ASHG Partners with ACMG for Congressional Briefing: The Undiagnosed Diseases Network

Posted By: Jil Staszewski, Policy & Advocacy Manager, ASHG

ASHG and the American College of Medical Genetics and Genomics (ACMG) have partnered together to launch a series of congressional briefings on Capitol Hill to educate Congress on the importance of genetics and genomics research and medicine. Congressional briefings provide an opportunity for organizations to engage members of Congress and their staff on a particular topic or issue.

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L-R: Katie Murray, a staffer in briefing sponsor Rep. Loebsack’s office; and speakers John Phillips III, MD; Bill Gahl, MD, PhD; Gail Jarvik, MD, PhD; and Danny Miller.

For genetics and genomics, it is important that members of Congress and their staff understand the value that sustained federal funding holds for genetics and genomics research, and its translation to clinical applications that benefit patients and research institutions nationwide.

On Thursday, September 26, the initial briefing in this series was held, titled, “The Undiagnosed Diseases Network (UDN): The Interface of Research and Clinical Care to Solve Medical Mysteries,” sponsored by Representative Dave Loebsack (D-IA). Gail Jarvik, MD, PhD, ASHG Secretary and Co-Principal Investigator at the University of Washington UDN, moderated the briefing.

In her opening remarks, Dr. Jarvik noted the value of this ASHG-ACMG partnership and the significance of highlighting the UDN, stating, “The expertise of these two organizations and their members spans the facet of genetics from basic research to clinical practice. Just as research informs clinical practice, information learned in the clinic also informs research. Not only is the Undiagnosed Diseases Network an excellent example of this, but it is also a great example of how federal funding for such a program can broadly impact clinical care and research beyond the program itself.”

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Dr. Gahl (middle) and Dr. Jarvik (right) discuss the importance of federal funding for clinical care and research.

Additional speakers included Bill Gahl, MD, PhD, Director of the Undiagnosed Diseases Program at NHGRI; John Phillips, III, MD, Co-Principal Investigator at the Vanderbilt University UDN; and Danny Miller, the father of two patients who were diagnosed through the Stanford University UDN.

Dr. Gahl spoke about the history of how his work with the Undiagnosed Diseases Program eventually evolved into the NIH-funded Undiagnosed Diseases Network in 2013. Dr. Phillips went into detail about some of the research and diagnoses he has been able to complete through the UDN, and how the UDN allows for a unique team-based approach in identifying undiagnosed diseases. Danny Miller gave a passionate testament of how the UDN has benefited the lives of his two children, and why continued, increased federal funding is so vital in helping other patients with undiagnosed diseases and their families nationwide.

If you are interested in hearing more about the speakers’ stories, stay tuned! A video of the briefing presentations will be made available in the near future.

Have an idea about a future briefing topic? Let ASHG know at policy@ashg.org. To stay up-to-date on genetics and genomics policy issues, subscribe to our monthly policy and advocacy email updates.

Inside AJHG: A Chat with Stephen Kingsmore

Posted By: Sara Cullinan, PhD, Deputy Editor, AJHG

Each month, the editors of The American Journal of Human Genetics interview an author of a recently published paper. This month, we check in with Stephen Kingsmore to discuss his paper “A randomized, controlled trial of the analytic and diagnostic performance of singleton and trio, rapid genome and exome sequencing in ill infants.”

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Stephen Kingsmore, MD, DSc, holding his patient, Maverick Coltrin. The photo was taken in April 2018 at the Frontiers in Pediatric Genomic Medicine Conference.

AJHG: What prompted you to start working on this project? 

Stephen: We’ve been working on implementing rapid whole genome sequencing in infants in intensive care units since 2011. We have two Guinness world records for fastest time to genetic diagnosis (the current benchmark is 19 hours). In the first 35 infants we tested, we saved two lives by changing therapy from that based on the clinical diagnosis to that based on the molecular diagnosis. Ever since then, we’ve been on a mission to understand how to make this reality in every intensive care unit in the world.

AJHG: What about this paper/project most excites you? 

Stephen:  Randomized controlled trials are very exacting. This is just the second randomized controlled trial of clinical genome sequencing! You’re never sure whether a clinical trial will really test the desired hypothesis. I was most excited that we clearly showed that ultra-rapid whole genome sequencing, with fastest time to diagnosis, was best for seriously ill infants in intensive care units (ICUs). As with every previous study, I now know how to redo the current one!

AJHG: Thinking about the bigger picture, what implications do you see from this work for the larger human genetics community?

Stephen: This manuscript is part of a growing body of evidence that demonstrates that infants in ICUs with diseases of unknown etiology benefit from rapid whole genome sequencing by virtue of the consequent implementation of precision medicine. We anticipate that 30,000 infants per year would benefit from this in the U.S. The current study was unique since almost one half of infants in ICUs were eligible for enrollment. As a result, we found that genetic diseases are much more common than previously expected.

