Northwestern Medicine scientists have characterized several variants of the gene GRIK2 that cause nonsyndromic neurodevelopmental disorder (NDD), according to a study published in the American Journal of Human Genetics.

These findings add two new genetic variants to a growing list of glutamate receptor mutations that can cause neurodevelopmental disorders, according to Geoffrey Swanson, PhD, professor of Pharmacology and senior author of the study.

When new variants are reported, they are incorporated into bioinformatics analyses. It's like a snowball effect — the more variants are reported, the more likely it will be picked up in new patients."

Geoffrey Swanson, PhD, Professor of Pharmacology, Northwestern Medicine

GRIK2 codes for one member of a family of kainate receptors (KARs), which are glutamate-gated ion channels that help maintain the excitatory and inhibitory balance in the brain. Previous research has shown that bi-allelic loss of function mutations in GRIK2 can cause NDD, but little was known about mono-allelic variants and their relationship to neurodevelopmental disorders.

In the current study, investigators reported on 11 individuals with de novo, mono-allelic mutations in GRIK2. Six individuals had a previously reported variant — a guanine-to-adenine point mutation — and five individuals had related but new variants.

Importantly, patient phenotypes were similar among those individuals with identical variants but exhibited substantial differences from patients with distinct variants. For example, some patients with the newly-discovered variant had what appeared to be the beginnings of neurodegeneration, evidenced by white matter abnormalities that intensified over time. These variants, while close in genetic distance, can have a substantial impact on severity or character of NDD, according to Swanson.

"These subtle differences really can have a massive consequence on the outcome of the kids," Swanson said.

Characterizing the specific variants and their phenotypes is valuable, as these findings will be added to databases for rare genetic diseases, according to the authors. This can help clinicians and families understand their child's condition and possible trajectory.

"These databases are important so neurologists around the world can compare notes about patients, what parents can expect and any possible treatments if they become available," Swanson said.

In the future, Swanson said he hopes to explore more GRIK2 variants that could cause NDD, and create platforms to better study the complex neural circuitry that these mutations affect.

"In order to really understand what’s going on at the level of synapses or circuits, we need to model those circuits and see how GRIK2 affects systems such as neuronal excitability," Swanson said.