Guest Column | January 11, 2022

Genome Sequencing Research For Rare Diseases & The Future Of The Field

A conversation with Tomi Pastinen, M.D., Ph.D., director of the Genomic Medicine Center at Children’s Mercy Research Institute

Genomic data visualization GettyImages-1328709525

Tomi Pastinen, M.D., Ph.D., is the director of the Genomic Medicine Center (GMC) at Children’s Mercy Research Institute (CMRI). In 2019, Dr. Pastinen, along with a team of CMRI researchers, launched Genomic Answers for Kids (GA4K), a first-of-its-kind pediatric data repository with the goal of collecting genomic data and health information from 30,000 children and their families over the next seven years to create a database of 100,000 genomes. Today, more than 3,700 families with rare disease and more than 7,000 individuals have enrolled in the GA4K program, which has resulted in more than 18,000 new genomic analyses and more than 600 genetic diagnoses and has already contributed to the reporting of 13 new disease genes. Since the start of his career in 1994, Dr. Pastinen has published 169 peer-reviewed scientific papers on human genomics and genetic disease research.

1. How did you first become interested in this field, how long have you been studying genomic sequencing, and what drew you to focus on pediatrics?

I initiated an M.D. Ph.D. program in late 1994 in the laboratory of Dr. Leena Peltonen, at the University of Helsinki, Finland. I got drawn into genetics research since it dealt with fundamental causes of human disease, which was not always the case in the days preceding evidence-based medicine. Also, in the early days of “positional cloning” (a systematic approach to map human genes causing disease), this research was very powerful in Finland and Dr. Peltonen’s was world leading in characterizing new disease genes – it was an international and exciting environment to get immersed into human disease genetics. It was always clear that genetic influences are more important in early-onset disease (childhood) and still today the largest clinical impact of genomics is in severe childhood diseases.

2. What would you consider to be the most notable or surprising result you’ve found so far in your whole-genome sequencing research, particularly in regard to etiological discoveries for rare disease patients?

One of the continuing “medical mysteries” is the lack of clear (interpretable) DNA changes in the large fraction of patients where a physician suspects a rare disease of genetic origin. This is evident from even the latest approaches for clinical genome sequencing. In line with the minority of cases diagnosed by the latter genome sequencing study a surprise to us is the complexity of some DNA changes that require many different technologies to appropriately resolve. Right now, we estimate that these complex variations explain as many as 10% of missed genetic diagnoses, but as we get better with research tools deployed in clinical sequencing, we may observe an even larger fraction. However, the greater surprise will be the themes of the human genome for the remaining missed diagnoses – we believe that many of these are in regions of the genome regulating gene expression rather than structure, and these latter changes are currently not interpreted in clinical settings.

3. Discuss your work with the Undiagnosed Diseases Network (UDN). How does their mission align with your genomic sequencing work at CMRI and why are UDN clinical sites integral to the evaluation and diagnosis of novel gene candidates?

UDN is an ambitious, disseminated approach to bringing together expertise in clinical, genetic, and basic research areas to solve medical mysteries similar to ones I discussed above. For example, our research leverages results from a large consortium study. UDN is serving to model a systematic approach for solving the unsolved cases, which we want to make accessible to a larger fraction of unsolved cases, since UDN is able to accept only of subset of referrals. The release and sharing of genetic and clinical data of the UDN cases is also pioneering within the field of rare disease, which we faithfully follow and have already shared our data with UDN groups to “crowd source” resolution of difficult genetic diagnoses.

4. You have shared that rare diseases affect approximately 1 in 20 people, but only a minority of patients receive a genetic diagnosis. Why do you suppose this is and how will your research and the GA4K data repository improve the likelihood of patients receiving a resolved genetic etiology?

Access to genetic testing and clinical genetic counseling is a key bottleneck in timely genetic diagnoses, along with the technical limitations of genome sequence interpretations I discussed above. Despite the high impact of genetic disease in childhood, the visibility of individual rare diseases is low and knowledge of their collective impact is lacking — they remain a leading cause of mortality in early childhood. The diversity of conditions has slowed down precision therapies, and the relative lack of therapies leads to a lower appetite for comprehensive solutions for testing and improving existing tests. This creates a vicious circle where families with rare genetic disease will go through years of futile medical evaluation in “diagnostic odysseys.” We believe that GA4K and other community driven programs developing deep awareness, sharing data, and improving tools for rare disease analyses are needed to break the cycle and resolve diagnostic odysseys.

