Rare Daily Staff

Though for many rare genetic diseases it may be easy to pinpoint an individual’s risks, their heterogeneous nature makes it hard to predict how severe they may be in any one patient.

A new study by researchers at the health system Geisinger considers the variability of severity of symptoms caused by a genetic disorder from patient to patient in 11 rare diseases. The study was published in Nature Communications.

“The findings open the door to improving how physicians manage and treat genetic diseases,” said David Ledbetter, 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 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 researchers said the use of polygenic scores could improve risk stratification, predict clinical severity, and help guide preventive care recommendations from growth hormones to lipid-lowering medications.

The team relied on electronic health records and DNA sequence data of more than 92,000 patient-participants in MyCode, Geisinger’s community health initiative. Geisinger said it represents 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 typically 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 diagnosis may be delayed as a result.

“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, lead author on the study. “These findings are likely to speed the momentum of genetic analysis in clinical care.”

Photo: David Ledbetter, study author and chief scientific officer of Geisinger

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