AJHG: What advice do you have for trainees/young scientists?

Stephen: Think about a career in genomic medicine – the genomic medicine tsunami is coming and we’ll need every genetic counselor and medical geneticist to deliver this new type of care. For the first time, genomics will save lives day in, day out.

AJHG: And for fun, tell us something about your life outside of the lab.

Stephen: I’m reading the Bible in a year. I’m 2/3 of the way through and it yields specific thoughts for each day, as well as continually adjusting my thinking to the bigger, long-term picture. It started as a chore and now is a vital part of my day.

Stephen Kingsmore, MD, DSc, is the President and CEO of Rady Children’s Institute for Genomic Medicine at Rady Children’s Hospital. He has been a member of ASHG since 2007.

Inside AJHG: A Chat with Christian Schaaf

Posted By: Sarah Ratzel, PhD, Science Editor, AJHG

Each month, the editors of The American Journal of Human Genetics interview an author(s) of a recently published paper. This month, we check in with Christian Schaaf to discuss his paper, “Functional consequences of CHRNA7 copy number alterations in induced pluripotent stem cells and neural progenitor cells.

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Christian Schaaf, MD, PhD, Baylor College of Medicine (courtesy Dr. Schaaf)

AJHG: What caused you to start working on this project?

Christian: My work on copy number variation of chromosome 15q13.3 started with a patient I saw as a genetics resident on the genetics consultation service at Texas Children’s Hospital. As a physician-scientist, all my work has been inspired by patients, and my ultimate goal is to provide a deeper understanding of the mechanisms of disease, which then can be translated into new therapeutic avenues for the respective disorders.

AJHG: What about this paper most excites you?

Christian: There are two aspects that are most exciting to me. First, we have been able to generate a human model of disease, and we can measure functional consequences of a genomic change in the patient-derived cell lines. This may become particularly relevant as we begin thinking about pharmacologic intervention, as it allows us to test new drugs and compounds on these patient-derived neuronal cell lines prior to subjecting actual human patients to those drugs in clinical trials.

Second, one of the most fascinating findings of our study is the fact that increased genomic copy number of the CHRNA7 gene does not necessarily lead to increased functionality of the respective protein. This may have important implications on how we think about this duplication, and how we would consider approaching it therapeutically.

AJHG: Thinking about the bigger picture, what implications do you see from this work for the larger human genetics community?

Christian: We have always been puzzled that for several genomic loci, both deletions and duplications of the same locus predispose to neurodevelopmental disorders that look somewhat similar. One would expect that opposing genomic events cause clinical phenotypes that are also in different direction. For 15q13.3, we now provide first pieces of evidence why opposing genomic events may lead to functional changes that are actually in the same direction. This could be the case for several other genomic disorders, and is kind of a paradigm-shifting concept.

AJHG: What advice do you have for trainees/young scientists?

Christian: For all trainees in the medical field: treat every patient with the care and curiosity as if you could learn something entirely new. All of my research projects started with individual patients. They continue to be the inspiration for everything that I do.

For all trainees and young scientists (MD and PhD): have a hypothesis for every experiment, but be completely open to the outcome. Do not “expect” a certain result. Some of your most important discoveries will originate in the unexpected.

AJHG: And for fun, tell us something about your life outside of the lab.

Christian: I have four children: 6 years, 5 years, 2 years, and 6 months old. Life is crazy at home. Coming to the laboratory feels like vacation to me.

Christian Schaaf, MD, PhD, is an Assistant Professor at Baylor College of Medicine and has been an ASHG member since 2009.

How I Work: Brian Shirts

Posted By: Elisabeth Rosenthal, PhD, Member of the ASHG Communications Committee

We sat down with ASHG member Brian Shirts, MD, PhD, to learn more about his work at the cutting edge of clinical genetic diagnostics, including how his work intersects with his faith.

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Brian Shirts, MD, PhD. (courtesy Dr. Shirts)

ASHG: Tell us about your position and how it fits into your institution and its goals.

Brian: I am Assistant Professor of Laboratory Medicine at the University of Washington. Being in a clinical department means part of my job is doing clinical genetic testing in patients. Since I am at a university, the other part of my job is teaching and doing research. In order to have this position, I did medical school and doctoral training in human genetics. Then I did specialty training to be board certified in Clinical Pathology and Molecular Genetic Pathology. When I started graduate training, I did not know that the position I currently have existed. When I first met a physician who specialized in genetic diagnosis, I quickly realized, “That is what I wanted to do all along!”