5. What was your incentive to launch GA4K? How scalable is the program and how can other organizations and researchers working in genomics adopt a similar strategy?

GA4K was launched to accelerate the application of contemporary genomic tools including whole genome sequencing, long-read sequencing, and single-cell genomics in pediatric disease to redefine “diagnosable” space and increase access to genomic medicine in general. With institutional strategic support and generous philanthropic support, we aimed the program to cover most rare disease families in our region, ultimately tens of thousands of patients over seven years, and provide a full picture of genomic changes across a diversity of rare diseases to serve as a new generation resource to deploy currently underutilized genomic methods in disease studies. The patients and families participate in the program knowing that the goal of the program is to advance the rare disease research and that therefore sharing their genomic sequences, together with relevant medical data in the wider rare disease research/clinical community, is important and is sometimes also needed for their own case to be solved. The shareable data repository ideology we embrace, if adopted by others, can revolutionize the currently unsolvable genetic diagnoses. We are consequently pioneering sharing of data through a real-time interface allowing investigators to access developing genetic sequencing linked to specific clinical signs and symptoms in addition to the more traditional sequence data sharing repository mechanisms hosted by the NIH/NCBI. The motivation for former mechanisms to share data is to “democratize” access to large genomics data without needing to be a computational scientist, but even a provider with rare disease practice can benefit from an intuitive web-based interface for interpretation of their own patient’s genomic findings.  

6. How has the field of genomic sequencing research shifted since the onset of the coronavirus pandemic?

The process of discussing the implications of the genetic research we are conducting in consenting families to our studies is critical to building the shareable data resource. As the pandemic started, lower access to one-on-one discussion (in person) was a challenge for our patient recruitment team, but also the reluctance of patients to visit hospital for research purposes (for providing blood sample) lowered recruitment. We have tested many other approaches, such as telemedicine visits, coupled with research recruitment, by-phone consenting, home care visits for key patients for recruitment and sampling, as well as self-sampling of DNA (buccal swab). Many of these solutions now remain as flexible options for patients even after pandemic restrictions are lifting – this may improve penetration of genomic medicine research to underserved populations in the future.

7. COVID-19 variants are currently being tested through similar genome sequencing technologies. How might this overlap effect the future of rare disease research moving forward?

Genomic technologies are powerful both for viral and human (host) DNA variation. Intriguingly, combining viral and host sequencing reveals that the host genome can also influence the response to any viral strain. There are rare human genetic defects that impair response to COVID-19, and these can define new groups of vulnerable individuals needing additional attention but can also inform researchers of critical human responses in defending against the virus.

8. What does genomic sequencing look like in other parts of the world and what can experts in the U.S. learn from gene sequencing developments overseas, and vice versa?

Many programs in the industrialized countries (including Canada, the European Union, the United Kingdom, and Japan) are designed for better access and higher resolution genomic medicine in rare disease. Within the U.S., there are UDN and the Mendelian Genomic Research Consortium, focused, in part, on genomic medicine in pediatrics and that do share full genetic data. As compared to these national and consortium initiatives, the GA4K program, integrated with the Children’s Mercy Kansas City clinical system, benefits from real-time access to providers and patients, giving us the ability to deliver medically relevant results without delay, and also observe changes in patients that can inform new genetic analyses, as well as allow us to learn from tissues available from medical procedures carried out in therapeutic or diagnostic interventions. In summary, the GA4K can model new ways of delivering genomic medicine, but all the national and global efforts are jointly needed to access sufficient numbers of each rare disease (with data sharing) to initiate a path to a full understanding of mechanisms to facilitate future therapeutic developments.

9. How have you seen the process of genomic sequencing evolve over the years? Where do you see this field of research growing?

The future of genome sequencing relies on sequencing full genomes using the best available technologies (to minimize error and ensure coverage of all DNA sequences). The next phase is developing a way to share this deep data, together with medical information, where the personal genome serves as a reference to understand disease, not only for diagnoses but also to predict future risks and target the best therapies. The earlier the personal genome is integrated with the health record, the better the chances are that it will be impactful. In a framework where genomic and medical privacy is protected, such data can grow rapidly and globally and be interpretable by computational approaches, keeping providers and patients automatically informed of risks and impactful interventions precisely tailored for the patient.