GENE GUIDE

GRIN1-Related Syndrome

This guide is not meant to take the place of medical advice. Please consult with your doctor about your genetic results and health care choices. This Gene Guide was last updated on 2024. As new information comes to light with new research we will update this page. You may find it helpful to share this guide with friends and family members or doctors and teachers of the person who has GRIN1-Related Syndrome.
a doctor sees a patient

GRIN1-related syndrome happens when there are changes to the GRIN1 gene. These changes can keep the gene from working as it should.

Key Role

The GRIN1 gene plays a key role in communication between brain cells, memory, and learning. The GRIN1 gene makes part of the NMDA receptor. The gene is called GRIN1, and the protein that makes up part of the NMDA receptor is called GluN1.

Symptoms

Because the GRIN1 gene is important for brain activity, many people who have GRIN1-related syndrome have:

  • Intellectual disability
  • Global developmental delay
  • Speech delay or absent speech
  • Seizures
  • Attention-deficit/hyperactivity disorder, also called ADHD
  • Inability to walk or movement issues
  • Autism
  • Sleep disruption
  • Poor feeding

GRIN1-related syndrome is a genetic condition, which means that it is caused by variants in genes. Our genes contain the instructions, or code, that tell our cells how to grow, develop, and work. Every child gets two copies of the GRIN1 gene: one copy from their mother’s egg, and one copy from their father’s sperm. In most cases, parents pass on exact copies of the gene to their child. But the process of creating the egg or sperm is not perfect. A change in the genetic code can lead to physical issues, developmental issues, or both.

Sometimes a spontaneous variant happens in the sperm, egg or after fertilization. When a brand new genetic variant happens in the genetic code is called a ‘de novo’ genetic variant. The child is usually the first in the family to have the genetic variant.

De novo variants can take place in any gene. We all have some de novo variants, most of which don’t affect our health. But because GRIN1 plays a key role in development, de novo variants in this gene can have a meaningful effect.

Research shows that GRIN1-related syndrome is often the result of a de novo variant in GRIN1. Many parents who have had their genes tested do not have the GRIN1 genetic variant found in their child who has the syndrome. In some cases, GRIN1-related syndrome happens because the genetic variant was passed down from a parent.

Autosomal dominant conditions

GRIN1-related syndrome is an autosomal dominant genetic condition. This means that when a person has the one damaging variant in GRIN1 they will likely have symptoms of GRIN1-related syndrome. For someone with an autosomal dominant genetic syndrome, every time they have a child there is a 50 percent chance they pass on the same genetic variant and a 50 percent chance they do not pass on the same genetic variant.

Autosomal Dominant Genetic Syndrome

GENE / gene
GENE / gene
Genetic variant that happens in sperm or egg, or after fertilization
GENE / gene
Child with de novo genetic variant
gene / gene
Non-carrier child
gene / gene
Non-carrier child

Why does my child or I have a change in the GRIN1 gene?

No parent causes their child’s GRIN1-related syndrome. We know this because no parent has any control over the gene changes that they do or do not pass on to their children. Please keep in mind that nothing a parent does before or during the pregnancy causes this to happen. The gene change takes place on its own and cannot be predicted or stopped.

Each family is different. A geneticist or genetic counselor can give you advice on the chance that this will happen again in your family.

The risk of having another child who has GRIN1-related syndrome depends on the genes of both biological parents.

  • If neither biological parent has the same genetic variant found in their child, the chance of having another child who has the syndrome is on average 1 percent. This 1 percent chance is higher than the chance of the general population. The increase in risk is due to the very unlikely chance that more of the mother’s egg cells or the father’s sperm cells carry the same genetic variant.
  • If one biological parent has the same genetic variant found in their child, the chance of having another child who has the syndrome is 50 percent.

For a symptom-free brother or sister of someone who has GRIN1-related syndrome, the sibling’s risk of having a child who has GRIN1-related syndrome depends on the sibling’s genes and their parents’ genes.

  • If neither parent has the same genetic variant causing GRIN1-related syndrome, the symptom-free sibling has a nearly 0 percent chance of having a child who would inherit GRIN1-related syndrome.

As of 2024, at least 128 people with GRIN1-related syndrome have been identified in a medical clinic. The first case of GRIN1-related syndrome was described in 2011.

People who have GRIN1-related syndrome may look different. Appearance can vary and can include some but not all of these features:

  • Smaller than average head size
  • Noticeable forehead
  • Upper jaw, cheekbones, and eye sockets that have not grown as much as the rest of the face

Scientists and doctors have only just begun to study GRIN1-related syndrome. At this point, there are no medicines designed to treat the syndrome. A genetic diagnosis can help people decide on the best way to track the condition and manage therapies. Doctors can refer people to specialists for:

  • Physical exams and brain studies
  • Genetics consults
  • Development and behavior studies
  • Other issues, as needed

A developmental pediatrician, neurologist, or psychologist can follow progress over time and can help:

  • Suggest the right therapies. This can include physical, occupational, speech, or behavioral therapy.
  • Guide individualized education plans (IEPs).

Specialists advise that therapies for GRIN1-related syndrome should begin as early as possible, ideally before a child begins school.

If seizures happen, consult a neurologist. There are many types of seizures, and not all types are easy to spot. To learn more, you can refer to resources such as the Epilepsy Foundation’s website: www.epilepsy.com/learn/types-seizures.

This section includes a summary of information from major published articles. It highlights how many people have different symptoms. To learn more about the articles, see the Sources and references section of this guide.

People with GRIN1-related syndrome may have one genetic variant in GRIN1 that causes the condition or two genetic variants on each copy of their GRIN1 gene.

