GENE GUIDE

IRF2BPL-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 IRF2BPL-Related Syndrome.
a doctor sees a patient

IRF2BPL-related syndrome is also called neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures (NEDAMSS). For this webpage, we will be using the name IRF2BPL-related syndrome to encompass the wide range of variants observed in the people identified.

IRF2BPL-related syndrome happens when there are changes to the IRF2BPL gene. These changes can keep the gene from working as it should.

Key Role

The IRF2BPL gene plays a key role in brain cell function.

Symptoms

Because the IRF2BPL gene is important for brain activity, many people who have IRF2BPL-related syndrome have:

  • Intellectual disability
  • Seizures
  • Movement issues, such as dystonia, a condition in which muscles contract uncontrollably, and ataxia, a condition that causes uncoordinated movement
  • Regression sometimes between 2 and 10 years old, which might include loss of walking, speech, and/or motor skills
  • Brain changes observed on magnetic resonance imaging (MRI)

IRF2BPL-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 IRF2BPL 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 IRF2BPL plays a key role in development, de novo variants in this gene can have a meaningful effect.

Research shows that IRF2BPL-related syndrome is often the result of a de novo variant in IRF2BPL. Many parents who have had their genes tested do not have the IRF2BPL genetic variant found in their child who has the syndrome. In some cases, IRF2BPL-related syndrome happens because the genetic variant was passed down from a parent.

Autosomal dominant conditions

IRF2BPL-related syndrome is an autosomal dominant genetic condition. This means that when a person has the one damaging variant in IRF2BPL they will likely have symptoms of IRF2BPL-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 have a change in the IRF2BPL gene?

No parent causes their child’s IRF2BPL-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 IRF2BPL-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 IRF2BPL-related syndrome, the sibling’s risk of having a child who has IRF2BPL-related syndrome depends on the sibling’s genes and their parents’ genes.

  • If neither parent has the same genetic variant causing IRF2BPL-related syndrome, the symptom-free sibling has a nearly 0 percent chance of having a child who would inherit IRF2BPL-related syndrome.

As of 2024, at least 73 people with IRF2BPL-related syndrome have been identified in a medical clinic. The first case of IRF2BPL-related syndrome was described in 2018. Scientists expect to find more people who have the syndrome as access to genetic testing improves.

People who have IRF2BPL-related syndrome do not look very different.

Scientists and doctors have only just begun to study IRF2BPL-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 IRF2BPL-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 focuses on a research study that included five people who had a change at the end of the IRF2BPL gene. These types of gene changes are linked to neurodevelopmental symptoms. To learn more about the articles, see the Sources and references section of this guide.

Speech and Learning

Some people with IRF2BPL-related syndrome had initial developmental delay. Regression of motor skills or language happened for some people. Note that this information may be limited due to the person’s age or what was selectively reported by the researchers.

Some researchers have suggested that people with genetic variants before the first PEST block of the IRF2BPL protein (before amino acid 198) had a later onset of the condition, less developmental delay, and more non-epilepsy features as compared with people who had variants further down.

  • 18 out of 52 people had initial developmental delay (35 percent)
  • 17 out of 52 people had motor regression (33 percent)
  • 9 out of 50 people had language regression (18 percent)
35%
18 out of 52 people had initial developmental delay.
33%
17 out of 52 people had motor regression.
18%
9 out of 50 people had language regression.

Behavior

Sometimes people with IRF2BPL-related syndrome had behavioral challenges, such as autism or features of autism, attention-deficit/hyperactivity disorder (ADHD), anxiety, aggressive behavior, obsessive compulsive traits, depression, catatonia, or psychotic symptoms.

Brain

Many people with IRF2BPL-related syndrome had seizures; brain changes on magnetic resonance imaging (MRI); and cerebral, cerebellar, or brainstem atrophy. Researchers have suggested that people with genetic variants in the polyQ domain (within amino acids 102 to 127) might have a higher rate of seizures than people with variants in other areas of the IRF2BPL protein.

