Following the Path of ASHG’s Statement on Pediatric Genetic Testing

Posted By: Cara Cavanaugh, MSc, Cell Press

What happens to a paper once it is published? After the research is over, the proofs are reviewed, and the paper is out in the world, how is it used and by whom?

To answer these questions, we traced the post-publication trajectory of ASHG’s position statement, “Points to Consider: Ethical, Legal, and Psychosocial Implications of Genetic Testing in Children and Adolescents.” The statement was published in The American Journal of Human Genetics (AJHG) in 2015 and was an update from two decades earlier. Following the history of the paper since its publication shows us the reach that an ASHG position statement can have over three years.

About the Position Statement

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Published in 2015, the statement has been cited by a variety of sources, including academic, legal, and public discourse.

The position statement gives recommendations for when and why families should decide to perform genetic tests on children and adolescents. “We felt that it was timely to update the statement across a range of issues,” says first author Jeffrey Botkin, MD, MPH, a professor and chief of the Division of Medical Ethics and Humanities at the University of Utah. “Our primary focus was genetically testing children for adult-onset conditions when there is no intervention during childhood. There hasn’t been a lot of research on the impact of such testing because folks felt that it was unethical under any context. We wanted to soften the perceived stance that such testing should never be conducted and have the position of the society be a little more flexible. We recognize that there may be circumstances when such testing might be appropriate for the child and family. We also wanted to encourage more research on these issues.”

Academic Citations and Public Conversation

Since its publication, the position statement is one of the top downloaded papers in AJHG’s history, with over 5,000 downloads as of 2018. After publication, to make the content more accessible to readers, ASHG created infographics that explain the issues and intricacy around childhood genetic testing. The paper has been cited by Genetics in Medicine, Pediatrics, Blood, Nature Reviews Genetics, and more than 80 other academic titles.

The statement has also been cited outside of the scientific research context. For example, it has impacted legal academic discourse. In one 2016 paper, Sénécal et al. discuss the legal approaches to healthcare decisions for minors in the European Journal of Human Genetics to the ASHG position statement as a “more nuanced approach” to how genetic testing should be pursued. They praise the statement for advising that physicians should inform families of all genetic testing options, even if the family has decided not to pursue any tests. Another paper by Otero in the European Journal of Health Law uses the position statement in a narrower context, specifically to analyze European and Spanish legal frameworks. These papers are just two of several examples of how one position statement from scientists can contribute to legal analysis internationally.

In addition to the academic studies discussed above, the position paper was also featured in the mainstream media. It gained coverage in NPR, VICE, and Pacific Standard. Exposure in these news sources helped engender public conversations online about the ethics of genetic testing in children.

What’s Next?

This paper shows the broad reach the ASHG community has in important societal and cultural issues of our time. As genetic testing appears more frequently in the news and becomes increasingly controversial, especially with products like direct-to-consumer genetic testing kits, it is imperative that we fully debate and consider how this could affect children and adolescents. ASHG policy statements, like the one published in 2015, provide us with long-lasting resources for continuing those discussions.

Cara Cavanaugh, MSc, is a Marketing Contractor at Cell Press. She earned a BA in History of Science from Princeton University and a MSc in Science Communication from Dublin City University while on a Fulbright Award.

Inside AJHG: A Chat with Alice Davidson

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

Each month, the editors of The American Journal of Human Genetics interview the authors of a recently published paper. This month, we check in with Alice Davidson, PhD, to discuss her paper, “Antisense therapy for a common corneal dystrophy ameliorates TCF4 repeat expansion-mediated toxicity.

