diarrhea.

“Even at that time, we knew that there were patients with similar symptoms that did not carry mutations in ASBT. But the genetic cause remained a mystery.” Dawson says. “What’s distinctive about this report is that these patients also have features of liver disease, which was not observed in previously described congenital bile acid diarrhea patients.” Read more

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Next generation sequencing roundup

The increasing clinical use of next generation sequencing, especially whole exome and whole genome, continues to be a hot topic. The ability to contribute to diagnosis, clinical utility, incidental findings and whether insurance will cover next-gen sequencing are all changing.

A Nature Medicine article lays out a lot of the emerging business issues on next-gen sequencing. On the topic of incidental findings, Buzzfeed science editor Virginia Hughes last week reported stories of women who receive a cancer diagnosis as a result of having a prenatal genetic test.

“These cases, though extremely rare, are raising ethical questions about the unregulated – and rapidly evolving – genetic-testing industry,” Buzzfeed says.

At a recent Department of Pediatrics seminar, Emory geneticist Michael Gambello described examples of how whole exome sequencing, performed to diagnose intellectual disability or developmental problems in a child, can uncover cancer or neurodegenerative disease risk mutations in a parent. The question becomes, whether to notify the parent for something that may or may not be actionable. This is why Emory Genetics Laboratory’s whole exome sequencing service has an extensive “opt-in/opt-out” consent process.

Emory Genetics Laboratory executive director Madhuri Hegde, working with the Association of Molecular Pathology, has been a leader in pushing genetic testing laboratories to adopt best practices. Read more

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Rare disease diagnosis, accelerated by social media

Seth Mnookin’s long piece in the New Yorker, on how social media accelerated the diagnosis of several children with a rare genetic disorder, is getting a lot of praise this week. This is the same story that was on CNN.com in March, titled “Kids who don’t cry”, and that Emory Genetics Laboratory director Madhuri Hedge mentioned as a recent diagnostic success for the technique of whole exome sequencing.

Briefly: parents of or doctors treating several children with a previously unknown metabolic disorder, with multiple symptoms — absent tear production, developmental delay, movement deficits, digestive problems etc — found each other via Internet searches/blog posts. The problems were traced back to mutations in the NGLY1 gene.

Emory geneticists Michael Gambello, Melanie Jones (now at the Greenwood Genetic Center in South Carolina) and Hegde are co-authors on the Genetics in Medicine paper that lays everything out scientifically.

Gambello, Jones and Hegde were responsible for sequencing the DNA of a North Georgia family (they live in Jackson County), whose members are mentioned in Mnookin’s piece. The Gambello lab is developing an animal model of NGLY1 deficiency and is studying the mechanisms of how NGLY1 deficiency affects brain development.

Posted on by Quinn Eastman in Neuro Leave a comment

Whole exome sequencing in IBD

Last year, pediatric gastroenterologist Subra Kugathasan gave an “old fashioned” grand rounds talk at Children’s Healthcare of Atlanta’s Egleston hospital, describing a family’s struggle with a multifaceted problem of autoimmunity.

Subra Kugathasan, MD

Now the Journal of Pediatric Gastroenterology and Nutrition paper, on how the genetic alteration underlying the family’s struggles was identified, is published. Kugathasan reports that the young man at the center of the paper is scheduled for allogeneic bone marrow transplant in the United States (but not in Atlanta) in the next couple months.

The list of troubles the members of the family had to deal with is long: gastrointestinal issues and food allergies, skin irritation, bacterial + yeast infections, and arthritis. The mother and her brother were affected to some degree, as well as all three of the kids (see tree diagram). The youngest brother is the “proband”, a geneticist’s term for starting point.

As determined by whole exome sequencing, the gene responsible is FOXP3, which controls the development of regulatory T cells. These are cells that restrain the rest of the immune system; if they aren’t functioning correctly, the immune system is at war with the rest of the body, like in this family.

The genetic variant identified was new — that’s why whole exome sequencing was necessary to find it. The authors conclude:

Supporting the utility of WES [whole exome sequencing] in familial clusters of atypical IBD [inflammatory bowel disease], this approach led to a definitive diagnosis in this case, resulting in a justifiable treatment strategy of allogeneic bone marrow transplantation, the treatment of choice for IPEX [Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome].

