WuXi NextCODE at ASHG17: Part II of our “Genomes For Breakfast” Series Featuring Major Precision Medicine Efforts in the US and Qatar

WuXi NextCODE ASHG2017

At the second WuXi NextCODE “Genomes for Breakfast” session at ASHG2017, Annerose Berndt, vice president of clinical genomics at University of Pittsburgh Medical Center, and Khalid Fakhro, director of genetics at Sidra Medical and Research Center in Qatar, outlined ambitious plans in large-scale genomics and precision medicine.

In my previous post, I described how Kari Stefansson started off this year’s ASHG breakfast session with a deep dive into deCODE’s toolbox and the powerful results the company has delivered.

Another of the renowned speakers at our “Genomes for Breakfast” session was Annerose Berndt, vice president of clinical genomics at UPMC (University of Pittsburgh Medical Center). She outlined UPMC’s ambitious plans in large-scale genomics and precision medicine. UPMC has a quite uniquely holistic role in underpinning the present and future healthcare of more than three million people in western Pennsylvania. It is an insurer, delivers healthcare through a rapidly growing network of dozens of hospitals, and conducts cutting-edge research in the life sciences and medicine, including through the University of Pittsburgh. It also has affiliated hospitals in nine countries apart from the U.S.

Last year, UPMC received one of the largest grants from the U.S. Precision Medicine Initiative and is investing in a large-scale genome sequencing effort that will both deliver patient care—through rare disease diagnostics and better-targeted cancer treatment—and create a major database for population-scale genomics research. Providing the integrated informatics, database, and tools for projects of such scale and combined clinical and research applications is what our platform does like no other, and we were very pleased to have UPMC present alongside and meet with our partners pursuing similar projects.

Closing out our population-focused breakfast we had the honor of hearing from our longtime collaborator Khalid Fakhro, director of genetics at our partner Sidra Medical and Research Center in Qatar. Sidra’s work, both on the Qatar Genome Programme and as the key maternity and pediatric hospital in Qatar, holds great promise for delivering higher-quality care to patients in Qatar and to advancing precision medicine around the world.

Echoing themes from Kari’s talk, Khalid outlined how Qatar’s population of 300,000, with its high consanguinity rates, is a fertile ground for identifying novel rare disease variants.

Leveraging data from 1,000 healthy Qataris and 600 families with rare disorders, Sidra has developed and published the first allelic map for any population in the Arab world. They are using WuXi NextCODE’s database and tools to drive forward with novel discoveries in a range of diseases, including congenital diarrhea and collagen disorders.

With the opening of Sidra’s hospital this year, and the integration of yet more data from the Qatar Genome Programme into our platform, Khalid emphasized that Qatar is well positioned to undertake not only a cutting-edge rare disease diagnostic testing program for pediatric patients but also drug target discovery. Much as deCODE has done with cardiovascular disease and numerous other conditions, the hope is to begin to analyze data for families and across the population in conditions such as type 2 diabetes. Such findings might well point to novel pathways that can be used to design treatments for those suffering from rare and common diseases alike.

I’ll also post soon about our second rare-disease focused breakfast session at ASHG: “Using NGS to diagnose rare disease—experiences from three continents.” Look for my next post about ASHG17.


WuXi NextCODE at ASHG17: Part I of our “Genomes for Breakfast” Series Highlights Leading Global Efforts to Understand and Diagnose Rare Disease

Kari Stefansson led the group of renowned scientists and clinicians who presented at

Hannes Smarason WuXi NextCODE ASHG2017

Kari Stefansson led the first of two sessions focused on rare diseases at WuXi NextCODE’s annual “Genomes for Breakfast” series at the ASHG 2017 meeting in Orlando, Florida.

WuXi NextCODE’s annual “Genomes for Breakfast” sessions at the ASHG meeting in Orlando, Florida last week. Two of these sessions focused specifically on rare diseases, one from a population perspective and the other from a clinical perspective.