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(L-R) Kirithika Muthusamy, Christina Zarouchlioti, Alison Hardcastle, Alice Davidson, and Beatriz Sanchez-Pintado (courtesy Dr. Davidson)

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

Alice: I work in the ophthalmic genetics field. Back in 2012, I was hugely intrigued by Eric Wieben and colleagues’ discovery that Fuchs endothelial dystrophy (FECD) was associated with a non-coding triplet repeat expansion within an intron of TCF4. I have always been fascinated by repeat expansion-mediated diseases and their respective pathophysiology. I also similarly have a longstanding interest in non-coding mutations and their contribution to human disease. The discovery that this non-coding repeat expansion was associated with a corneal endothelial disease, a group of conditions I had already begun to research with my mentor Alison Hardcastle and clinical collaborator Steve Tuft, gave me the impetus I needed to begin to develop my own independent research program. In 2015, I was awarded a Fight for Sight fellowship to work on the genetics of primary corneal endothelial disease and decided to initially focus my effort on developing endothelial cell culture methods to study the pathophysiology of TCF4 triplet expansion-mediated FECDs. Alison, Steve, and I subsequently partnered with Pete Adamson at ProQR therapeutics to explore the therapeutic potential of antisense oligonucleotides (ASO) therapy to treat this repeat expansion-induced pathology.

AJHG: What about this paper most excites you?

Alice: I find the translational potential of this project hugely exciting. FECD is a common, age-related disease. The non-coding TCF4 repeat expansion is now recognized as by far the most common genetic cause of the disease in a wide range of ethnically diverse populations. Invasive corneal transplantation surgery is the currently the only treatment option available to restore vision and prevent blindness for FECD patients. This treatment relies upon specialist facilities, can be associated with operative complications, and is dependent on the availability of healthy donor material, of which there is currently a global shortage. These issues, in addition to the global aging population, highlight the need for alternative and effective treatment strategies to be developed for FECD. Our paper highlights the potential of an ASO mediated therapy to treat this common, sight-threatening disease.

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

Alice: Our study has impact beyond the ophthalmic research field, given that a wide range of neurological and neuromuscular diseases are caused by similar repeat expansion mutations, such as Huntington disease, myotonic dystrophy, and amyotrophic lateral sclerosis/frontotemporal dementia. Using our patient-derived corneal endothelial cell model has enabled us to study the cellular consequences of the repeat expansion within its native genomic and cellular context. The cornea is an easily accessible tissue that can be readily monitored for pathological and sub-symptomatic signs, unlike many of the neuronal tissues affected by other repeat-mediated diseases. We hope that any future therapeutic advances regarding TCF4 repeat expansion-mediated FECD and using the eye as a model system could be adopted for other, less tractable, non-coding repeat expansion mediated disease.

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

Alice: Don’t be scared to just give things a try. Often, as scientists, we can feel overwhelmed by the enormity of what we are trying to achieve and it is easy to focus on the problems and limitations associated with our experiments. Overcoming our personal fears of failure and giving ‘the impossible’ a try can often lead to unexpected and rewarding outcomes. I believe that the saying ‘it is always better to have tried and failed than to have never tried at all’ is very applicable to science.

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

Alice: I gave birth to my first child in October 2016 and since then my life has been a real juggling act between work and family. At the moment nothing makes me happier than spending quality time with my little boy and husband outside of work. I love to do bikram (hot) yoga to help me relax and generally lift my spirits, especially on dark, cold winter days – which are plentiful, living in London!

Alice Davidson, PhD, is a Senior Research Associate at the Institute of Ophthalmology at University College of London. She has been an ASHG member since 2018.

Inside AJHG: A Chat with Andy McCallion, Loyal Goff, and Paul Hook

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

Each month, the editors of The American Journal of Human Genetics interview the authors of a recently published paper. This month, we check in with Andy McCallion (@FunctionalDNA), Loyal Goff (@loyalgoff), and Paul Hook (@paul_hook_HuGen) of Johns Hopkins University to discuss their paper, “Single-cell RNA-seq of mouse dopaminergic neurons informs candidate gene selection for sporadic Parkinson’s disease.”

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(L-R) Paul Hook, Andy McCallion, and Loyal Goff

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

Andy: The challenge presented by endeavoring to connect common variation identified through genome wide association studies (GWAS) to affected genes and ultimately to the mechanistic understanding of disease gives all of us a headache. Where to start?

