Orphan Autoimmunity
Whole Exome Sequencing, Whole Genome Sequencing & Biomarker Studies
My last two posts on VEXAS (vacuoles, E1-ubiquitin-activating enzyme, X-linked, autoinflammatory, somatic), found here and here, illustrate the potential of Whole Exome Sequencing for defining autoimmune disease diagnoses more accurately. In response, a reader reached out to ask me to look into where Whole Exome Sequencing might be available. In my search, I had to confront the ethical implications of presenting this information. I’m not endorsing any of these options, and I don’t receive money from any of these organizations or companies.
I question the legitimacy of the direct-to-consumer options. What results do they deliver, how readable are they, and what interpretive tools do they provide? If they identify potentially disease-causing variants, how many, and what type of, analyses made that interpretation? If your sequenced data is stored or transmitted online, then it has little assurance of privacy safeguards, despite company claims. How does the company use client data? Is it in the client’s best interest to have what could be confusing and inconclusive information. In the end, though, I found a number of different options, which I am sharing here, because I fundamentally reject the patronizing barriers that are placed between patients and their access to critically evaluating their testing options.
Distracted by ethics, I took a brief detour into reading Genetic screening: A primer for primary care. I found a lot to disagree with in this article, but I was struck by the following quote:
Rare diseases have been defined as having a low prevalence of less than 1 in 2000.24 There exist between 5000 and 7000 distinct rare diseases that together affect between 6% and 8% of the world’s population, including an estimated 54 million people in Europe and North America combined. Thus, taken together, rare diseases are in fact not so rare.25
Owing to the low prevalence of each disease in isolation, however, rare diseases have not traditionally been considered a public health concern. Some progress has been made,26 but it remains difficult to get rare diseases onto the agendas of policy makers and pharmaceutical companies.27,28 Many rare diseases are therefore also orphan diseases, which receive little attention in terms of research focus, market interest, and public health policies.27,29 Special efforts are needed to reduce morbidity and mortality related to orphan diseases.30
(Andermann & Blancquaert, 2010)
The key to research breakthroughs in autoimmune disease is to gather numbers and influence by considering autoimmunity one disease process. I believe broad genetic testing is one piece of that puzzle.
There were three types of Whole Genome Testing that I came across in the U.S. I’ve listed them in order from most reputable to least reputable: 1. large health system studies, such as the Geisinger study, which facilitated the breakthrough in VEXAS; 2. private labs that partner with physicians for Whole Exome/Genome Sequencing; 3. private labs with direct-to-consumer options.
Large Health System Studies
All of Us
In the U.S. the National Institutes of Health has an extensive research program titled All of Us, that has a genetic testing component. It’s unclear whether this testing is available to all participants, but signing up for this study is an option in my area of the country, so I plan to sign up, and report back. What is clear from the information that they provide is that if you are genetically tested as part of your participation, you do receive your results. It’s unclear from the preliminary information that I have read whether those results include Whole Exome Sequencing, and if data is interpreted in the context of autoimmune disease signs and symptoms:
Beyond making genomic data available for research, All of Us participants have the opportunity to receive personal DNA results at no cost to them. So far, the program has offered genetic ancestry and trait results to more than 100,000 participants. Plans are underway to begin to share health-related DNA results on hereditary disease risk and medication-gene interactions later this year.
