Shortening the Diagnostic Odyssey

This is certainly a major limiting factor in terms of healthcare access. There are several options to pursue. We should empower community physicians and medical centers to encourage their patients to. participate in treatment trials. We should promote information about emerging trials and work on finding the financial resources for families to travel (which may be available through trial sponsors). Depending on the nature and frequency of treatment and assessments required, we can consider telemedicine for some visits along with good communication between specialist guiding the therapy trial and the local healthcare team. 

Besides what is in the literature, good resources are child neurologists and researchers working on specific disorders, foundation websites for specific disorders, as well as clinicaltrials.gov. Connecting with researchers/authors involved in particular genes can also help find many of the unpublished/studies in pipeline in this quickly evolving field. 

It definitely depends on the type of treatment. Drug repurposing (of available FDA-approved drugs) typically involves costs similar to other drugs. Drug development and delivery of experimental therapeutics, such as N of 1 anti-sense oligonucelotides, involve costs related to research, infrastructure, production, and delivery that can be in the range of millions of dollars. If a treatment of this nature were applicable to more patients, the cost per patient would of course be lower. Until now, most N of 1 treatments have been developed to demonstrate proof of concept and feasibility using an IND/compassionate use route. The plan is to take them to Phase I and II trials to include more patients. 

Some foundations have been interested in supporting these endeavors. Academic centers have also supported these efforts at least partially, as well as some industries collaborating with academic centers. Access to funding for these treatments raises issues related to access to care and resources, as discussed below. 

In addition to requiring an IND from the FDA for compassionate use of a new compound for a rare and sometimes progressive disease, there are several internal/institutional committees involved in oversight and support at every step of trial design and implementation, including hospital and department leadership. There are mechanisms in place for standard drug trials, including regulatory approval (IRB) and practical considerations (e.g., by an experimental trials unit team). Additional oversight for N of 1 treatments may derive from a hospital oversight committee for personalized experimental therapeutics and/or an ethics committee regarding the specific treatment under consideration as well as issues around patient selection. 

Social determinants have a major impact at every step of these trials and therapies. Starting with diagnosis, many patients and communities do not have access to specialists or diagnostic resources. At the level of therapy, knowledge of available therapies or advocacy for new therapies to be considered or designed is not widely available. Physical access to tertiary centers and thus experimental therapies, and cost, are not available to all patients. This is an area that needs more dedicated attention broadly—from access to care and diagnosis to genetic testing and therapies. 

I think this process should rely on collaboration between institutions, as these disorders are very rare. Even the largest institutions do not have all the animal models or the specific resources for different types of pre-clinical studies. For example, a diagnosis is made, and there is a plausible mechanism for a potential drug (whether already available or in need of design/production), the first step would be to reach out to the experts in that particular disorder nationally and internationally to look at their available data, and look into collaboration on utilizing their available resources. If no such resources are available and a lot of work needs to be done from scratch, then teaming up with parent groups and organizations for funding of pre-clinical work can be a good start. 

There are several leukodystrophy centers (e.g., MGH in Boston, Dr. Van der Knaap in Europe) where precision/genetic diagnosis could be pursued and then treatment. Precision (including N of 1) therapy will require a precision diagnosis. 

In the limited circumstances for which the natural history is tightly defined, it may be possible.  NCL and SMA are examples of using historical controls as the comparison group for actively treated patients.  It seems that all N-of-1 trials rest on pre-post treatment comparisons, which is most valid if the trajectory of disease is clearly defined and can be shown to stabilize or improve with treatment. 

Our expert panel is not best suited to comment on the corporate perspective. This would be a good topic for future discussion as it highlights the questions of generalizability of and access to specific and specialized treatments and sustainability of this overall approach. 

I think that education is key. We need to continue to find ways to keep non-genetics physicians up to date on advances in genetic diagnosis, help them know how/when to refer to genetics if they are not in a situation to order the test. 

I am unable to comment on the legal question as I do not have that expertise. It is difficult to keep up with new reports of genetic testing, though more and more, “new” genes are added to testing panels / analysis quite rapidly. This is why reanalysis or re-testing is important. The timing is a moving target, but generally we recommend considering reanalysis if it has been >1 yr or so. 

Exome or genome sequencing has been recommended as a first or second-tier test for congenital anomalies (birth defects), developmental delay, and intellectual disability. In general, it should be considered early in the diagnostic workup if possible. If there is a very specific diagnosis suspected and a specific test, that could be done first. For nonspecific diagnoses, exome is often more efficient.  

Early! Of course, it depends on the disorder. 

This is under active investigation by several groups, though not much is clinically available yet. Some disorders have an epigenetic “signature” or pattern that can be recognized and may help with diagnosis, even when the DNA mutation is not found. 