We were honored to host all our speakers, each of whom are leaders in their fields. They included some of our distinguished longstanding and newer partners as well as some of our own WuXi NextCODE colleagues. We had near-capacity crowds of some 300 attendees for each of the breakfasts. That setting provided an inspirational showcase of progress in understanding rare disease and also how WuXi NextCODE’s global platform can help accelerate this critical work.

The goal for us all is to enable rapid and affordable diagnosis of rare diseases in as many countries as possible. And WuXi NextCODE is uniquely positioned to support this endeavor.

As only he can do, Kari kicked the population session off with a deep dive into what he has gleaned from looking at the unique genetics resources he has amassed at deCODE genetics in Iceland over the past 20 years. These resources are of astonishing scale, including the directly sequenced whole genomes of nearly 50,000 Icelanders and 10,000 others; imputed whole genome from 400,000 Icelanders; and SNP data from nearly a million people around the world.

It was an even more notable event, because this year, Kari received the William Allen Award, the ASHG’s highest honor; so the full breadth of the work he and his deCODE colleagues have achieved was featured at several points in our events and elsewhere during the three-day meeting. Underscoring the reach and global outlook of deCODE’s work, Kari pointed out that deCODE is currently collaborating with over 250 international groups and 25 consortia. And his talk was particularly significant for us, because deCODE is not only the world’s first and largest population genomics effort, it is also the crucible in which our technology was forged and the inspiration for the large-scale genomics efforts that we partner with around the world.

Leading off the first breakfast session, entitled “Using Population Genomics to Understand Common and Rare Diseases,” Kari spoke to how deCODE has set out to capture and correlate not just variation in the genome and phenome, but also how genetic diversity itself is actually generated. He pointed out that you could look at life forms as entities whose function is to protect DNA, rather than the other way around. Understanding how DNA changes through generations is a mission-critical task for applying genomics to human health. Where are the sites of the most recombination? Under what circumstances and where are you most likely to see de novo mutations arise?

A pivotal 2002 paper from deCODE provided the world with the first high-resolution recombination map of the entire genome. That map was used to complete the assembly of the Human Genome Project (HGP): Before that paper was published, the HGP’s assembly was about 91% accurate. After the data from deCODE were incorporated, the map reached 99% accuracy.

One of Kari’s observations was that all physiological function is spread across populations in an essentially normal distribution. Looking at extremes—the rare phenotypes—is important, because they often reflect rare genetic factors that can reveal important information about biochemical pathways relevant not only to those carrying the mutations, but also to the rest of the population that has more common, but less extreme, perturbations in those pathways. In this sense, rare variant identification is important for public health in two ways: to diagnose and better treat those with rare disorders, and to find drug targets that can benefit all of us. Rare disease, it turns out, is a common challenge that we all need to meet together.

Kari was followed by two other outstanding speakers and WuXi NextCODE partners: University of Pittsburgh Medical Center’s Annerose Berndt and Khalid Fakhro of the Sidra Medical and Research Center in Qatar. I will provide details about their talks in my next post.

Why We Need Big Infrastructure For Tackling Rare Disease

Hannes Smarason big data rare diseases

Having bigger databases, and having a mechanism that flags genomic variants, is key to optimizing patient care for entire families

Uncovering the genetics of schizophrenia is vital but challenging. As I wrote in my last post, mutations in more than 100 spots in the genome have been linked to the condition. But which ones actually play a role in the disease, and which ones are just there for the ride—innocent bystanders that just happen to occur alongside the real culprits? That’s the crucial question for scientists seeking new treatments for this condition, among them leading researchers and clinicians at our close partner, Boston Children’s Hospital (BCH).

One thing we’ve learned recently is that even a small amount of knowledge about genetic underpinnings of disease can have a big potential benefit for patients. For example, the 16p13.11 region deletion I described in that last post ended up being very important for several patients later, particularly one father and his son, recently described by our colleagues at BCH. This case highlights the importance of expanding the scope and scale of such research, and of updating and alerting patients as more is discovered—not just in schizophrenia, but across rare disease.

In their previous work, the BCH team used chromosomal microarray analysis to determine that a young boy with symptoms of schizophrenia, including psychosis, was missing an entire chunk of DNA—one copy of the chromosomal region 16p13.11, which spans several genes.

