A new study on a significant cause of heart failure and sudden death raises questions about previously assumed genetic causes of this disease and may prevent potentially tragic outcomes due to incomplete genetic screening.
The disease is arrhythmogenic right ventricular cardiomyopathy (ARVC), an inherited heart muscle disorder where damaged heart muscle is gradually replaced by scar tissue and fat. ARVC often requires heart transplantation and can cause heart failure and sudden death, particularly in young people.
In a study published online February 2 (February 9 issue) in the Journal of the American College of Cardiology, researchers find that the genetic basis of ARVC is not related only to a single gene, known as PKP2, but may include multiple mutations in a single gene or in many genes at the same time – particularly those in "cell junctions” where cells are held tightly together. The Cincinnati Children’s Hospital Medical Center study also reveals that individuals known to carry a single mutated gene may show no clinical evidence of the condition.
"Cell junctions are the final common pathway for ARVC,” says Jeffrey A. Towbin, MD, executive co-director of the Cincinnati Children’s Heart Institute and senior author of the multicenter study. "This study has a significant impact on clinical genetic testing, as simple single-gene analysis, particularly for PKP2 alone, is too narrowly defined and the potential for inaccurate interpretation high. Furthermore, the moderate number of genes that encode for the primary working components of cell junctions strongly suggests that all genes in this pathway should be screened in all subjects.”
Towbin and his research colleagues identified 21 variants in PKP2 in 38 of 198 (19 percent) of those with ARVC and their families. Of those 38 subjects, nine had two or more mutations in the PKP2 gene, while mutations in additional desmosomal genes – those that form where two cells adhere – were identified in 16 of the 38 subjects with PKP2 mutations who were studied. In 14 of all 198 subjects, mutations occurred in non-PKP2 genes encoding cell junction proteins.
"Unless all genes are screened, individuals may have a non-disease-causing gene variant mistakenly assigned as disease-causative, and "at-risk” family members may be either mistakenly diagnosed with a causative mutation or inappropriately be given a negative result,” says Towbin. "In the latter case, this could lead to discharge from follow-up despite actually carrying a disease-causing mutation in another gene that wasn’t analyzed. This could lead to tragic outcomes.”
ARVC may cause abnormal electrical heart rhythms and weakening of the pumping action of the heart. In many cases, the disease does not limit the quality or duration of life. A proportion of people with ARVC, however, develop complications, all of which are treatable. Left untreated, sudden death may occur – particularly in young, healthy and athletic individuals. This is why evaluation and follow-up by a cardiologist knowledgeable about ARVC is recommended.
The study included researchers from Baylor College of Medicine, Houston; the University of Padua Medical School, Italy; Beth Israel Deaconess Medical Center, Harvard University, Boston; University of Rochester Medical Center, New York; Johns Hopkins School of Medicine and ARVD Program, Baltimore; and the University of Arizona, Tucson.
The study was funded in part by grants from the National Heart, Lung and Blood Institute of the National Institutes of Health.