Rare genetic diseases can be difficult for doctors to recognize, particularly when the symptoms of a disease fall short of dramatic, telltale manifestations described in a textbook.

While there’s a tendency to think that a person either has a genetic disease or they don’t, the reality may be that these diseases exists across a spectrum.

In the case of recessive genetic diseases—those that require that both parents pass on the same genetic mutation to their offspring for them to develop a given condition—the ill-effects of a mutated version of a gene from one parent may only be muted by a normal version of the same gene from the other parent but still cause some level of disease. It is also possible that one variant of a gene may cause a less severe version of a disease than a variant known to cause a given condition.

A new study from researchers at Vanderbilt University Medical Center suggest people with a variety of common ailments, such as heart failure, respiratory disease, infertility, or kidney disease, may actually have an undiagnosed rare monogenic disease driving their conditions.

The study, published in the March 15 edition of the journal Science, examined the electronic health records of more than 21,000 patients. The researchers developed a means of scouring a set of electronic health records and assigning what they termed a “phenotypic risk score” based on the clinical manifestations of patients’ conditions against the phenotypes of more than 1,200 Mendelian diseases. The researchers than examined whether patients with high phenotypic risks scores for a Mendelian disease shared any rare genetic variants.

Individuals for the study were drawn from BioVU, a large repository that links DNA samples to de-identified electronic health records. The team then replicated their results at a second biobank at the Marshfield Clinic and confirmed them through tests in labs at Vanderbilt University Medical Center and the University of Oklahoma.

The findings were surprising. Of the 21,701 patient records the researchers analyzed, 807 patients were found to have associations between 18 genetic variants and high phenotype risk scores. Some of these variants were well known to geneticists, such as two variants that cause cystic fibrosis, but most of the associations were for variants that had not previously been identified. Of the 807 patients the researcher discovered had an underlying genetic variant to explain their symptoms, only eight had been diagnosed by their doctors to have a Mendelian disease. The rest had been misdiagnosed or never diagnosed.

“What the phenotype risk score shows us is that if you start with specific combinations of symptoms, the chances of finding a potentially causative genetic variant are pretty high,” said co-author Dan Roden, senior vice president for Personalized Medicine. “This is a really important step to using clinical genotyping to assess patient risk and inform more precise prevention and treatment of common conditions.”

The study is provocative on several levels. It not only makes the case for the importance of matching phenotype to genotype, but the approach the researchers developed to review large groups of electronic health records to score patients who may have a rare genetic condition could be used more broadly to help identify patients who are misdiagnosed or undiagnosed.

It suggests that rare diseases may be more common than currently believed today. The data set the researchers used, when considered in terms of the large sets of electronic health records are genetic information that are being established, could lead to a more substantial discovery of people with medical condition related to underlying monogenic diseases.

And while the study didn’t consider whether such an approach could ultimately lead to better outcomes for patients, it is not hard to imagine that finding an underlying genetic explanation for a medical condition could provide new avenues for treatments that slow or halt the progression of a condition for patients in cases where the rare disease has therapeutic alternatives.

For instance, the study found that 14 percent of the patients with a genetic variant for primary hyperoxaluria, a condition affecting the kidneys had kidney transplants. In another instant, the researchers found that of the patients with a variant associated with hemochromatosis, a condition affecting the liver, 10 percent of those patients underwent liver transplants. It would be worth investigating whether using existing treatments for these condition could mitigate the need for transplants in this group of patients.

“I don’t pretend to think this phenotypic score can do it on its own,” she said. “It’s just one more line of evidence,” said Lisa Bastarache, lead data scientist with Vanderbilt’s Center for Precision Medicine and lead author on the Science paper, who said learning more about these rare variants can help solve more undiagnosed patients and potentially allow for more tailored interventions.

“The ultimate goal and the most exciting goal is to think about how to take this information back and impact clinical care,” said Bastarache. “If there are individual that have a monogenic disease and they are not diagnosed, if knowing that information could either give them more information about their prognosis or change their treatment, that’s something we want to explore. Use this method to find individuals who can benefit from genetic testing.”

March 21, 2018
Photo: Lisa Bastarache, lead data scientist with Vanderbilt’s Center for Precision Medicine, and Josh Denny, professor of Biomedical Informatics and Medicine and director of the Center for Precision Medicine (photo by john Russell)