Improved Resolution of Disease Phenotypes With Multilocus Genomic Variation Interview with:
Jennifer E Posey MD, PhD

Assistant Professor
Department of Molecular and Human Genetics
Baylor College of Medicine

Tamar Harel MD, PhD
Clinical Genetics Academic Research Fellow
Department of Molecular and Human Genetics
Baylor College of Medicine

Current affiliation:
Department of Genetic and Metabolic Diseases
Hadassah-Hebrew University Medical Center
Jerusalem, Israel What is the background for this study? What are the main findings?

Response: As physician scientists and geneticists, our goal is to understand how genetic variation in each of us can impact health and disease. Physicians are often taught that the simplest explanation for a medical condition is the most correct explanation, and have historically searched for a single unifying diagnosis. However, in our own practice, we have met – and learned from – individuals who have more than one genetic condition affecting their health.

In the past, it was difficult for physicians to diagnose such individuals. Genetic testing required a physician to recognize the potential for more than one genetic diagnosis in an individual. Single-gene and gene panel testing provided an additional barrier to accurate diagnoses, as they are more narrow in scope, and more than one molecular test was often needed to identify all conditions. Targeted testing also required a physician to accurately pre-suppose which combination of genetic conditions was most likely, and choose the correct targeted tests.

The clinical availability of whole exome sequencing (WES) has removed these barriers: WES is a broad-based, unbiased analysis of an individual’s genetic variation that does not pre-suppose a specific genetic cause. If analysis is pursued systematically, WES can identify more than one genetic diagnosis in an individual, even when not suspected.
In our study, we have been able to assess the frequency with which individuals can have more than one genetic diagnosis, and have begun to understand how genetic variation at more than one place in the genome can affect how a condition may present. We found that among 7,374 individuals referred for WES, 2,076 (28%) had a molecular diagnosis. Of these 2,076, 5% had two, three, or four molecular diagnoses. In our analyses of the clinical features that may be observed in an individual with two genetic conditions, we found that pairs of diagnoses with overlapping clinical features may be incompletely diagnosed as having one or the other condition, and pairs of diagnoses with very distinct clinical features may be erroneously diagnosed in the clinic as having an entirely new condition. What should readers take away from your report?

Response:It is important for physicians to consider that many individuals presenting with a condition may have more than one genetic diagnosis – unbiased testing, such as WES, is the best approach to diagnosing these cases. The diagnoses can have either distinct or overlapping features, and can be modeled computationally. What recommendations do you have for future research as a result of this study?

Response: In our analyses, we used a structured framework of clinical features, the Human Phenotype Ontology, to computationally model the interplay between sets of clinical features that can result from more than one genetic diagnosis. As our knowledge of the genetic basic of disease continues to grow, we will need to rely increasingly on bioinformatic tools that enable us to study clinical and genetic data in an integrated fashion. The field of Precision Medicine will benefit directly from continued research and development of such tools. Is there anything else you would like to add? Any disclosures?

Response: Baylor College of Medicine (BCM) and Miraca Holdings Inc. have formed a joint venture with shared ownership and governance of the Baylor Genetics (BG) Laboratories, which performs clinical exome sequencing. Drs. Posey and Harel were employees of Baylor College of Medicine during the time of the study.


Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation
Jennifer E. Posey, M.D., Ph.D., Tamar Harel, M.D., Ph.D., Pengfei Liu, Ph.D., Jill A. Rosenfeld, M.S., Regis A. James, Ph.D., Zeynep H. Coban Akdemir, Ph.D., Magdalena Walkiewicz, Ph.D., Weimin Bi, Ph.D., Rui Xiao, Ph.D., Yan Ding, M.D., Fan Xia, Ph.D., Arthur L. Beaudet, M.D., Donna M. Muzny, M.S., Richard A. Gibbs, Ph.D., Eric Boerwinkle, Ph.D., Christine M. Eng, M.D., V. Reid Sutton, M.D., Chad A. Shaw, Ph.D., Sharon E. Plon, M.D., Ph.D., Yaping Yang, Ph.D., and James R. Lupski, M.D., Ph.D., D.Sc.
N Engl J Med 2017; 376:21-31January 5, 2017DOI: 10.1056/NEJMoa1516767

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

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Last Updated on January 9, 2017 by Marie Benz MD FAAD