Working at a university, I need to be on the cutting edge of clinical genetic diagnostics. I specialize in hereditary cancer testing and understanding the health effects of extremely rare genetic variants. When I say “extremely rare”, I mean genetic variants that I may see for the first time when I look at the results of a patient receiving clinical genetic testing, or a variant that may have only been seen in one or two other people in the world. In cancer risk genes, these variants are usually inherited and clustered in families, so I like to call them family-specific variants.

I am lucky because my research interests and my clinical work go well together. I spend over half of my time doing research and developing translational applications that will allow myself and others to apply my research discoveries to clinical diagnostics.

ASHG: How do you keep up with the latest in genetics science and use this in your work?

Brian: I try to attend the ASHG Annual Meeting and the Association for Molecular Pathology meeting as often as I can, as I think these are the best forums for the latest in genetics science and genetic diagnostics, respectively. I also read several journals and go to journal club presentations as often as I can.

ASHG: What are your favorite genetics websites?

Brian: I have to give a plug for my website on family studies for rare variant classification: findmyvariant.org. Some of my other favorite genetics websites for non-geneticists are: Genetics Home ReferenceLearn.Geneticsmy46, and Genetic Alliance.

ASHG: What are you currently reading/thinking about?

Brian: I am always thinking about how to apply population genetics principles to clinical diagnostics. For something completely different, I like to read the best books that my kids are reading. I am currently reading “Mr. and Mrs. Bunny–Detectives Extraordinaire!” by Polly Horvath.

ASHG: What everyday thing are you better at than everyone else? What’s your superpower?

Brian: When I go to church, others tell me that I have an extraordinary talent for asking appropriate yet thought provoking questions during Sunday School. Being an outspoken scientist in a faith community can be difficult to navigate, but communicating with people from different backgrounds is a really important skill to develop.

Brian Shirts, MD, PhD, is Assistant Professor of Laboratory Medicine at the University of Washington. He has been a member of ASHG since 2004.

A Genetic Counselor’s Perspective of ACMG 2017

Posted by Karen Hanson, MS, MBA, CGC, Health Professional Education Programs Manager at ASHG

Last month, I had the opportunity to attend the American College of Medical Genetics and Genomics (ACMG) 2017 Annual Meeting. As a genetic counselor working on health professional education at ASHG, one theme stood out to me: the rapid integration of whole genome/exome sequencing (WGS/WES) into clinical practice.

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Karen Hanson (right) and Director of Education Michael Dougherty, at the ASHG booth in the ACMG Exhibit Hall.

Apparently, we are sequencing everyone – sick people, healthy people, adults, children, babies, and fetuses. The inspiring talk by William Gahl, MD, PhD, NHGRI, NIH about the work of the Undiagnosed Diseases Network (UDN) reminded us all of why we (researchers, clinicians, laboratorians) entered this field. This session showcased what could be thought of as the most traditional use of WGS/WES in the clinic: using advances in genomic sequencing to improve diagnostic outcomes in patients with suspected genetic disease. It’s now less likely that patients and families will struggle without a diagnosis for years.

Infants born with congenital anomalies or metabolic disease are also benefiting from rapid sequencing technologies that allow their physicians and families to quickly treat and manage them. And it’s not just ‘sick’ babies that are being offered sequencing. Several clinical trials are looking at the efficacy and outcomes of sequencing ‘healthy’ newborns. For years, the genetics community has talked about when the day would come that all newborns have a ‘genetic’ barcode (consider that the movie Gattaca turns 20 this year!). Newborn screening programs have already expanded to include dozens of carefully selected disorders, and WES almost seems like a logical next step. However, in at least in one clinical trial, the majority of parents of healthy newborns who were offered WES declined testing. So maybe we are not quite ready yet.

Another session was devoted to genomic sequencing in ‘healthy’ adults. The current scientific atmosphere certainly seems right for this, when you consider the advances in sequencing technology, the rapid growth of variant databases, and the push for personalized medicine. It did occur to me that we haven’t really worked out the ethical and logistics dilemmas we encounter through WGS/WES of ‘unhealthy’ individuals. However, to paraphrase Les Biesecker, MD, FACMG, NHGRI, genome sequencing is here and it’s not going away. The dilemmas associated with sequencing ‘healthy’ people are not new – variant classification, not enough genetic professionals, health provider education, and access to diverse and underserved populations. But overall, the intention is good – to use genomic technology to improve health and patient care. Which for me begs at least one question: who’s going to manage all these ‘patients’? After all, we will all be ‘patients’ after we get our WGS test results.

So, as a genetic counselor working on health professional education at ASHG, I think of all this as job security. My job – our job as geneticists – is cut out for us. We need to educate our medical workforce and all the rest of the ‘patients’ out there about genomic medicine. And who better to do it then those of us who have been and still are in the trenches.

Karen Hanson, MS, MBA, CGC, is Health Professional Education Programs Manager at ASHG. Read more about ASHG’s educational programs for health professionals.