Studies combine genetic testing, electronic health records to find undiagnosed diseasesApr. 28, 2022, 10:08 AM
by Leigh MacMillan
Combining genetic testing with information from electronic health records can reveal undiagnosed heart rhythm disorders and new conditions associated with inherited cancer gene mutations, according to a pair of recent studies.
The findings add support to the growing use of genetic information in clinical care, said Dan Roden, MD, Senior Vice President for Personalized Medicine at Vanderbilt University Medical Center, and senior author of the arrhythmia study published in the journal Circulation.
The new reports draw on data from the eMERGE (Electronic Medical Records and Genomics) network, a national consortium organized and supported by the National Human Genome Research Institute, part of the National Institutes of Health. VUMC has served as both a network site and the national coordinating center since eMERGE started in 2007.
For the latest studies, eMERGE recruited nearly 25,000 people across 10 network sites and sequenced a custom panel of 109 genes. The goal, Roden said, was to identify people with unrecognized Mendelian diseases (diseases resulting from mutation of a single gene) and return that information to them.
Overall, the consortium found that about 3% of participants had a disease-associated pathogenic or likely pathogenic (P/LP) variant in one of the genes.
“The questions we asked were: how many people — who had no previous indication for cardiac genetic testing — had pathogenic or likely pathogenic variants; and how many of those people actually had a phenotype in the electronic health records?” Roden said.
Among 21,846 participants, they found that 120 (0.6%) had P/LP variants in the arrhythmia-associated genes. In the analysis of electronic health records, they found a higher percentage of arrhythmia phenotypes in individuals with P/LP variants, compared to those without the variants.
The team was able to return results to 54 participants and, with clinical follow-up, make 19 diagnoses of inherited arrhythmia syndromes.
In addition to the P/LP variants, the researchers found that 1,838 individuals (8.4%) had “variants of uncertain significance” (VUS) in an arrhythmia-associated gene. VUSs pose a challenge to genomic medicine, Roden said, because their contribution to disease is unknown.
Overall, VUS carriers did not have more electronic health record arrhythmia phenotypes compared to non-carriers, but 116 VUSs occurred in at least one participant with an arrhythmia phenotype. The researchers selected 50 of these VUSs to study in vitro using high-throughput patch clamp electrophysiology (to assess the effects of the variant on protein function). They were able to reclassify 11 variants: three to likely benign and eight to P/LP.
Another study, published in JAMA Oncology and led by Chenjie Zeng, PhD, MPH, and Joshua Denny, MD, at NHGRI, explored the spectrum of diseases associated with inherited cancer syndromes using data from eMERGE and two other large cohorts.
The researchers, including Lisa Bastarache, MS, Georgia Wiesner, MD, and others at VUMC, conducted a phenome-wide association study to find electronic health record phenotypes associated with P/LP variants in 23 hereditary cancer genes. In addition to replicating established gene-cancer associations, they identified 19 new associations: seven for different cancers and 12 for conditions including ovarian cysts, acute pancreatitis and chronic gastritis. The findings could facilitate early detection and better management of cancers, the researchers noted.
“The take-home message is that 3% of people will carry a pathogenic or likely pathogenic variant in a disease-causing gene and many others will carry variants of uncertain significance,” Roden said. “We can use genetic testing, electronic health record phenotypes, and in vitro technologies to evaluate and find people who have unrecognized genetic disease and save lives by making earlier diagnoses.”
Roden, who holds the Sam L. Clark, MD, PhD Endowed Chair, is professor of Medicine, Pharmacology and Biomedical Informatics, and director of the John A. Oates Institute for Experimental Therapeutics. Glazer is assistant professor of Medicine and Davogustto is instructor in Medicine. The research was supported by grants from the NIH and American Heart Association.