ExAC: Revolutionizing Rare Disease Diagnosis

ExAC: Revolutionizing Rare Disease Diagnosis

Hiding in the genomes of the average person are nearly 54 mutations that look as if they should sicken or even kill their bearer. Some do, and some don’t. This is what makes finding the exact cause of a rare disease so difficult. In 2010, Vallabh witnessed her mother die from a rare illness called fatal familial insomnia, in which misfolded prion proteins cluster together and destroy the brain. The following year, Vallabh tested positive for the prion-protein gene, PRNP, with the identical genetic mutation that was hypothesized to have caused her mother's illness.1 This seemed like a sure death sentence; however, she was determined to figure out what this mutation really meant. Was it really responsible for her mother's death and could it lead to hers?


“Hiding in the genomes of the average person are nearly 54 mutations that look as if they should sicken or even kill their bearer.”

Few would have thought to ask such a question in years past, but now, with the creation of the largest genetic database in history, the Exome Aggregation Consortium, or ExAC, Vallabh and the millions of others sufferers with rare genetic mutations may finally get to understand the true impact of these mutations.2,3 As rare diseases can be caused by a single genetic variation that results in life-threatening outcomes, it is up to researchers to identify the exact genetic mutation underlying a patient’s condition.4 To determine what genetic variant might be the cause, patients undergo a genetic analysis in comparison to a standard DNA database. These databases contain a huge variety of genetic variations that are not only essential for the understanding of human population biology, but also in providing critical resources for the clinical diagnosis of patients with rare diseases.4,5


“Within little over a month, ExAC has already overturned decades of scientific work and revolutionized rare disease diagnosis.”

Before 2013, the available datasets of human DNA sequences were too small, lacking substantial diversity.1 Although this may not appear to have been a severe injustice to those diagnosing and being diagnosed with rare diseases, it was. Without a large enough database to compare a patient’s DNA code to, misdiagnoses were all too common. Fortunately, in August of 2016, scientists at the Broad Institute of MIT and Harvard released the first publication of the largest catalogue of human genetic variants: ExAC.2,3 Its unparalleled size offered important insights into rare genetic variations across an enormous set of diverse populations. Created in 2013, ExAC showcases DNA from over 60,000 people, with over 7.4 million variants, most of them brand new (78% had never been observed in a previous database) and documents the first findings of many rare mutations.3 Within little over a month, ExAC has already overturned decades of scientific work and revolutionized rare disease diagnosis.


“Before ExAC, 80% of rare disease patients visited more than seven doctors before their condition was accurately determined, and nearly one-third of patients received more than three incorrect diagnoses.”

Preceding the release of ExAC, rare disease misdiagnoses were countless.6 With insufficient DNA data to compare patient DNA to, genetic variants that were normal in healthy individuals were sometimes rare in the small database, falsely linking these variants to a disease. Shockingly, since ExAC’s release, the causes of 126 rare diseases have already been reclassified.2 A recent study elucidated this phenomenon and the impact that ExAC has already made.6 The paper focused on the rare inherited disease hypertrophic cardiomyopathy, which alters the size of the heart and its ability to pump blood around the body. The researchers uncovered that seven patients had been told they carried the DNA mutation linked to the life-threatening heart disease, which ExAC has now classified as benign. With seven of the patients being of African ancestry, the lack of DNA representation from populations of African descent in the previous databases made this variant seem rare, causing this misdiagnosis. If there had been proper ethnic representation in the databases, the doctors wouldn't have drawn the wrong conclusion. Sadly, this misdiagnosis did not only hinder the lives of the diagnosed patients, but their family members as well. Since hypertrophic cardiomyopathy is strongly linked to genetic inheritance, the family members had undergone risk assessments and preventative measures for the false diagnosis, demonstrating the impact that false leads have on both the patients and their loved ones.6


“With approximately 50% of rare diseases lacking specific charity support or research into their rare disease, ExAC has brought new hope to the nearly three million people in Canada suffering from a rare disease.”