Although powerful, GWAS are inherently biologically agnostic. Despite the wealth of loci they implicate in disease, GWAS tell us nothing of the cellular context of disease or how variants mediate their effect/s. This, and the significant distances over which regulatory sequences/variants can act, complicates efforts to systematically identify gene candidates. We wanted to ask whether, beginning with an underlying biological insight into a pathologically vulnerable cell population, we could make progress on this challenge.

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

Andy: Perhaps the most exciting thing is that this work provides a biologically informed framework that systematically prioritizes candidate genes for an entire field, Parkinson’s Disease (PD). We were able to ask what (if anything) makes the transcriptomes of neurons in the substantia nigra unique among central nervous system dopamine neurons. We reasoned that any differences may contribute to their preferential vulnerability of this population in PD. The data we generated facilitated the exploration of gene networks underpinning the identity of all assayed dopamine subpopulations and in turn revealed that networks most associated with PD are active in the nigral population.

Stepwise integration of this data allowed us to establish a rubric, filtering over 1000 potential genes in 49 PD GWAS intervals to approximately 100. The genuine excitement was driven by the fact that the data holds up! Among these candidates are many established familial/syndromic PD genes. Further, we validate the functional requirement of a gene not previously known to be mutated in PD.

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

Andy: Our work demonstrates that starting from an informed biological hypothesis of (one) cellular context in which a subset of variation might be expected to mediate their effect, can yield robust, testable hypotheses of the genes modulated in disease. We’re not naïve enough to think this story is complete; we recognize that much more work needs to be done – similarly evaluating other cell populations, conditions, etc. Many others are similarly seeking ways to reveal what cellular contexts are most pertinent to a range of disorders. We see this as a proof of principle whose observations will (hopefully) synergize with those from other groups.

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

Andy: That’s a tough one! My advice would not be technical. I frequently joke with my trainees that life is not complicated – we all have only two responsibilities. First, you need to get the best out of yourself – work hard, be curious, invest in the intellectual and technical platform you create for your science, think rigorously and creatively. Second, you need to get the best out of everyone else – be fair, honest, empathetic; share information generously, recognize what you can learn from the experiences of others.

Hold those things in tension and you will reach for your success, want to ensure the success of others, and simultaneously avoid being a jerk­. The field of genetics/genomics has become so multi-disciplinary that throughout your career, you will need to develop many relationships – networks of colleagues. Hold yourself accountable for how you work and how you build and maintain relationships.

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

Andy: Outside of the lab, Paul is an avid cook and enjoys time in the kitchen. Loyal is a talented photographer and musician but currently spends most of his time chasing after his two young children. I spend much of my free time woodworking – both at home and as the carpenter on the restoration of an active second world war Liberty Ship and living museum, working alongside my teenage son. Collectively our labs (Goff and McCallion) enjoy almost anything that involves food, drink, our families, and a great laugh.

Andy McCallion, PhD; Loyal Goff, PhD; and Paul Hook, BS, study neurogenetics at the Johns Hopkins University McKusick-Nathans Institute of Genetic Medicine. Dr. McCallion, an ASHG member since 2001, served on the Society’s Program Committee from 2012-13 and as its Chair in 2014. Dr. Goff and Mr. Hook have been ASHG members since 2015.

 

 

Inside AJHG: A Chat with Tony Capra and Will Bush

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 John A. (Tony) Capra and Will Bush, to discuss their paper, “Comprehensive Analysis of Constraint on the Spatial Distribution of Missense Variants in Human Protein Structures.

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Tony Capra, PhD, left, and Will Bush, PhD, right

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

Tony: The roots of this project go all the way back to when I was in graduate school. As a graduate student, I studied how quantifying evolutionary patterns in protein sequences and structures between species could help us understand their functions (e.g., Capra et al. 2009). Then, I transitioned to working on the genetics of recent human evolution and didn’t think much about proteins for several years. When I started my own lab, a colleague came to me with a question about the function of a protein-coding variant in a human protein. As lead author Mike Sivley and I mapped the evolutionary conservation of this variant and its 3D neighborhood across species, we realized that it was silly not to include the wealth of information about genetic variation within human populations in these analyses as well. Around the same time, my colleague Will Bush had a similar idea. Once we got together and implemented a pipeline to map a few variants into protein structures, there was nothing (except lots of debugging!) to stop us from doing it comprehensively. More than 4 million variants later, we had this paper.

