In her obituary, Laura Tandy’s family remembered her as a young woman who wasn’t defined by her rare disease.
“Her most defining features weren’t disability related,” her mother, Patricia Tandy, wrote. “A feisty determined nature, a full engagement with life, a strong intuitive facility, and an ability to engage with those who cared for her were her strongest characteristics.”
Her health problems included severe intellectual disability, delayed development, and behavioral and communication problems. All were due to a genetic disorder called 1p36 deletion syndrome.
But it was cardiomyopathy, another complication of this syndrome, that ended Laura’s life in 2009. Her heart had just one-third of the function of other people. At 23, Laura suffered a heart attack and entered a hospital in Melbourne, Australia, for the first time since infancy. She died there 14 weeks later.
Now, a small nationwide study, conducted in conjunction with University of Utah Health scientists, suggests that 1p36 patients who lack a key genetic component in their heart cells are at greater risk of dying of cardiomyopathy, a disease that enlarges and thickens the heart muscle, making it harder to pump blood throughout the body.
The study appears in Circulation: Genomics and Precision Medicine.
“It appears that individuals with 1p36 deletion syndrome who have PRDM16 deficiency are at significant risk of developing cardiomyopathy and congenital heart defects,” says Sihem Boudina, Ph.D., an associate professor in the Department of Nutrition & Integrative Physiology at the University of Utah College of Health. “Their hearts don’t work at a very high capacity. Interestingly, we found this trait was particularly prevalent among women.”
1p36 Deletion Syndrome Explained
About one in every 5,000 infants born worldwide each year are born with 1p36 deletion syndrome. Fewer than 200,000 people in the United States are living with this disorder, according to the Genetic and Rare Disease Information Center at the National Institutes of Health.
Most cases of 1p36 deletion syndrome are not inherited. They result from a chromosomal deletion that occurs as a random event during the formation of reproductive cells (eggs or sperm) or in early fetal development. There is no cure. However, reports suggest many of those who have 1p36 deletion syndrome can live into early adulthood, Boudina says.
The syndrome can manifest itself in many ways, including seizures, the inability to form words or phrases, and hearing problems. About one in four children with the syndrome also develop cardiovascular problems, including cardiomyopathy.
Previous research suggests some patients who have 1p36 deletion syndrome lack a gene called PRDM16. This gene produces a protein that helps maintain the structure and function of heart cells and other body tissues. Without it, these individuals are more susceptible to cardiomyopathy.
Missing Gene Increases Risk of Cardiomyopathy
Digging deeper, Boudina and her colleagues conducted one of the largest retrospective studies of 1p36 deletion syndrome patients to date. Of the 66 patients they studied, they found that 38% of those who lacked PRDM16 developed cardiomyopathy versus 8% of 1p36 patients who had the gene. Half of the 1p36 patients who lacked PRDM16 were more likely to receive beta blockers and other heart medications than those who had the gene.
Among those who had PRDM16 missing, 35% of women had cardiomyopathy compared to about 17% of men. Women who didn’t have PRDM16 also had a greater risk of death from heart disease than a similar group of men who had 1p36 deletion syndrome.
Mice Offer Additional Clues
In a separate set of studies, Boudina and her colleagues at U of U Health determined that mice lacking PRDM16, specifically in cardiac cells, were more likely to have scarring (fibrosis) of their cardiac muscle than mice who had a functioning form of the gene. As a result, they concluded that PRDM16 prevents fibrosis in heart muscle and plays a critical role in maintaining heart health. Boudina also observed similar sex-related differences in male and female mice that were found in humans.
“It’s imperative that cardiologists in clinical practice be aware of this and pay extra attention to these patients and, if necessary, adjust their care as needed.”
Although the researchers don’t yet know why these differences exist, Boudina suggests doctors should be diligent about screening girls and women with 1p36 deletion syndrome for PRDM16.
“The bottom line is that people with 1p36 deletion syndrome who have lost PRDM16 are at a much higher risk of cardiomyopathy and subsequent death, or the need for a heart transplant or a ventricular assisted device,” Boudina says. “It’s imperative that cardiologists in clinical practice be aware of this and pay extra attention to these patients and, if necessary, adjust their care as needed.”
In addition to Boudina, University of Utah Health scientists Amir Nima Fatahian, Omid MT Rouzbehani, and Marissa Hathaway participated in this study. Researchers from Duke University School of Medicine, University of Tennessee Health Sciences Center, Baylor College of Medicine, Baylor Genetics Laboratories, and Northwestern Feinberg School of Medicine also contributed to the research.
The study, “PRDM16 deletion is associated with sex-dependent cardiomyopathy and cardiac mortality: A translational, multi-institutional cohort study,” appears in Circulation: Genomics and Precision Medicine.
- Doug Dollemore