What is GRI?

GRI disorders are a group of genetic conditions associated with ionotropic glutamate receptors. This class of glutamate receptors are critical for neural communication, and changes in these receptors can be linked to various neurological disorders. These receptors are essential for learning and memory, along with other vital biological processes.

GRI disorders relate to genes called GRIA, GRID, GRIK or GRIN. They are commonly known by the gene name alone (e.g. ‘GRIN2B’).

Diagnosing GRI

Getting a diagnosis

There are many different journeys through diagnosis. GRI gene variants are ultra-rare and while there can be similarities between patients, variants manifest differently in each affected person – even if they are located in the same gene, only rarely will two patients have an identical variant or identical symptoms. Some children may have seizures or other health complications from the day they are born, heightening awareness that there may be an underlying genetic cause. For other children, they may develop typically until someone recognises they are not meeting the same milestones as children of the same age. And for some, they may have lived into adulthood with the disorder before having a test identifying the GRI variant later in life.

Even once symptoms appear, other more common conditions may need to be ruled out, and you may first be told that your child has ‘global developmental delay’ which is a broad term that is used by doctors when a specific cause hasn’t yet been found for the symptoms and missed milestones.

To get a GRI disorder diagnosis it is necessary for genetic testing to be conducted. The NHS is introducing whole genome sequencing, which is a single test that looks at many genes at the same time. To have genetic testing, you will need to be referred by a doctor such as a neurologist or a paediatrician. You may attend a specialist clinic before having genetic testing, where they will talk through your medical and family history and take samples from the patient and their family members. You should also be offered some information and guidance which can help you understand the risks and benefits, results and what they mean, what the impact may be and any options available. You may also be offered genetic counselling.

The NHS has a range of resources on genetic testing at https://www.nhs.uk/conditions/genetic-and-genomic-testing/ and organisations like the Genetic Alliance can provide more information about what’s involved in genetic testing (geneticalliance.org.uk).

So you have a GRI diagnosis, what next?

We are pleased that you have reached us at GRI-UK! We are here to help you navigate the complex world of having GRI or supporting someone with a GRI condition. If you have any questions, would like to support us, or just want to get in touch with other families in similar circumstances, get in touch.  

When you get your genetic diagnosis, you should receive a letter which outlines exactly what variant has been diagnosed. This should specify which gene is affected, what type of genetic ‘spelling mistake’ you have, and where exactly that is located within the gene. This information is very important for researchers and clinicians to understand how your individual variant disrupts the normal behaviour of glutamate receptors and may help them find the best treatment.

All of our genes are made up of thousands of letters of genetic code and sometimes one or more of these can get mixed up, swapped around or be completely missing, creating a range of variants. Any of these changes can cause the protein that is encoded by a gene (like glutamate receptors) to not work properly. The most common variants in GRI genes are ‘missense’ variants, where one letter of DNA is incorrect, which leads to one piece of the glutamate receptor protein being incorrect.

Some variants are shared amongst a few people, and some will be entirely unique to one person. As more people are diagnosed, we expect that more people will share the same variants.

If you or someone you care for has been diagnosed with a GRI gene disorder, start off by watching this great video on YouTube developed by the GRI registry. A lot of the information is relevant to all GRI variants. 

Patient Registries​

The world’s understanding of GRI conditions has moved forward rapidly in recent years and there are lots of people all over the world working hard on understanding the impact of variants and how cures and treatments might be possible for the different variants.
  
However, scientists can only do this with information such as what variants people have been diagnosed with, the characteristics and symptoms which people experience with their genetic variant and how a variant affects change at a molecular and cellular level.
 
At GRI-UK we encourage all patients to register their variants and their characteristics/symptoms. There are currently 2 complementary opportunities to do this:
 
 

  1. Through a short form and questionnaire in the GRI Registry. The GRI Registry can be found at the GRI(N) Portal – an interactive website for families, clinicians and researchers dedicated to comprehending GRI(N)-related disorders, it can be found at https://grin-portal.broadinstitute.org/.
  2. In August 2024, the CureGRIN Foundation launched the GRI Census, for our whole community. The census will remain open for anyone with a GRI variant to enter their information. It aims to collect baseline data from families to help advance the search for treatments and cures for GRI disorders. It is available in multiple languages and can be found at https://curegrin.org/gricensus.

 
 
Both these registries will contribute significantly towards providing the right levels of information on GRI worldwide, to help find cures and treatments.

Functional analysis

Functional analysis helps determine how a variant functions at a cellular and molecular level. How a variant functions is crucial to developing potential treatments and cures. Functional analysis identifies whether its function is too active (known as ‘Gain of Function’ or GoF variants), underactive (known as ‘Loss of Function’ or LoF variants), or a mix of both at any one time. Gain of Function (GoF) variants are variants which cause proteins in the cells to have a greater or different effect than typically functioning proteins. Loss of Function (LoF) variants change the proteins in the cells, so they have either less function than typical proteins or no function.

Helpful infographic link: ‘Gain of Function’ and ‘Loss of Function‘ explained

If you don’t know whether your variant, or that of the person you care for, is ‘Loss of Function’ or ‘Gain of Function’ check out the GRI Registry. The GRI Registry can be found at the GRI(N) Portal. It holds a database of all identified variants, which have been submitted by patients. Many variants have already been through functional analysis, so this is the best place to start.

At the moment, the information from functional analysis is not clinically actionable, but is necessary for clinical trials, research and natural history studies.

What is GRI

GRIA (GRIA1, GRIA2, GRIA3, GRIA4)

GRIA genes are a gene family that encode the subunits of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors in the brain. AMPA receptors are critical for fast synaptic transmission in the central nervous

Read More »

GRID (GRID1, GRID2)

GRID genes are a gene family which includes genes that encode the subunits of the delta glutamate receptors, which are less commonly understood receptors compared to the more widely known

Read More »