Will: I have had a long fascination with structural biology, and have focused much of my work on genomic analyses that are informed in some way by the biological context where variation occurs. This project started for me when multiple studies were published using technologies that explicitly target coding variation, which point to protein-level thinking. Around this time, I met Tony with expertise in protein evolution, and this project felt like the perfect way to start a new collaboration.

AJHG: What about this paper most excites you?

Tony: This paper is a great example of how looking across fields can help solve hard problems. Once we had mapped protein-coding variants into 3D structures, we needed to find a way to quantify whether their spatial patterns exhibited evidence of constraint. After several failed attempts, we realized that this problem had a lot in common with questions that field ecologists commonly ask about the distribution of individuals across physical ranges. A bit of reading revealed the Ripley’s K framework for evaluating and comparing spatial distributions of observations. We had to adapt the methodology for our application, but making this connection to a problem in another field provided the foundation for our solution. I like that an approach from ecology helped us to re-establish a strong link between human genetics and structural biology.

Our results also illustrate why data sharing is so important. By putting two big publicly available databases together, we were able to learn something new about how genetic variants are constrained in 3D space. It would not have been possible without the efforts and foresight of the groups that collected and maintain protein structural data (the Protein Data Bank) and genetic variation data (gnoMAD, COSMIC, TCGA, and ClinVar). Thank you to all of them!

Will: Like Tony, I am excited about the potential of modeling genomic data in a totally different way! The field of geospatial analysis has grown dramatically over the last few years, so using Ripley’s K just scratches the surface of the potential approaches that could be applied in this context. Given all the data that is available for research, the idea of data integration has become quite popular, but there are often many methodological hurdles to combining data of different types or from different domains in a coherent way. I’m excited that our work contributes in this area, and I echo Tony’s thanks to all the wonderful resources that provided the data we used in this work.

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

Tony: This paper provides a framework that I believe will improve analysis strategies in both human genetics and structural biology. Both fields have seen substantial increases in the amount of data available over the past 15 years, and our work illustrates the potential to extract insight from the integration of patterns of human genetic variation with 3D structures. We have many new ideas about fully leveraging this combined point of view.

I hope that the human genetics community will recognize that structural biology has many powerful tools that can help us with variant interpretation. However, our results demonstrate that getting the full benefit of the structural perspective requires considering the complex 3D context of variants. This goes beyond the basic structural information, like secondary structure, that is often included in variant pathogenicity predictors.

We also think that we human geneticists have a lot to teach structural biologists, especially about the flexibility and dynamics of their structures. But that’s a topic for another paper!

Will: Beyond our key findings, I hope that this work will inspire other ways to think of the genome in 3D! Chromatin conformation studies are now producing spatial maps of DNA within the nucleus, and we know that these patterns influence gene expression.  Long non-coding RNAs fold into complex forms to achieve their functions – many possibilities exist!

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

Tony: Talk to diverse scientists (and non-scientists). This will help you make unexpected connections between fields. Much of the motivation for this project came out of the fact that my office happens to be on the same floor as the Vanderbilt Center for Structural Biology. Different fields have powerful datasets and methods that have direct relevance to important problems (like variant interpretation). The challenge is finding them and then figuring out how they fit together! It is much easier to be creative when you have a broad knowledge of what is state-of-the-art in different fields.

Will: Keep your work organized and persevere. Mike Sivley is a meticulous note-taker, so it was easy at any given moment to go back to prior results and put everything together. Taking good notes is also a great way to know what questions you are asking, and to push through until you have an answer. With any project, there is a time when multiple setbacks make you question the whole endeavor. Looking back over notes from an entire project is the best way to see how much you’ve learned in the process, and that can be a strong motivator to push forward.

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

Tony: I secretly want to be a bartender. I suspect this is because I watched too many re-runs of Cheers when I was young. I also hate getting to work before noon.