I think that epigenetics and polygenic risk may be the next type of testing developed, though these should not be implemented until we have clear indication that the results are useful. Another test that may be used more is RNA sequencing. 

Long-read sequencing may identify ring chromosomes and is another test that may be offered more frequently in the clinical setting; karyotypes should be considered (i.e., not forgotten!) in the diagnostic process, probably after genome/exome unless there is a specific phenotype that suggests a ring chromosome, then it should be done earlier. 

If the analysis focuses on the exome, the number of VUS should not be much different that exome sequencing. The tools to annotate noncoding variants and predict a potentially pathogenic effect need to improve before many are reported clinically.   

Ideally, there is a functional study that can be done (this would probably have to happen through research) that can determine whether the VUS is pathogenic or benign. You can reach out to experts who study the gene to get input. Sometimes you can use clinical judgment. 

Depends on where the test is done. I recommend checking with the company doing the test to know whether they report CNVs from exome data. Some only report del/dup of a certain size. In this case, CMA may be useful. 

Agree. We also need to gain experience predicting the effect of noncoding variants from genome sequencing. Implementing cellular assays can be difficult, as different assays (and cell types) may be required for different genes. Ideally, doing prospective studies in research labs (e.g. massively parallel reporter assays, other approaches) to determine the effect of any potential variant in a gene ahead of time would benefit interpretation. Agree that RNAseq can be an important additional test. 

Should probably be done specifically (for some diagnostic labs, you can specify if you want exome PLUS mito) – it can be picked up but is not always reliable unless specifically interrogated. 

Post-translational changes may be due to an underlying DNA defect, but if not, would not be picked up by sequencing. 

WGS is available some places clinically. I’d recommend working with a geneticist or genetic counselor to order. 

YES, depending on the disease. Exome tends to have higher yield. The ACMG recommends exome (or genome) as a first- or second-tier test for congenital anomalies, DD, ID. 

Insurance! Manpower – having enough geneticists/GCs to see patients and order testing. 

Please see above, question 9. 

Yes! The current Undiagnosed Diseases Network includes a number of institutions that do exactly this (at the NIH site, our panel meets once/month). If the expertise is not represented on the board (which is rare but does happen), then other experts are pulled in to help. This has been a part of all these programs since their inception. 

The Undiagnosed Diseases Network was conceived as part of an ongoing funding stream called the NIH Common Fund. This program is administered by the NIH Director’s Office. Projects are approved initially for five years of funding, which can be renewed only once. After that, the programs need to evolve into their own funding stream. That said, the NIH Institute Directors and their staff (in conjunction with the current network sites) are developing a long-term sustainability plan in recognition of the importance of this program. The funding burden needs to shift but the goal is for the main programmatic elements to be maintained. 

Yes, there is a variety of contract research organizations (CROs) and academic institutions that can perform a wide range of services like this. 

This is something that is very much on the radar screen for several NIH Institutes and other organizations. The NIH All of Us Program (aims to collect all sorts of biological and environmental data from a diverse population. Another important initiative that is supported by NIH and other research funders is called the H3Africa program. One of its goals is to sequence data from non-European populations. There are some repositories in Asia, as well. 

In the limited circumstances for which the natural history is tightly defined, it may be possible.  NCL and SMA are examples (maybe the only two) where trials used historical controls as the comparison group for actively treated patients. 

There are costs and consequences of any and every action.  For example, what is a lethal disease is converted to a chronic disease and managed so that the person can go about his or her life.  What if that person wishes to have children and can pass on this disease?   Many of these questions are far beyond the purview of scientific studies and are better addressed in the realm of morals and values.  I know these are important questions. I do not presume to have the answers. 

Not sure about evidence over the lifespan; however, the Baby Bear project in California (Dimnock et al. AJHG 2020 & 2021) provides a sense of what it can do in critically ill neonates. 

Anne Berg has been working with several parent-formed groups to advance this very goal.  If you are interested, she gave a talk on this at the KCNQ2 summit in October.  “Rare Disease – Rare Outcomes: What does better look like for children with KCNQ2-DEE?”   The link will take you to all of the talks.  Just scroll to find Anne’s.  

Most disease advocacy organizations that support research do so with the advice of volunteer experts who provide peer review of research project proposals that enable the agency to make decisions about investing their hard-won resources into projects that have the best chances of impacting their goals. I can speak to how the National MS Society makes its funding decisions – we rely on the advice of leading scientists, physicians, and other experts from virtually every field related to MS to help us make decisions about which research projects and programs have the best chance of moving us closer to a world free of MS. The committee members review applications in terms of the significance of the project, the relevance of the project to MS, the approach, or methods to be used, the innovation of its concepts, the investigator’s qualifications and available resources, and suitability of the proposed budget.  We also layer in a community review of projects to ensure their aims align with the concerns of people affected by MS. We also carefully monitor annual progress reports by funded investigators to make sure they stay on track, and we strongly encourage the publication of their findings in peer reviewed journals to move the field forward.  