Schizophrenia in children is rare, and some researchers believe it could be an extreme variation of the disease, and so might hold important clues for the treatment of this condition in both young and old. A search of our and BCH’s databases showed that several other young patients also showed variations in that region. Just as important, it was confirmed that a parent of one of those patients also carried that deletion, and it seemed likely that another parent (not available for testing, but with reported symptoms of schizophrenia) also likely carried the deletion.

Clearly 16p13.11 seemed to be emerging as a “hotspot” for variations linked to psychosis. But the scientists were only finding this because they could go back and search the databases, and they were working their way backwards from pediatric cases to learn information that might have been medically relevant to the parents as well. All this suggests that having bigger databases, and having a mechanism that flags such variants, is key to optimizing patient care for entire families.

One case uncovered by the BCH scientists, regarding a young man who we will call Jack, brought this into sharp focus. As a teenager, Jack had undergone detailed genetic screening at BCH because of symptoms that included learning disabilities and recurrent seizures. It was determined that he had a 16p13.11 deletion, but at the time of his screening, that mutation hadn’t yet been linked to psychosis. So it became just one more detail in Jack’s medical record.

Separately, a few years later, Jack’s father was diagnosed with ADHD and treated with a high dose of mixed amphetamine salts. Within a few weeks Jack’s father experienced a manic-psychotic episode. He was prescribed an anti-psychotic and eventually recovered. Unfortunately, his son was deeply affected by his father’s breakdown and became withdrawn and depressed. Eventually, Jack also developed psychotic symptoms, which were so serious he was hospitalized.

Jack’s symptoms, thankfully, responded to anti-psychotic medication, but his doctors wondered if there was any connection between the breakdowns suffered by the father and son.

A check of Jack’s medical record revealed the 16p13.11 deletion. And seeing that detail after the link had been made between 16p13.11 and psychosis, his doctors immediately speculated that it might be a cause of Jack’s symptoms. Further, they suspected that mutation could be the “linchpin” causing psychosis in the father and the son. Jack’s father was tested, and he also carries a 16p13.11 deletion.

So here’s the lesson: if Jack’s doctors had known about the link between 16p13.11 and psychosis as soon as it emerged, they might have also suggested testing Jack’s father. If they had, the BCH doctors “believe that the psychosis could have been averted in both father and son.”

In light of this case, the BCH researchers write that they see a keen need for broad, integrated, and sophisticated infrastructure to support genomics-driven precision medicine. They have several recommendations, including that physicians need to receive regularly updated risk information about specific mutations; genetic reports on parents who are “carriers” but seem unaffected should note that problems could arise later, and families that include carriers of variations that increase risk should be monitored and given counseling.

Such activities will be well supported by tools such as WuXi NextCODE’s Genomically Ordered Relational (GOR) database and global platform for diagnosing rare disease and building a global knowledgebase. This can act as one of the key spokes in the “wheel” of genomic diagnostic process. But we also need to build in others, such as means to automatically alert doctors to important knowledge updates, monitor patient records, and connect doctors to specialists who can help refine a diagnosis as new discoveries are made. We and our partners at BCH are committed to helping create these tools.

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Headed to ASHG? If you are attending ASHG this month, join us to hear more about how rare disease studies can inform our understand of common diseases at two of our “Genomes for Breakfast” events: “Using Population Genomics to Understand Common and Rare Disease” (Oct. 18), and “Using NGS to Diagnose Rare Disease—Experiences from Three Continents” (Oct. 19).

From Rare to Common: How Rare Diseases Could Advance Schizophrenia Treatment

Rapidly advancing our understanding of rare diseases is a key area of focus for us at WuXiNextCODE. We believe genomics can both transform our ability to understand and diagnose rare conditions, and that this is going to point us is the direction of developing new treatments. At the same time, there is a growing body of evidence and even approved new therapies that show that an understanding of rare diseases can also shed new light on the genetics of complex diseases, such as heart disease, arthritis, and schizophrenia.

Understanding complex diseases is a mammoth challenge because multiple genes are usually involved as well as environmental factors. It’s particularly hard with neurologic conditions. No animal models can really mimic what happens in people’s brains, and human studies usually only provide hints of the information needed to identify potential treatments.

