Being an undiagnosed patient, a physician, a scientist...or all of the above

While flipping through the May 24th issue of The New England Journal of Medicine, we came across a perspective article titled “p53 and Me” (1). This article written by Dr. Shekinah N.C. Elmore, an oncologist-in-training in the Radiation Oncology Program at Harvard Medical School, describes her personal story of being diagnosed with Li-Fraumeni syndrome the year she started medical school, and how she has been handling the vast amount of knowledge related to this disease and the consequences of that both as a patient and as a physician. Li-Fraumeni syndrome is primarily caused by mutations in the TP53 gene, the best studied gene in the human genome that encodes the tumor-suppressor protein p53 (2). Despite there are >9.000 articles in PubMed regarding the function of TP53, at the present, there is no effective cure for Li-Fraumeni syndrome, and there are little interventions physicians can currently offer. Dr. Elmore uses her medical knowledge to balance the risk-benefit of specific tests and treatments, and describes challenges that arise due to a genomic diagnosis – “my knowledge on personal genome has both empowered and broken me”, she writes - for a disease that predisposes patients to significant increases in the risks of developing diverse cancers throughout life. While the scientific community is making incredible efforts to discover the causes of unnamed conditions, a young patient-physician depicts and warn readers on how troublesome and upsetting could be to shoulder any knowledge that’s available on a condition with the uncertainty of the prognosis and where the modification on medical care because of the genetic mutation could be very limited. Although being a patient-physician helped her to go along with the syndrome, of outmost importance remains the close relationship with a multi-specialized team to be properly supported and driven between the present boundaries and future genetic scenario of the disease.  

Recently, there has been a strong emphasis on fostering the development of physician-scientists who can function as liaisons between the clinical and scientific communities. In contrast, models of how physicians and patients as well as scientists and patients can work in a collaborative manner to facilitate rare diseases research in a way have not been explored as rigorously as interactions between physicians and scientists. Similar to engaging more physician-scientists into the research field to bridge the gap between medicine and basic research, identifying patient-physicians (as in the case of Dr. Elmore) and patient-scientists who are willing to share their experiences may allow the rare and undiagnosed disease research field to identify how new medical and scientific information should be dealt and shared with patients and their family members.

Dr. James R. Lupski at Baylor College of Medicine is an excellent example of a ‘Physician-Scientist-Patient’. Dr. Lupski, a prominent pediatrician and a geneticist who identified causative genes for a number of Mendelian diseases throughout his medical and scientific career, was born as one of the four (out of eight) siblings who developed Charcot-Marie-Tooth disease. After a long quest to identify the autosomal dominant mutation that caused this disease in his family, he was able to find his answer using whole-genome sequencing in collaboration with Dr. Richard Gibbs, a work that was published in the New England Journal of Medicine in 2010 as one of the first examples of using this technique for medical diagnosis (3). More recently, a scientist in Oregon Health & Science University was featured in an article in New York Times titled “Infinitesimal Odds: A Scientist Finds Her Child’s Rare Illness Stems From the Gene She Studies”. The article highlighted Dr. Soo-Kyung Lee who is an outstanding developmental biologist with expertise in neural development and works on FOXG1, a gene that was found to be mutated in her daughter who have been suffering from an undiagnosed neurologic condition. Another example of a ‘Scientist-Patient family member’ is Dr. Liqun Luo, a renowned neuroscientist at Stanford University who published a paper on RAI1 in 2016, the causative gene for Smith-Magenis Syndrome that affects his daughter (4).

We feel that the undiagnosed disease research community can learn many things from these physicians and scientists who have underwent diagnostic odyssey for themselves and for their loved ones. By developing better bridges for communication and collaboration based on the experiences of these ‘interdisciplinary’ individuals, advancements in research, disease management and treatment for rare and undiagnosed conditions will be facilitated, mutually benefitting the patient, clinical and scientific communities.


1. Elmore, S.N.C. (2018) p53 and Me. N Engl J Med, 378, 1962-1963.

2. Dolgin, E. (2017) The most popular genes in the human genome. Nature, 551, 427-431.

3. Lupski, J.R., Reid, J.G., Gonzaga-Jauregui, C., Rio Deiros, D., Chen, D.C., Nazareth, L., Bainbridge, M., Dinh, H., Jing, C., Wheeler, D.A. et al. (2010) Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy. N Engl J Med, 362, 1181-1191.

4. Huang, W.H., Guenthner, C.J., Xu, J., Nguyen, T., Schwarz, L.A., Wilkinson, A.W., Gozani, O., Chang, H.Y., Shamloo, M. and Luo, L. (2016) Molecular and Neural Functions of Rai1, the Causal Gene for Smith-Magenis Syndrome. Neuron, 92, 392-406.

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