Will: I intentionally schedule my meetings with Tony before noon, and I really love a good bourbon, especially from Tony’s bar.

Tony Capra, PhD, Assistant Professor at Vanderbilt University, has been an ASHG member since 2012. Will Bush, Assistant Professor at Case Western Reserve University, has been an ASHG member since 2005 and served on the Society’s Communications Committee from 2012-17.

AJHG Welcomes Its New Editor: Q&A with Bruce Korf

Posted By: Staff

A warm welcome to Bruce R. Korf, MD, PhD, new Editor-in-Chief of The American Journal of Human Genetics (AJHG)! We chatted with Dr. Korf about his vision for the journal, which he also described in an editorial in this month’s AJHG.

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Bruce R. Korf, MD, PhD, Editor of AJHG

ASHG: What excites you about human genetics research today?

Bruce: Human genetics encompasses an enormous range of research activity. We are in a golden age of gene discovery, including the identification of genes that underlie rare disorders and revealing genetic contributions to common disorders. From my own perspective as a medical geneticist, it’s exciting that disorders we used to only be able to diagnose are now potentially treatable as we uncover the genetic mechanisms and underlying pathophysiology.

There is also fascinating research into human origins and history, independent of medical implications. As a reader of the Journal I did not previously focus on this type of work, but now as AJHG Editor, I am finding this work to be really interesting – these papers bring together ideas we can all relate to.

ASHG: How do you view AJHG’s role in advancing the field?

Bruce: AJHG is the place for geneticists to showcase their best research. It’s a forum to publish findings of broad interest in genetics, and has long been trusted for its scientific rigor, integrity, and careful review of manuscripts. It’s also a resource for the next generation of geneticists, to both encourage and educate early-career scientists and trainees.

As we learn more about ways to diagnose and increasingly, to treat genetic conditions, the Journal can be involved in publishing papers that demonstrate the clinical utility of these interventions – to show that they actually improve outcomes in a cost-effective way. Findings published in AJHG also help highlight the value of publicly funded research: this important work produces new knowledge that leads to better health care and outcomes.

ASHG: ASHG members receive a free subscription to AJHG and are exempt from publishing fees. What other benefits does AJHG offer members?

Bruce: When you’re reading AJHG, you’re looking at the final product of an intense team process. Our staff and editorial board share a strong sense that the papers should represent as carefully vetted a story as possible, which happens at every step from submission to review to acceptance and editing of manuscripts. AJHG and Cell Press put in a lot of effort to ensure reliability of the findings we publish.

The Journal can also serve as an educational forum, for example to help trainees understand the background of why and how a study was put together.

As AJHG is the Society’s journal, we would welcome members’ advice and suggestions on what we can do better, do more of, etc.

ASHG: Are there new areas of emphasis where you’d like to see more submissions?

Bruce: Genetics has advanced tremendously in recent years, and conditions that we could previously only identify can now be treated. I would love to see more submissions on treatment, from preclinical testing to even reporting of clinical trials.

Cancer genetics is another area of interest. Historically, many cancer papers published in AJHG have emphasized germline and Mendelian changes associated with cancer risk. I would like to see more submissions on somatic cancer genetics in addition to work on inherited predisposition to cancer.

ASHG: You’ve also expressed interest in addressing genetics questions that affect society more broadly. Tell us about that.

Bruce: Advances in genetics are bringing up ELSI-related questions, such as how to responsibly use genetic information and how to protect genetic privacy. We look to ASHG to serve as a voice of reason and thoughtful analysis, weighing in on important issues of the day through Society statements. Beyond those statements, I would like to see more Commentaries from individuals in the genetics community, which provide a venue to share personal opinions and generate thoughtful discussion.

Inside AJHG: A Chat with Barbara Evans

Posted By: Sara Cullinan, PhD, Deputy Director, 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 Barbara Evans of the University of Houston, to discuss her Commentary, “HIPAA’s individual right of access to genomic data: reconciling safety and civil rights.”

