Study shows many common genetic factors determine severity of rare genetic diseases

DANVILLE, Pa., Oct. 29, 2019 /PRNewswire/ -- Geisinger today announced the release of a study about "variable expressivity," or how the severity of symptoms caused by a genetic disorder varies from individual to individual, in 11 rare diseases. The study was led by Geisinger researchers, Drs. Matt Oetjens, David Ledbetter and Christa Martin, and was published in Nature Communications on Oct. 25, 2019.

Collectively, rare genetic disorders are surprisingly common. From cystic fibrosis and sickle cell anemia to certain forms of obesity and breast cancer, almost every family can point to a genetic condition resulting in disease. Yet the severity of those diseases varies from individual to individual, even among members of the same family.

"The findings open the door to improving how physicians manage and treat genetic diseases," said David Ledbetter, Ph.D., study author and chief scientific officer of Geisinger. "By measuring genetic risk more accurately, we hope to improve prognosis and disease management for individuals with a rare genetic disease."

To understand why some people have mild symptoms of a genetic disease, while others with the same genetic condition have severe complications, the research team employed a powerful new tool called polygenic scores (PGS) that combine the effects of thousands to millions of common genetic differences. The team measured those effects to determine if common inherited genetic factors contribute to the degree and ways in which a genetic disease is expressed.

The team relied on electronic health records and DNA sequence data of more than 92,000 patient-participants in MyCode^TM, Geisinger's community health initiative, the largest such data set from a single healthcare system anywhere in the world. The program collects and sequences DNA from consenting patients to analyze their genetic risk for conditions that can be managed if identified and treated early, including hereditary heart disease and cancer.

Identifying more than 600 unrelated individuals with one of 11 rare genetic diseases that affect three clinical conditions — cholesterol levels, height, and weight — the researchers showed that polygenic scores can significantly modify the clinical symptoms of these diseases. For example, patients with Turner Syndrome, a chromosomal condition affecting females, are usually very short, a symptom usually clear by the age of 5. But those who happen to have extremely tall parents are likely to be taller, and so diagnosis may be delayed.

"This study shows that in many disorders caused by a single genetic change, like some forms of obesity, there is a wealth of genomic information beyond the primary cause that can meaningfully contribute to a patient's clinical severity," said Matt Oetjens, Ph.D., lead author on the study. "These findings are likely to speed the momentum of genetic analysis in clinical care."

The addition of polygenic scores in the clinical toolbox could improve risk stratification, predict clinical severity, and help guide preventive care recommendations from growth hormones to lipid-lowering medications. With this increased understanding of variable expressivity, the future of precision medicine is now more precise.

About Geisinger
Geisinger is committed to making better health easier for the more than 1.5 million people it serves annually. Founded more than 100 years ago by Abigail Geisinger, the system now includes 13 hospital campuses, a 600,000-member health plan, two research centers and the Geisinger Commonwealth School of Medicine. With 32,000 employees and 1,800 employed physicians, Geisinger boosts its hometown economies in Pennsylvania and New Jersey by billions of dollars annually. Learn more at geisinger.org or connect with us on Facebook, Instagram, LinkedIn and Twitter.

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