Regional medical centers, community health centers, and medical centers run by the U.S. Department of Veterans Affairs participate in the All of US research program including:
Cherokee Health Systems, Knoxville, Tennessee
Community Health Center, Inc., Middletown, Connecticut
Eau Claire Cooperative Health Center, Columbia, South Carolina
Sun River Health, Peekskill, New York
Jackson-Hinds Comprehensive Health Center, Jackson, Mississippi
San Ysidro Health, San Ysidro, California
Health Resources and Services Administration (HRSA) (Collaborator)
MITRE Corporation (Collaborator)
Wisconsin
Marshfield Clinic Research Institute
Gundersen Health System, Lacrosse
Froedtert & Medical College of Wisconsin, Milwaukee
University of Wisconsin School of Medicine and Public Health, Madison
California
University of California San Diego
Cedars-Sinai Medical Center, Los Angeles
San Diego Blood Bank
University of California, Davis
University of California, Irvine
University of California, San Francisco
University of Southern California, Los Angeles
Illinois
Northwestern University, Chicago
University of Chicago
University of Illinois at Chicago
NorthShore University HealthSystem, Chicago
Rush University Medical Center, Chicago
New England
Partners HealthCare System
Brigham and Women’s Hospital
Massachusetts General Hospital
Boston Medical Center
Newton-Wellesley Hospital
New York City
Columbia University Medical Center
NYC Health + Hospitals/Harlem
NewYork-Presbyterian, New York City
Weill Cornell Medicine, New York City
Southern
University of Alabama at Birmingham
Cooper Green Mercy Health Services, Birmingham, Alabama
Huntsville Hospital, Alabama
Louisiana State University Health Sciences Center, New Orleans
Tulane Medical Center, New Orleans
Tuskegee University, Alabama
UAB Hospital, Birmingham, Alabama
UAB School of Medicine’s Montgomery Internal Medicine and Selma Family Medicine programs, Birmingham, Alabama
University of Mississippi Medical Center, Jackson
University of South Alabama Health System, Mobile
University Medical Center, Tuscaloosa, Alabama
Southeast
University of Miami Miller School of Medicine, Florida
Emory University, Atlanta
Grady Hospital, Atlanta
Morehouse School of Medicine, Atlanta
OneFlorida Clinical Research Consortium led by the University of Florida in Gainesville
Participants not organized by state or region
Henry Ford Health System, Detroit
Baylor Scott and White Health, Dallas
Essentia Institute of Rural Health, Minnesota
HealthPartners Institute, Minnesota
Meyers Primary Care Institute at the University of Massachusetts Â
Reliant Medical Group, Massachusetts
Spectrum Health, Grand Rapids, Michigan
University of Arizona, Tucson
Banner Health, Phoenix
Mariposa Community Health Center
University of Pittsburgh at Pittsburgh
Temple University
The University of Texas Health Science Center at Houston
The University of Texas health Science Center at Tyler
Virginia Commonwealth University, Richmond, Virginia
Washington University, St. Louis, Missouri
U.S. Department of Veterans Affairs Medical Centers
Mayo Clinic
The Mayo Clinic has opportunities to participate in biomarker studies specific to autoimmune disease. Whether the biomarkers they use include Whole Exome Sequencing is unclear, and may be study specific.
Biomarkers in Autoimmune and Inflammatory Diseases
ABOUT THIS STUDY
The purpose of this study is to identify biomarkers in people with autoimmune or inflammatory disease and in healthy people. We will use these biomarkers to develop tests that will help us better understand the same biomarkers in the blood of people who have autoimmune and inflammatory diseases.
Participation eligibility
Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.
Private Labs That Partner with Physicians, Not Patients
The following labs conduct whole exome sequencing, but require a physician’s order to do so. My guess is that a physician’s order is required because the lab does not provide interpretive services for results. A physician would consider the person’s clinical presentation together with the whole exome sequencing data in order to interpret the results. It is not clear from the company’s websites what methods they use to determine potentially disease-causing variants, if they do this kind of analysis at all.
Private Labs with Direct-to-Consumer Options
All kinds of questions came up for me when reviewing these options. Perhaps I’m too steeped in the gatekeeping that is endemic to medical culture, but I saw all sorts of red flags on the legitimacy of these options. Are these companies a scam? If they’re not a scam, what exactly are the results delivered? What interpretive services are available? What methods are used to determine potentially disease-causing variants, if such a service is offered at all? Without a reputable variant analysis, how useful are these services for determining causative factors for autoimmune disease? These are all considerations that you’re able to judge for yourselves.
Nebula Genomics claims to offer complete DNA testing for two different prices: $249 or $899
Sequencing offers variable pricing of $399 and/or $1999.
Why It Matters
I wasn’t able to discover all of the unknowns about options I found for genetic testing. The options I list have many caveats, drawbacks and question marks. I limited my search to the U.S. to control the breadth of this post. For international options, there is the UK biobank and the Australian Health Biobank (available by invitation only), and many more, I’m sure. I strongly believe that the future of autoimmune disease research is genetic analysis, and specifically the more timely and cost-effective whole exome sequencing. This is the way toward more accurate diagnoses. Accurate diagnoses is the way to achieve effective treatment.
Has genetic testing, of any type, helped you to a more accurate diagnosis? Have you participated in genetic studies of autoimmune disease?
References
Andermann A, Blancquaert I. Genetic screening: A primer for primary care. Can Fam Physician. 2010 Apr;56(4):333-9. PMID: 20393090; PMCID: PMC2860823.