CENTER FOR FUNCTIONAL EVALUATION OF RARE VARIANTS (CFERV)

The overarching goal of the Center for Functional Evaluation of Rare Variants (CFERV) is to expand our understanding of the relationship between genetic variants and health consequences. Such understanding will lay the foundation for the design and execution of promising clinical trials of disease modifying therapies. A key hurdle in advancing our understanding is the lack of functional data that can be used to determine what impact the genetic variant has on cellular function and disease characteristics. CFERV will focus on filling this critical gap, and advance our understanding of both disease mechanism and therapeutic options. CFERV serves as a national clearing house for mutations in the glutamate receptor gene family (GRIN, GRIA, GRIK, and GRID), with the goal of providing experimental data on the functional consequences of each mutation. CFERV has clinical partners in all 50 states, as well as multiple international partners. These activities will catalyze more accurate diagnoses and suggest opportunities for applied precision medicine. The ultimate goal is to broaden the effort to include many gene families.

http://functionalvariants.emory.edu/

FREQUENTLY ASKED QUESTIONS

How do I get in contact with CFERV to get this testing done on my child?

Previously, we instructed parents to contact CFERV directly. As of 2021, this process has changed. We now ask that you enroll in the GRIN Variant Registry first. Once enrolled, your variant info will be forwarded to CFERV.

What is the specific process for testing a variant to determine if it is Gain or Loss of function?

We reproduce the genetic variant in plasmid cDNA that encodes the respective human glutamate receptor gene. This variant receptor is then expressed in Xenpous laevis (frog) oocytes.  Using conventional two-electrode voltage clamp electrophysiology we quantify four specific properties for each variant-receptor. These are: 1) sensitivity to activation by both L-glutamate (EC₅₀ values), 2) sensitivity to activation by glycine (EC₅₀), 3) sensitivity to inhibition by magnesium ions (IC₅₀), and 4) sensitivity to inhibition by lower pH (i.e., protons; %). Results for each property are compared to those from a wild-type (i.e., unchanged receptor) receptor, run the same day, to determine if the genetic variant results in a gain or a loss of function. We also measure cell surface expression levels of variant receptors.

Note:  If the gene variant is in the GRIN2A gene we also measure sensitivity to inhibition by zinc ions (IC₅₀) as this genes receptor subunit is particularly sensitive to zinc ions.

Can this functional testing be performed by other Research facilities?

Yes! We are working to gather the contact information for those facilities. Please continue to check our website for updates.