Through such Commentaries, AJHG encourages individuals in the genetics community to share their personal views on a policy issue. Distinct from journal editorials and official ASHG statements, it is our hope that these commentaries will help spur discussion within the field.

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Barbara Evans, University of Houston (Credit: S. Chandler)

AJHG: How did you become interested in this topic?

Barbara: Last summer, I was getting a lot of calls from research participants who were having trouble exercising their HIPAA right of access to their own genomic data. The HIPAA Privacy Rule is a U.S. federal privacy law. It grants people a right to obtain copies of data about themselves that is stored at HIPAA-regulated facilities. Since 2013, the Privacy Rule protects genetic data and, since 2014, its access right extends to data stored at HIPAA-regulated labs. People heard that they have a right to see their data, so naturally they wanted to see it. Many were being told “no.” Law professors play an informal role as society’s help line for questions about the laws we write about. I write about HIPAA, so I’m like the canary in the coal mine if a new HIPAA problem is emerging: my phone starts to ring. I checked around, and other HIPAA lawyers were getting those same calls from frustrated research participants. “Strange…why now?” we wondered. It seemed worth looking into—which, for a Law Prof, means you write an article. This is the article.

AJHG: What about this topic most interests/concerns you?  

Barbara: Regulatory lawyers are like primary-care docs: when someone shows up with a regulatory problem, you order a battery of diagnostic tests. The first test you run is to trace back in legal history till you find the statute (the Act of Congress) that gave rise to the regulation. Like most people, I always assumed that HIPAA’s access right must flow from the HIPAA statute. That’s true, but with a fascinating twist. As it relates to genetic information, HIPAA’s access right flows from a mandate Congress laid down in the Genetic Information Nondiscrimination Act of 2008. It’s a civil right! That fact has impacts that my commentary explores.

What concerns me most? Under the U.S. system of law, one of the worst ways things can go wrong in a democracy is if government agencies, which are supposed to protect people, take actions that deprive people of their civil rights. Your right under HIPAA to see your own genetic information is a federally protected civil right. That limits the range of actions regulators like the U.S. Food and Drug Administration and the Centers for Medicare and Medicaid Services, which regulates clinical labs, can take to block people’s access to their own genomic data. My commentary hopes to spark a dialogue about ways to address valid safety concerns about individual data access, without violating people’s civil rights.

AJHG: Tell us a bit more about the bigger picture—for scientists and the general public.

Barbara: Using people’s genomic data in research offers huge benefits to society, but it exposes people to privacy risks and other threats to their civil rights. Dating back to the dawn of the information age in the early 1970s, Congress has approved policies that let researchers use people’s data to advance public health and research. The quid pro quo is that Congress has consistently stood by the idea that if researchers have broad access to your data, then you should have broad access, too. Doesn’t that seem fair?

People who want to block individuals’ access to data need to appreciate that, over the past 50 years, Congress gave this matter a lot of thought and commissioned multiple ethical analyses. What they found is that if you want to take people’s access away, you can do so. But in return for taking people’s access away, you would then need to severely curtail researchers’ access to people’s data as an alternative way to protect people’s civil rights. So which world do you want? In World 1, researchers and people both have broad access to the people’s data. In World 2, neither group has access. Those are the two ethical options. It’s just not ethically defensible to have a World in which researchers have broad access to people’s data, but the people do not.

AJHG: What advice do you have for trainees?

Barbara: If your job doesn’t excite you and make you feel useful most of the time, get another job. Risks work out more often than we are led to believe. Take them. You hold your talents in trust, and you have a fiduciary duty to shepherd your talents to a green pasture where they can thrive.

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

Barbara: It’s generally tranquil, but last year was anything but with Hurricane Harvey, 52 inches of rain, fences down, and administering a portfolio of family interests across Texas. The saving grace is the lack of speed limits on rural Texas highways and discovering—in the fullness of middle age—the joy of really fast cars.

Barbara Evans, PhD, JD, LLM, is an Alumnae College Professor of Law and a Professor of Electrical and Computer Engineering at the University of Houston.

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.