For children with two GRIN1 genetic variants, where the parents had only one variant, the parents did not have any GRIN1-related syndrome medical findings. The information below includes people with one genetic variant in GRIN1 causing GRIN1-related syndrome or two affected GRIN1 genetic variants causing GRIN1-related syndrome.

Genetic variants in GRIN1 result in a gain of function, a loss of function, or a mixed function of the GluN1 protein. It is not always obvious how a change in the GRIN1 gene will affect the GluN1 protein. To better understand this requires further testing in the research laboratory.

Researchers are working to understand the differences between gain of function and loss of function GRIN1 variants. The information below includes both gain of function and loss of function variants.

Everyone with GRIN1-related syndrome had intellectual disability (ID), and many people did not have speech.

  • 90 out of 90 people had ID (100 percent)
  • 48 out of 89 people were non-verbal (54 percent)

The severity of ID varied among people:

  • 3 out of 77 people had mild ID (4 percent)
  • 5 out of 77 people had moderate ID (7 percent)
  • 69 out of 77 people had severe to profound ID (90 percent)
4%
3 out of 77 people had mild ID.
7%
5 out of 77 people had moderate ID.
90%
69 out of 77 people had severe to profound ID.

Behavior

Many people with GRIN1-related syndrome had behavioral challenges, such as autism or features of autism, self-injurious behavior, hyperactivity, and aggressive behavior.

  • 21 out of 89 people had autism or features of autism (24 percent)
  • 4 out of 62 people had self-injurious behavior (7 percent)

Brain

Many people with GRIN1-related syndrome had seizures. The age of seizure onset was between birth and 11 years old. The average age of onset was 22 months old. Some people had brain changes on magnetic resonance imaging (MRI) and a smaller than average head size, or microcephaly. Brain changes on MRI included defects in cortical development and cerebral atrophy (loss of brain volume).

  • 60 out of 89 people had seizures (67 percent)
  • 41 out of 89 people had brain changes seen on MRI (46 percent)
  • 20 out of 74 people had microcephaly (27 percent)
Human head showing brain outline
67%
60 out of 89 people had seizures.
46%
41 out of 89 people had brain changes seen on MRI.
27%
20 out of 74 people had microcephaly.

Mobility

People with GRIN1-related syndrome had movement disorders and lower than average muscle tone. But, there have been people with hypertonia identified. Movement issues included spasticity, dystonia, dyskinesia, choreiform movements, and ataxia.

  • 43 out of 89 people had a movement disorder (48 percent)
  • 55 out of 89 people had lower than average muscle tone (62 percent)
  • 25 out of 62 people had spasticity (40 percent)
48%
43 out of 89 people had a movement disorder.
62%
55 out of 89 people had lower than average muscle tone.
40%
25 out of 62 people had spasticity.

Feeding and digestion

Some people had feeding issues, such as swallowing difficulties, reflux, or oral dysphagia.

  • 19 out of 62 people had feeding difficulties (31 percent)

Other medical findings

Some people with GRIN1-related syndrome had cortical visual impairment or sleep disturbances.

  • 26 out of 74 people had cortical visual impairment (35 percent)
  • 14 out of 77 people had sleep issues (18 percent)

Where can I find support and resources?

CureGRIN Foundation

CureGRIN Foundation is dedicated to improving the lives of people around the world with GRI Disorders (GRIA, GRID, GRIK, and GRIN) and their families through research, education, and support. We work closely with scientists and the medical community to drive patient-centered research that will lead to treatments and cures. 

CureGRIN Foundation Facebook group

GRIN1 Parent Support Group on Facebook

Giggling GRIN1s Facebook group

Simons Searchlight is another research program sponsored and run by the Simons Foundation Autism Research Initiative, also known as SFARI. As part of the next step in your research journey, Simons Searchlight offers you the opportunity to partner with scientists and other families who have the same gene change. Simons Searchlight is a registry for more than 150 genetic changes that are associated with neurodevelopmental conditions, including autism spectrum disorder. Simons Searchlight makes it easier for researchers to access the information they need to advance research on a condition. To register for Simons Searchlight, go to the Simons Searchlight website at www.simonssearchlight.org and click “Join Us Today”.

Sources and References

The content in this guide comes from published studies about GRIN1-related syndrome. Below you can find details about each study, as well as links to summaries or, in some cases, the full article.

  • Lemke JR. et al. Neurology, 86, 2171-2178, (2016). Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy www.ncbi.nlm.nih.gov/pmc/articles/PMC4898312
  • Fry AE. et al. Brain, 141, 698-712, (2018). De novo mutations in GRIN1 cause extensive bilateral polymicrogyria
    www.ncbi.nlm.nih.gov/pmc/articles/PMC5837214
  • Platzer K. and JR. Lemke GeneReviews, (2021). GRIN1-related neurodevelopmental disorder www.ncbi.nlm.nih.gov/books/NBK542807
  • Santos-Gómez, A., Miguez-Cabello, F., Juliá-Palacios, N., García-Navas, D., Soto-Insuga, V., García-Peñas, J. J., Fuentes, P., Ibáñez-Micó, S., Cuesta, L., … Altafaj, X. (2021). Paradigmatic de novo GRIN1 variants recapitulate pathophysiological mechanisms underlying GRIN1-related disorder clinical spectrum. International Journal of Molecular Sciences, 22(23), 12656. https://pubmed.ncbi.nlm.nih.gov/34884460/
  • Xu, Y., Song, R., Perszyk, R. E., Chen, W., Kim, S., Park, K. L., Allen, J. P., Nocilla, K. A., Zhang, J., … Traynelis, S. F. (2024). De novo grin variants in M3 helix associated with neurological disorders control channel gating of NMDA receptor. Cellular and Molecular Life Sciences, 81(1), 153. https://pubmed.ncbi.nlm.nih.gov/38538865/

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