Genomics: When Is It Putting the Cart Before the Horse?
Genomics in medicine has outpaced and surprised us all. When DNA was first isolated in 1869 and its structure identified by Watson and Crick in 1953, molecular biology had hardly been born. DNA was simply a series of nucleic acids arranged in base pairs, that could be replicated and transcribed, and somehow encoded the information that made every individual unique. The growth pace of molecular biology has been staggering; merely 50 years after Watson and Crick announced their discovery, the Human Genome Project was completed.
As anesthesiologists, we may feel that, unlike primary care physicians, we will not be responsible or involved in the care of patients who require genetic counseling for inherited diseases. The most visible genetic disorder affecting the practice of anesthesiology is the muscle disorder of malignant hyperthermia, whose autosomal dominant genetic predisposition has been associated with variations of the CACNA1S and RYR1 genes. The genetic coding for pseudocholinesterase deficiency also has been isolated (BCHE gene) and is currently being identified in large extended genetic screening panels being administered to pregnant patients. It is in this particular population that I have come to realize the liabilities and risks that accompany our rapidly advancing knowledge in genomics.
The ability to screen for hundreds of genetically controlled disorders is not a mandate to do so; it is an option, so long as we embrace the professional responsibility and ethical judgment to use the information properly.
There are many examples of genetic disease in cardiovascular medicine that we may see in our practices. As perioperative physicians and directors of the perioperative surgical home, we have the ability to diagnose illness and discuss treatments with colleagues. It is critical to note those disease states that are genetically defined and treatable so first order relatives of the affected individual can be tested. If a positive genetic test preempts the clinical manifestation of illness, preventative treatment options can be offered to relatives. This can be appropriate depending on the known penetrance of the gene, resultant phenotype, and morbidity of the disease in question. Common examples of this are mastectomy for the BRCA breast cancer gene and internal cardio-defibrillator placement for certain forms of cardiomyopathy.
How has the uptick in genetic screenings come to affect my practice? As an anesthesiologist with expertise in blood management, I have recently been consulted on the results of an egregious genetic testing practice in obstetric patients. Commercial genetic screens were once offered only to patients at increased risk; they are now offered to the population at large. These panels include hundreds of genetic tests for autosomal recessive diseases. For many of these diseases, the relationship between gene mutation and clinical expression of disease is variable, absent, or unknown, and it is difficult to know how the results of such tests should be used. One of the diseases on the panel is Factor XI deficiency, a rare deficiency that is more common in the Ashkenazi Jewish population (8%). There are now women presenting for labor and delivery who have a positive genetic test for Factor XI deficiency. In this condition, homozygotes and complex heterozygotes often present as bleeders and can be identified by a thorough history and testing.1 Heterozygotes can be, and often are, asymptomatic. They have no history of increased bleeding or bruising, have not bled during surgery, and have normal coagulation assays. Furthermore, genetic identity does not correlate with bleeding risk; factor XI level does not correlate with bleeding risk; and coagulation testing is unreliable.2 We have convened a multidisciplinary group of physicians to discuss management of these patients. For the management of maternal bleeding, expectant therapy and bleeding algorithms suffice and are promulgated. However, the next recommendation we will discuss is the volume of plasma they should be transfused before they are offered epidural analgesia! That’s right, allogeneic plasma transfusion for an asymptomatic patient whose genetic marker was randomly identified by a shotgun approach in expanded screening. Is this where the advances in molecular biology have led medicine? The American Congress of Obstetrics and Gynecology and the American College of Medical Genetics and Genomics (ACMG) have recommendations for genetic screening. They advocate screening for certain diseases such as cystic fibrosis and Tay Sachs. These diseases are either fatal in childhood or are associated with severely reduced life expectancy; thus, they fall into a category that defines them as severe enough to require reproductive decision making. ACMG also states that for each condition, the causative mutation frequencies should be known, and there must be a validated clinical correlation between the mutations detected and the severity of the disorder. This is clearly not the case for the Factor XI deficiency gene. This situation causes me great concern.
I am awed by the advancement of science and the strides we have made in molecular medicine. However, we have a responsibility to regulate how that knowledge is translated, contribute to appropriate decision making, and understand the ethical and personal implications for our patients.
- Martin-Salces M, Jimenez-Yuste V, Teresa Alvarez M, Quintana M, Hernandez-Navarro F. Review: Factor XI deficiency: review and management in pregnant women. Clin Appl Thromb Hemost. 2010;16:209-213.
- Gomez K, Bolton-Maggs P. Factor XI deficiency. Haemophilia. 2008;14:1183–1189