Stage fright: don't get over it, get used to it

Many can feel empathy with the situation Banerjee describes: facing “a room full of scientists, who for whatever reason, did not look very happy that Read more

Beyond birthmarks and beta blockers, to cancer prevention

Ahead of this week’s Morningside Center conference on repurposing drugs, we wanted to highlight a recent paper in NPJ Precision Oncology by dermatologist Jack Arbiser. It may represent a new chapter in the story of the beta-blocker propranolol. Several years ago, doctors in France accidentally discovered that propranolol is effective against hemangiomas: bright red birthmarks made of extra blood vessels, which appear in infancy. Hemangiomas often don’t need treatment and regress naturally, but some can lead Read more

Drying up the HIV reservoir

Wnt is one of those funky developmental signaling pathways that gets re-used over and over again, whether it’s in the early embryo, the brain or the Read more

Madhuri Hegde

Emory team part of undiagnosed conditions challenge

An Emory team of geneticists and genetics counselors is participating in the Clarity Undiagnosed competition, hosted by Boston Children’s Hospital and Harvard Medical School.

The team is led by genetics counselor Dawn Laney MS, CGC, CCRC. Team members include: Madhuri Hegde, PhD, William Wilcox, MD,PhD, Michael Gambello, MD, PhD, Rani Singh, PhD, RD, Suma Shankar, MD, PhD, Alekhya Narravula, MS,CGC, Kristin Cornell, MS, CRC, Cristina da Silva, MS, Sarah Richards, MS, CGC and Kimberly Lewis, MS, CGC.

In Clarity Undiagnosed, five families of patients with undiagnosed conditions provide DNA sequence information and clinical summaries to up to 30 competing teams. The teams then do their best to interpret the data and provide answers, and a $25,000 prize will go to the team that solves the mysteries in the most complete way.

At the discretion of the families, short videos of the patients may be available to investigators through producers of a forthcoming documentary film, Undiagnosed, but the teams are barred from direct interaction with the families. A glimpse of some of the families is possible by viewing the trailer. Teams have until September 21 to submit their reports and the results of the competition will be announced in November.

Boston Children’s and Harvard held a similar competition in 2012, which attracted teams from all over the world.

The competition grows out of the NIH-sponsored Undiagnosed Diseases Network; Emory pharmacologists Stephen Traynelis and Hongjie Yuan have been working with the related Undiagnosed Diseases Program based at NIH (very complex 2014 paper, blog post on personalized molecular medicine).

Posted on by Quinn Eastman in Uncategorized Leave a comment

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

Posted on by Quinn Eastman in Uncategorized Leave a comment

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

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.

Posted on by Quinn Eastman in Uncategorized 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.”

Posted on by Quinn Eastman in Uncategorized Leave a comment

DNA copying problems explain muscular dystrophy mutations

Geneticist Madhuri Hegde and her colleagues have a paper in the journal Genome Researchthat addresses the question: where do copy number variations come from?

Madhuri Hegde, PhD

Copy number variations (CNVs), which are deletions or duplications of small parts of the genome, have been the subject of genetic research for a long time. But only in the last few years has it become clear that copy number variations are where the action is for complex diseases such as autism and schizophrenia. Geneticists studying these diseases are shifting their focus from short, common mutations (often, single nucleotide polymorphisms or SNPs) to looking at rarer variants such as CNVs. A 2009 discussion of this trend with Steve Warren and Brad Pearce can be found here.

Hegde is the Scientific Director of the Department of Human Genetics’ clinical laboratory. Postdoctoral fellow Arun Ankala is the first author. In the new paper, Ankala and Hegde examine rearrangements in patients’ genomes that arose in 62 clinical cases of Duchenne’s muscular dystrophy and several other diseases. Mutations in the DMD gene are responsible for Duchenne’s muscular dystrophy.

The pattern of the rearrangement hints what events took place in the cell beforehand, and hint that a problem took place during replication of the DNA. The signature is a tandem duplication of a short segment next to a large deletion, indicating how the DNA was repaired.

The authors note that the DMD locus is especially prone to these types of problems because it is much larger than other gene loci. The gene is actually the longest human gene known on the DNA level, covering 2.4 megabases (0.08 percent of the genome.)

Replication origins are where the DNA copying machinery in the cell starts unwinding and copying the DNA. Bacterial circular chromosomes have just one replication origin. In contrast, humans have thousands of replication origins spread across our chromosomes. In the discussion, the authors suggest that DNA copying problems may also explain duplications and historically embedded rearrangements of the genome.

Posted on by Quinn Eastman in Neuro Leave a comment