Bone marrow transplant is a big deal; doctors are essentially wiping out the immune system then bringing it back, with several associated risks. So the decision to go ahead is not taken lightly. In general, whether bone marrow transplant — either autologous (patient donates back to self) or allogeneic (the donor is someone else) — is appropriate as a treatment for inflammatory bowel disease is still being investigated. Here, since a genetic origin is clear and there are autoimmune effects beyond the digestive system, it becomes the treatment of choice.

Posted on by Quinn Eastman in Immunology Leave a comment

Next-generation sequencing, amplified by social media

Emory Genetics Laboratory, with its whole exome sequencing business accelerating, is launching a new Medical EmExome product to provide clinicians with additional confidence and coverage. To go with this, EGL director Madhuri Hegde sent us some examples of recent diagnostic successes.

One of these was part of a paper that was recently published in the journal Genetics in Medicine: a young girl with multiple symptoms (developmental delay, movement disorder, digestive and breathing problems) was diagnosed with a new type of metabolic disorder, having inherited two mutated copies of the NGLY1 gene.

Two parents whose children were diagnosed with NGLY1 mutations have an interesting commentary in the same journal, describing how next-generation sequencing and social media went hand-in-hand. [this story was also on CNN.com as “Kids who don’t cry”] Here is an excerpt from the parents’ essay:

Six of the eight patients presented in the accompanying article were linked together after parents, physicians, or scientists working on isolated cases searched online for “NGLY1.” They found a blog post describing the disorder written by the parents of the first confirmed patient. The blog chronicles the boy’s journey (initial evaluation, visits to multiple specialists, incorrect diagnoses, and ultimately the discovery of heterozygous mutations in NGLY1). It was this personal account that allowed the ordering physician, who had been tracking a second patient with NGLY1 variants, to feel confident that the two patients were suffering from the same disorder. Another patient was discovered, on a distant continent, when a parent’s Internet search for his/her child’s symptoms stumbled upon the aforementioned blog. This prompted the parents to suggest targeted NGLY1 sequencing to their child’s physician. Parent/patient-to-physician collaboration such as this is remarkable and is likely happening in other rare diseases with the advent of NGS.

As untrained people, we are not qualified to analyze whole-exome/whole-genome data. We cannot develop a therapeutic compound. We cannot design a diagnostic assay. That being said, parents can offer observations and ideas, and we can push for solutions. Nineteen months after the initial report by Need et al., five viable approaches to treatment are under active consideration, thanks to relentless digging by afflicted families…

Another case study Hegde sent us describes a baby that was born but died after just 10 days, unable to swallow and with poor muscle tone. During pregnancy, the mother had felt reduced fetal movement. For the baby, doctors ordered a variety of gene panels without finding abnormalities, but a muscle biopsy detected signs of congenital muscular dystrophy, type unknown. Whole exome sequencing was able to show that the baby’s disease came from inheriting two mutated forms of the RYR1 gene. Now the mother is pregnant again, and reports feeling lots of movement.

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Personalized molecular medicine part 2

This is a continuation of the post from last week on the early-onset epilepsy patient, whom doctors were able to devise an individualized treatment for. The treatment was based on Emory research on the molecular effects of a mutation in the patient’s GRIN2A gene, discovered through whole exome sequencing.*

For this patient, investigators were able to find the Ray Ban Baratas cause for a previously difficult to diagnose case, and then use a medication usually used for Alzheimer’s disease (memantine) to reduce his seizure frequency.

Last week, I posed the question: how often do we move from a disease-causing mutation to tailored treatment? Read more

Posted on by Quinn Eastman in Cancer, Neuro Leave a comment

The face behind a case

Last week Emory posted a news item about a case report published in the American Journal of Human Genetics. The paper described how geneticists at Emory, in cooperation with Sanford Burnham Medical Research Institute in San Diego, used “whole exome sequencing” — a sort of executive summary scan of the genome — to find the cause of a metabolic disease in a young boy.

The case was an illustration of the trend of whole exome sequencing, which is starting to enter clinical practice as a diagnostic technology. A photo of the patient, courtesy of his parents and Sanford Burnham, is a powerful reminder that within every case report, there’s a real person’s history.

Courtesy of Heather Buschman

“Over the years, we’ve come to know many families and their kids with glycosylation disorders. Here we can tell them their boy is a true ‘trail-blazer’ for this new disease,” says Hudson Freeze, director of the Genetic Disease program at Sanford Burnham. “Their smiles—that’s our bonus checks.”

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