  • 27 out of 43 people had seizures (63 percent)
  • 21 out of 49 people had brain changes seen on MRI (43 percent)
  • 15 out of 49 people had cerebral, cerebellar, or brainstem atrophy (31 percent)
Human head showing brain outline
63%
27 out of 43 people had seizures.
43%
21 out of 49 people had brain changes seen on MRI.
31%
15 out of 49 people had cerebral, cerebellar, or brainstem atrophy.

Mobility

Mobility issues were common among people with IRF2BPL-related syndrome. They had dystonia (a condition with muscle contractions resulting in repetitive movements or postures), ataxia (poor muscle control that causes clumsy movements), and pyramidal signs (indication that there is an issue in the nerves of the brain stem and spinal cord).

  • 20 out of 55 people had dystonia (36 percent)
  • 41 out of 56 people had ataxia (73 percent)
  • 30 out of 56 people had pyramidal signs (54 percent)

Where can I find support and resources?

Tough Genes

Founded by parents of a child with IRF2BPL-Related Disorder, Tough Genes is a 501c3 nonprofit organization dedicated to advancing scientific knowledge and medical understanding of the IRF2BPL gene. Their mission is based upon raising awareness and funds for IRF2BPL-Related Disorder research. They strive to transform lives by driving breakthroughs in science, increasing awareness, and securing the resources necessary to find treatment and improve the quality of life for those impacted by this disorder.

Stand by Eli Foundation

The Stand By Eli Foundation was created to provide funds needed to research, and ultimately treat and cure, children affected with mutations and truncations (shortening) of the IRF2BPL gene.

IRF2BPL Foundation

This website provides the information on IRF2BPL-related disorders for patients, family members, physicians and biomedical scientists working all together to solve the medical mystery on IRF2BPL.

Simons Searchlight

Simons Searchlight is an online international research program, building an ever growing natural history database, biorepository, and resource network of over 175 rare genetic neurodevelopmental disorders. By joining their community and sharing your experiences, you contribute to a growing database used by scientists worldwide to advance the understanding of your genetic condition. Through online surveys and optional blood sample collection, they gather valuable information to improve lives and drive scientific progress. Families like yours are the key to making meaningful progress. To register for Simons Searchlight, go to the Simons Searchlight website at www.simonssearchlight.org and click “Join Us.”

Sources and References

The content in this guide comes from published studies about IRF2BPL-related syndrome. Below you can find details about each study, as well as links to summaries or, in some cases, the full article.

  • Marcogliese PC. et al. American Journal of Human Genetics, 103, 245-260, (2018). IRF2BPL is associated with neurological phenotypes
    www.ncbi.nlm.nih.gov/pubmed/30057031
  • Tran Mau-Them F. et al. Genetics in Medicine: Official Journal of the American College of Medical Genetics, 21, 1008-1014, (2019). De novo truncating variants in the intronless IRF2BPL are responsible for developmental epileptic encephalopathy www.ncbi.nlm.nih.gov/pubmed/30166628
  • Chen, P. S., Chen, Y. F., Chiu, J. Y., Wu, M. C., Tai, C. H., Chang, Y. Y., Lan, M. Y., Lee, N. C., & Lin, C. H. (2024). Genetic analysis of IRF2BPL in a Taiwanese dystonia cohort: The genotype and phenotype correlation. Annals of Clinical and Translational Neurology, 11(6), 1557-1566. https://pubmed.ncbi.nlm.nih.gov/38650104/
  • Kristiansen, K., Vernal, D. L., & Hulgaard, D. R. (2024). Expanding the phenotype of NEDAMSS with a psychiatric perspective: Analysis of a new case, and a systematic review of the literature. European Child & Adolescent Psychiatry. https://pubmed.ncbi.nlm.nih.gov/39031186/

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