In the social media groups I’m aware of, participation is limited to only those who are personally impacted by the disease in some capacity and would likely not allow participation by healthcare professionals.  However, there may be opportunity for discussion themes to be captured and shared.  In this case, a healthcare advocacy organization might be an appropriate facilitator/moderator.   

It’s an interesting thought, but I have some hesitation since the NBS system wasn’t really developed for this type of issue and would need to be carefully considered from many perspectives. For example, generally conditions for newborn screening have to meet certain criteria including that the conditions should have effective treatments available, which is unfortunately not the case for most genetic disorders. It would also be very complicated to interpret genetic data in these cases, as the ACMG variant classification criteria are designed for use in patients who are already suspected to have an underlying genetic condition. Lots to think about before such an idea could possibly be put into action. 

In ACMG variant classification, de novo status of a variant is one piece of evidence for pathogenicity that is accounted for (though it doesn’t in and of itself imply pathogenicity). De novo variants may still be classified as VUS once the comprehensive evidence is considered. 

If an insurance company denies the initial request, appeal with a peer-to-peer review. In terms of suggested phrases etc, given that insurance plans vary a lot from state to state, I would suggest reaching out a geneticist/genetic counselor in your area for advice — you can find a directory of GCs at nsgc.org. As a field, one thing we can do is to conduct systematic evidence reviews (example of one just done for epilepsy: Sheidley et al., Epilepsia, 2020) and develop and publush practice guidelines in partnership with professional societies. These types of publications provide demonstration of what the field considers to be standard of care.  

Varies based on insurance coverage. Many genetic testing labs have a maximum out-of-pocket cost for patients to help alleviate cost issues, so don’t assume genetic testing will be out of reach for a patient just because of poor insurance coverage. 

Clinicians may keep a record of genes of interest and submit on GeneMatcher to be connected to other researchers who are interested and working on that gene. Generally, clinicians are not accessing the massive data files generated during WES/WGS, these are maintained at the lab and are available for re-analysis at the clinician request. (Note, each lab has different re-analysis policies — e.g., limiting it to one free reanalysis etc.) 

Even when WES is performed, clinical labs employ variant filtration algorithms so that they are only curating & returning variants that have a potential connection to the presenting symptoms. (This is why it is important to accurately fill out the phenotyping section on genetic test requisitions.) Clinical labs would not return ALS, Huntington, APOE etc. unless such testing was specifically ordered. Clinics that specialize in these conditions will have detailed pre-testing counseling and evaluation procedures before ordering such testing. 

I don’t have any that I’m familiar with, but found this one from the ClinGen Resource which looks promising: https://www.youtube.com/watch?v=s4eNR61GXXQ 

Many groups are trying to develop guidelines around test selection, though as you can imagine these efforts often take a while to come to publication — and may not move as fast as the genetic technology. Genetic testing labs employ genetic counselors & other professionals who are available to discuss testing options with providers and ensure the most appropriate test is ordered. 

For Genetic Counselors, NSGC’s Website 

For Medical Geneticists, ACMG’s Website 

For Neurogenetics experts: most tertiary hospitals will have a group or several groups within Neurology focusing on evaluation and treatment of genetic disorders. 

If you have already done a panel, additional panels may not be that helpful as they may have many overlapping genes. In general (noting there may be exceptions), I would probably consider exome next. Many labs will let you order a panel with reflex to exome if the panel is negative, which is efficient, avoids additional sample draws from the patient etc. 

Ideally, the fact that the testing might result in VUS would be discussed with a patient during the pre-test consent process, so they are prepared for such an outcome. I think it’s useful to talk about whether there may be candidate variants that the clinician and/or family want to submit to GeneMatcher or Matchmaker Exchange, as a way to connect with others interested in the same gene. Also talk about the next steps for clinical management in light of the VUS result — a genetic diagnosis may have changed some aspects of the management but there may be others that would stay the same. 

In ACMG variant classification, de novo status of a variant is one piece of evidence for pathogenicity that is accounted for (though it doesn’t in and of itself imply pathogenicity). De novo variants may still be classified as VUS once the comprehensive evidence is considered. 

There are many groups who offer seminars in genetics for non-genetics physicians. I suggest keeping your eye out for such courses — NHGRI may be a good place to start. Talks and workshops at professional meetings (e.g., American Epilepsy Society Genetics Workshop) are emerging to address the need for neurologists to learn more about the content and practice of genetics related to neurological disorders.