But rare diseases are often caused by single variants that perturb specific and identifiable biological pathways. That’s why recent genetic studies of rare types of early-onset psychosis have inspired so much interest among researchers studying schizophrenia. This disease affects more than 50 million people worldwide, but early-onset cases are very rare, suggesting they may be extreme manifestations.

A new line of inquiry into this condition emerged after a group of our close collaborators at Boston Children’s Hospital, including a scientist now at WuXi NextCODE, used chromosomal microarray analysis and whole exome sequencing in a six-year-old with profound symptoms of psychosis. They discovered this patient had a variation in the ATP1A3 gene, which was not previously associated with schizophrenic symptoms. The team wondered: was that mutation helping cause his symptoms? Would the same mutation be found in other children with early-onset schizophrenia? Could this new lead point to a biological pathway common to many people, young and old, with these same symptoms?

That would be a real breakthrough, both for this child and potentially for many other people.

The Puzzle of Schizophrenia Genetics

Schizophrenia is one of the most serious and common mental illnesses. It is often very difficult to treat, in part because of available drugs’ side effects. There are already about a dozen anti-psychotics on the market for this condition. Besides causing serious side effects, treatment must also usually be life-long. Doctors often have to try different drugs until they find something that works and which the patient can tolerate. Even then, the patient’s response can change over time.

The genetics of the disease are still not well understood. Studies of families and populations show it is heritable – the more affected close relatives someone has, the more likely that person will develop it. Many families are afflicted by both schizophrenia and bipolar disease, suggesting the two conditions are biologically related.  Both conditions seem to be associated with multiple mutations to possibly dozens of genes. Still, even in identical twins – who share exactly the same mutations – it’s not uncommon for only one twin to be affected.  Clearly, there is something other than genes afoot.

Scientists, notably including our colleagues at deCODE genetics, have put their fingers on a few genes and key pathways. Another large genomic study, with more than 30,000 cases and 100,000 controls, pointed to over 100 potential spots in the genome with mutations associated with schizophrenia. Both have found an association with mutations in a region called MHC (Major Histocompatibility Complex), a result that reinforced a then percolating idea that schizophrenia might be related to immune dysfunction.  And then just this week, Chinese researchers reported a new trove of suggestive genetic factors. But despite these massive gene hunts, we are still far from a complete picture of what genes cause this disease and how.

A Promising New Lead?

As described in the BCH blog Vector, The BCH team who found that ATp1A3 mutation in the six-year-old boy decided to do some more digging. The chromosomal microarray analysis showed that he was missing an entire chunk of DNA – one copy of the chromosomal region 16p13.11.  Next, they searched their database and found several other children with variations in that area.  One had a duplication of the 16p13.11 region, rather than a deletion. She had started experiencing hallucinations at the age of 4.  Those findings prompted the BCH researchers to launch a large-scale study, which has already enrolled at least 50 children with early-onset psychosis and will be able to leverage WuXi NextCODE’s informatics and global knowledgebase to find more cases, at BCH and beyond.

The researchers hope that ultimately their studies will not only help children with early-onset schizophrenia but also point to the biological pathways that cause the more prevalent form of the disease, which usually strikes adolescents and young adults.

Such research will hopefully provide firm leads on novel pathways that can be used to identify new drug targets. There is a tremendous need for new medicines. Most of the antipsychotic drugs we have today were developed back in the 1950s and act on the dopamine and/or serotonin receptors. They don’t improve all of patients’ symptoms, and as noted earlier, they can have serious side effects.

By uncovering new biological pathways, groups like the researchers at BCH, able to leverage massive global genomic data like that we are able to provide, aim to uncover such targets and begin the journey to providing better options for patients with rare and common diseases alike.

If you are attending ASHG this month, join us to hear more about how rare disease studies can inform our understanding of common diseases at two of our “Genomes for Breakfast” events:  Using Population Genomics to Understand Common and Rare Disease (Oct. 18), and Using NGS to Diagnose Rare Disease – Experiences from three continents (Oct. 19).