Genetic counseling aids in developing treatment plans for patients with inherited retinal diseases (IRDs). Ocular genetics, however, is highly complicated, and terms used to describe a range of functionalities can produce more confusion than clarity when mining the literature for guidance. Such is the case with the term hypomorphic variant.
Toblin B.T. Thuma, DO, and colleagues sought to identify the challenge of using hypomorphic as a descriptor in genetic counseling for IRDs. Their study’s findings were published in Survey of Ophthalmology. Dr. Thuma spoke with PW about the study’s implications.
PW: Why is hypomorphic variation important to study in IRDs?
Dr. Thuma: We think of Mendelian genetics as being autosomal, dominant, or recessive —kind of like a one or zero paradigm. But hypomorphic is somewhere in between. If you have a loss of function in an allele that is hypomorphic, that loss might be 50%, it might be 30%, or it might be 70%. Hypomorphic can be anywhere in the gray zone, and it’s difficult to quantify for so many variants. There are not enough resources to do a full in vivo study on each variant.
Why is clarification of the term “hypomorphic variant” needed?
One of my colleagues, Rebecca A. Propcopio, MS, LCGC, is a genetic counselor who deals directly with these patients. In my conversations with her, she told me it’s difficult to incorporate this term because what does it really mean? Is it a strong loss of function, or is it a weak loss of function? How clinically significant might it be? If a research group uses the term hypomorphic, what do they specifically mean? This is often unclear, and it is difficult to counsel patients. To put it simply, there’s a knowledge gap.
It is, therefore, difficult to explain to patients what will happen with their disease process and what they should expect because we don’t know in many cases. It’s not black and white. Despite a patient’s understandable eagerness to have answers, we sometimes have to wait and see how the disease progresses. This can leave the patient and the provider frustrated. We want to treat the condition appropriately and prevent things from getting worse, but we are often left with ambiguity. We don’t have enough prognostic tools at our disposal.
How can physicians apply these findings to improve the care of IRDs?
I think we should have some grace with ourselves and acknowledge that we may not have a definitive answer when something is described as hypomorphic. The application of the term doesn’t always provide a clear pathway to understanding where the disease will fall on the spectrum.
In terms of pharmacology, it’s important to know the amount of protein function if you have a hypomorphic variant. This information can determine if a drug will be effective or if the drug is even indicated at all. Given that the cost of some of these prescriptions is high, knowing whether they are appropriate is important. Will it help your patient or benefit a patient with a more severe disease state? An increase from 70% to 90% protein functionality may be a big clinical difference for the patient. This is why clarifying the term hypomorphic is important to pursue.
What should researchers focus on in the future?
There are exciting frontiers in the future in terms of using artificial intelligence and machine learning to explore some of these things. We could achieve a better understanding of what the resultant protein might be, how functional it might be, and what the implication of this is regarding a patient’s disease. Developing those tools will be helpful to counsel patients and perhaps predict their disease process with better precision.
Drug development and the application of these drugs would also be positively impacted because of clearly defined hypomorphic parameters. So, I think we have a lot to do. We already know a great deal, but there is a great deal more to discover. It’s an exciting time. And although it’s going to take a great deal of effort, the possibilities are encouraging.