The authors of the study revealed that the problem they uncovered is unlikely to be limited to hypertrophic cardiomyopathy.6 “We believe that what we’re seeing in the case of hypertrophic cardiomyopathy may be the tip of the iceberg of a larger problem that transcends a single genetic disease,” said the first author of the study, Arjun Manrai, PhD (Harvard).7 With the release of ExAC, the uncovering of misdiagnoses will only grow. With that, ExAC will also eradicate the previously long and traumatic wait for patients and their families to get a correct diagnosis. Before ExAC, 80% of rare disease patients visited more than seven doctors before their condition was accurately determined, and nearly one-third of patients received more than three incorrect diagnoses.8 Thus, through ExAC, researchers and doctors will be able to minimize these errors and provide patients and families with a true diagnosis more efficiently and accurately than ever before.


“The scale and diversity of the ExAC resource is invaluable. It gives us the ability to discover extremely rare variants and offers an unparalleled window into the roots of rare genetic diseases.”

As ExAC continues to impact the scientific field and the lives of thousands of patients with rare disease diagnoses, the research team has big plans to expand its database further.2,3 The scientists leading its creation hope to include another 120,000 genetic sequences by next year, all for public access.9 This expansion relies greatly on the cooperation of research institutions to share genetic information, investment from public and private sources, and increased awareness surrounding the importance of rare diseases and their diagnosis.9 With approximately 50% of rare diseases lacking specific charity support or research into their rare disease, ExAC has brought new hope to the nearly three million people in Canada suffering from a rare disease, and new insights into the possible causes of their conditions.10 By improving the early detection of these diseases and the accuracy of diagnoses, ExAC has paved the way for further research on rare diseases. As said by Dr. MacArthur, Co-director of the Program in Medical and Population Genetics at the Broad Institute, “The scale and diversity of the ExAC resource is invaluable. It gives us the ability to discover extremely rare variants and offers an unparalleled window into the roots of rare genetic diseases.”11


Works Cited:

1. Check Hayden E. Computer scientist makes prion advance. Nature. 2014. doi:10.1038/nature.2014.16047.

2. Song W, Gardner SA, Hovhannisyan H, et al. Exploring the landscape of pathogenic genetic variation in the ExAC population database: insights of relevance to variant classification. Genetics in Medicine. 2015;18(8):850-854. https://www.ncbi.nlm.nih.gov/pubmed/26681313.

3. Analysis of protein-coding genetic variation in 60,706 humans. 2015. http://www.nature.com/nature/journal/v536/n7616/full/nature19057.html.

4. Fu, W. et al. Analysis of 6,515 exomes reveals the recent origin of most human protein-coding variants. Nature. 2012;493, 216–220.

5. Li, H. & Durbin, R. Inference of human population history from individual whole-genome sequences. Nature. 2011;475, 493–496. http://www.nature.com/nature/journal/v475/n7357/full/nature10231.html.

6. The 1000 Genomes Project Consortium: A global reference for human genetic variation. Nature. 526, 68–74. https://www.ncbi.nlm.nih.gov/pubmed/26432245.

7. Husten L. CardioBrief: Imprecise medicine: genetic tests lead to misdiagnosis. Medical News. 2016. http://cardiobrief.org/2016/08/17/imprecise-medicine-genetic-tests-lead-to-misdiagnosis/.

8. Years of misdiagnosis for patients with rare diseases. Selina McKee. http://www.pharmatimes.com/news/years_of_misdiagnosis_for_patients_with_rare_diseases_981934.

9. Accurate diagnosis of rare diseases remains difficult despite strong physician interest. Global Genes. https://globalgenes.org/raredaily/accurate-diagnosis-of-rare-diseases-remains-difficult-despite-strong-physician-interest/. Published October 3, 2016.

10. Macarthur, D.G. Announcing the exome aggregation consortium paper. Macarthur Lab. https://macarthurlab.org/2016/08/17/announcing-the-exome-aggregation-consortium-paper/. Published August 17, 2016.

11. Catalogue of human genetic diversity expands. National Institutes of Health. https://www.nih.gov/news-events/nih-research-matters/catalog-human-genetic-diversity-expands. Published September 6, 2016.


Cite This Article:

McKee H., Zheng K., Chan G., Ho J. ExAC: Revolutionizing Rare Disease Diagnosis. Illustrated by M. Yi. Rare Disease Review. January 2017. DOI:10.13140/RG.2.2.32552.98561.

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