By: Meagan Collins

A new study suggests that GRIN Disorder might not be quite as rare as previously thought. This information could hypothetically put the number of people living with GRIN Disorder around the world at well over 1 million.

CureGRIN had previously used an estimate of 5,000 to 10,000 GRIN Disorder cases in the United States, which would have put the estimated global total at no more than 250,000. 

Most GRIN patients have what is known as a de novo (‘new’) gene variant. This means that the change in a GRIN patient’s genes happened by chance and the condition was not inherited from either parent. The most common variants in GRIN patients are missense variants. These variants result in one letter of DNA getting switched out for a different one. This de novo missense variant in one of the GRIN genes results in GRIN Disorder, which are characterized by a variety of different neurodevelopmental symptoms, such as developmental delay, intellectual disability, and epilepsy. 

Recently, an article was published by López-Rivera and colleagues in the scientific journal Brain using different tools to predict the incidence, or the number of cases of a factor disease during a given period of time in a population, of neurodevelopmental disorders. In the article, “A catalogue of new incidence estimates of monogenic neurodevelopmental disorders caused by de novo variants”, the researchers predicted the incidence of 101 known monogenic (involving only one gene) neurodevelopmental disorders and 3,106 suspected monogenic disorders. These rare disorders, many of which are subtypes of conditions such as epilepsy and autism, are caused by de novo variants. To do these analyses, the researchers used a statistical approach. They made estimates of the incidence of each gene by using data from public databases, genetic testing results, and epidemiological incidence estimates from numerous research articles. 

Dr. Johannes Lemke, a member of CureGRIN’s Scientific Advisory Board, published a commentary on this article in the same issue of Brain, “Predicting incidences of neurodevelopmental disorders“, discussing the findings. Using the algorithm of López-Rivera and colleagues, Dr. Lemke calculates that GRIN Disorders due to variants in either GRIN1, GRIN2A, GRIN2B or GRIN2D occur in one out of every 5,208 births (19.2 per 100,000). 

Dr. Lemke says that there are some biases within the López-Rivera and colleagues’ method including overestimation and higher incidence predicted for some genes. For example, if a genetic variant results in death before birth, the incidence estimates might be too high because those individuals might not be included in genetic and clinical screenings of living patients. Additionally, if the symptoms from a variant in a particular gene are more mild-to-normal, then the predicted incidence according to this new algorithm may be underestimated.

For GRIN1-related Disorder, the predicted incidence per 100,000 births is 5.45, meaning that out of every 100,000 babies born, roughly 5 babies would have a de novo variant in GRIN1. There were 3,791,712 babies born in the U.S. in 2018, and using the prediction model, this would mean that 207 babies born would be predicted to be affected with a variant in GRIN1 in the U.S. in 2018.

For GRIN2A-related Disorder, the predicted incidence per 100,000 births is 3.23. Therefore, out of every 100,000 babies born, roughly 3 babies would have a de novo variant in GRIN2A. Using the prediction model, the predicted number of affected babies with a variant in GRIN2A born in the U.S. in 2018 is 122. GRIN2A-related Disorder is likely significantly underestimated because these numbers do not capture individuals without intellectual disability, who are estimated to make up more than a third of the GRIN2A patient population.

For GRIN2B-related Disorder, the predicted incidence per 100,000 births is 5.91, meaning that out of every 100,000 babies born, about 6 babies would have a de novo variant in GRIN2B. By using the prediction model, the number of affected babies predicted to have a variant in GRIN2B born in the U.S. in 2018 is 224. GRIN2B-related Disorder appears to have the highest incidence among all GRIN-related disorders. 

For GRIN2D-related Disorder, the predicted incidence per 100,000 births is 4.61, meaning that out of every 100,000 babies born, about 4-5 babies would have a de novo variant in GRIN2D. Using the prediction model, the predicted number of affected babies with a variant in GRIN2D born in the U.S. in 2018 is 175. This finding appears to overestimate the prevalence of GRIN2D cases. After all, we know of fewer than 20 individuals living with pathogenic GRIN2D variants. One possible explanation is that GRIN2D may be less tolerant, with fewer embryos surviving until birth, Dr. Lemke said.

Though Dr. Lemke finds some limitations in the López-Rivera and colleagues research, he says that this statistical method will be a useful tool until we have larger epidemiological studies on rare disorders available.