TRIO-Related Syndrome
TRIO-related syndrome is also called neurodevelopmental disorder, autosomal dominant 44, with microcephaly (MRD44) or neurodevelopmental disorder, autosomal dominant 63, with macrocephaly (MRD63). For this webpage, we will be using the name TRIO-related syndrome to encompass the wide range of variants observed in the people identified.
What is TRIO-related syndrome?
TRIO-related syndrome happens when there are changes to the TRIO gene. These changes can keep the gene from working as it should.
Key Role
The TRIO gene plays a key role in the basic function of the cell.
Symptoms
Because the TRIO gene is important for basic cell function, some people with TRIO-related syndrome may have:
- Developmental delay
- Intellectual disability
- Delayed motor development
- Delayed walking or loss of walking
- Speech delay
- Seizures
- Behavioral challenges
- Autism or features of autism
- Attention-deficit/hyperactivity disorder (ADHD)
- Obsessive-compulsive behavior
- Aggressive behavior
- Recurrent infections
- Feeding difficulties
What causes TRIO-related syndrome?
TRIO-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 TRIO 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 TRIO plays a key role in development, de novo variants in this gene can have a meaningful effect.
Research shows that TRIO-related syndrome is often the result of a de novo variant in TRIO. Many parents who have had their genes tested do not have the TRIO genetic variant found in their child who has the syndrome. In some cases, TRIO-related syndrome happens because the genetic variant was passed down from a parent.
Autosomal dominant conditions
TRIO-related syndrome is an autosomal dominant genetic condition. This means that when a person has the one damaging variant in TRIO they will likely have symptoms of TRIO-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
Why does my child or I have a change in the TRIO gene?
No parent causes their child’s TRIO-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.
What are the chances that other family members or future children will have TRIO-related syndrome?
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 TRIO-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 TRIO-related syndrome, the sibling’s risk of having a child who has TRIO-related syndrome depends on the sibling’s genes and their parents’ genes.
- If neither parent has the same genetic variant causing TRIO-related syndrome, the symptom-free sibling has a nearly 0 percent chance of having a child who would inherit TRIO-related syndrome.
- If one biological parent has the same genetic variant causing TRIO-related syndrome, the symptom-free sibling has a 50 percent chance of also having the same genetic variant. If the symptom-free sibling has the same genetic variant, their chance of having a child who has the genetic variant is 50 percent.
For a person who has TRIO-related syndrome, the risk of having a child who has the syndrome is about 50 percent.
How many people have TRIO-related syndrome?
As of 2026, about 99 people in the world with changes in the TRIO gene had been described in medical research. The first case of TRIO-related syndrome was described in 2012. Scientists expect to find more people who have the syndrome as access to genetic testing improves.
Do people who have TRIO-related syndrome look different?
People who have TRIO-related syndrome may look different. Appearance can vary and can include some but not all of these features:
- High forehead
- Forehead that sticks out
- Smaller than average head size, also called microcephaly
- Larger than average head size, also called macrocephaly
- Small jaw, also called micrognathia
- Large ears or earlobes
- Thick eyebrows
- Arched eyebrows
- High bridge of the nose
- Short nose
- Upward tilting nostrils
- Large mouth
- Thin upper lip
- Full lips
- Roof of mouth with a high arch
- Finger defects
How is TRIO-related syndrome treated?
Scientists and doctors have only just begun to study TRIO-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:
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- 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:
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- Suggest the right therapies. This can include physical, occupational, speech, or behavioral therapy.
- Guide individualized education plans (IEPs).
Specialists advise that therapies for TRIO-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.
Genetic variants linked to
Variants in the TRIO gene result in either a gain of function OR a loss of function. It is not always obvious what a TRIO gene variant will do to the TRIO protein. Understanding the effect of a gene variant needs to be tested in the laboratory.
Below are two summaries of clinical information for people with loss-of-function TRIO variants and people with gain-of-function TRIO variants.
Loss-of-function TRIO variants
Certain TRIO variants are expected to result in a loss of function in the TRIO protein. These variants could be frameshift, nonsense, splice site, or insertion/deletion variants. Some missense variants can also result in a loss of protein function.
This section includes a summary of information from a major published article describing 10 people who have the syndrome. It highlights how many people have different symptoms. To learn more about the article, see the Sources and references section of this guide.
Behavior and development concerns linked to loss-of-function TRIO-related syndrome
Speech and Learning
All people with loss-of-function TRIO-related syndrome had developmental delay, which ranged from mild to severe. Some people also had delayed speech and language development.
- 36 out of 36 people had developmental delay (100 percent)
- 3 out of 8 people had speech and language delays (38 percent)
Severity of developmental delay varied:
- 32 out of 36 people had mild-to-moderate developmental delay (89 percent)
- 4 out of 36 people had moderate-to-severe developmental delay (11 percent)
Behavior
Most people with loss-of-function TRIO-related syndrome had behavioral challenges, which included stereotypies, poor attention, aggression, obsessive-compulsive disorder, features of autism, or attention-deficit/hyperactivity disorder (ADHD).
- 29 out of 31 people had behavioral challenges (94 percent)
Brain
Some people with loss-of-function TRIO-related syndrome had seizures. Many people who had brain magnetic resonance imaging (MRI) had an abnormal result and/or had a smaller than average head size, also called microcephaly.
- 8 out of 24 people had seizures (33 percent)
- 6 out of 10 people had brain defects (60 percent)
- 33 out of 45 people had microcephaly (73 percent)
Medical and physical concerns linked to loss-of-function TRIO-related syndrome
Other medical findings
People with loss-of-function TRIO-related syndrome had growth issues, gastrointestinal issues, skeletal issues, or dental issues. Skeletal issues included defects in the curvature of the spine, also called scoliosis. Dental issues included crowded teeth and delayed eruption of the teeth.
- 14 out of 22 people had infant feeding difficulties (64 percent)
- 8 out of 13 people had intrauterine growth restriction (62 percent)
- 8 out of 13 people had constipation (62 percent)
- 6 out of 20 people had scoliosis (30 percent)
- 6 out of 19 people had dental crowding (32 percent)
- 5 out of 17 people had delayed eruption of the teeth (29 percent)
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Gain-of-function TRIO variants
Certain TRIO variants are expected to result in a gain-of-function in the TRIO protein. These variants are often missense variants, but some missense variants can also result in a loss of protein function.
Behavior and development concerns linked to gain-of-function TRIO-related syndrome
Speech and Learning
All people with gain-of-function TRIO-related syndrome had moderate-to-severe developmental delay and intellectual disability.
- 21 out of 21 people had moderate-to-severe developmental delay (100 percent)
- 20 out of 20 people had intellectual disability (100 percent)
Behavior
Many people with gain-of-function TRIO-related syndrome had behavioral challenges, which included stereotypies, poor attention, aggression, obsessive-compulsive disorder, features of autism, or attention-deficit/hyperactivity disorder (ADHD).
- 16 out of 19 people had behavioral challenges (84 percent)
Graphs
16 out of 19 people had behavioral challenges
Brain
Some people with gain-of-function TRIO-related syndrome had seizures and abnormal brain magnetic resonance imaging (MRI) results. Almost everyone had a larger than average head size, also called macrocephaly.
- 8 out of 20 people had seizures (40 percent)
- 4 out of 10 people had brain defects (40 percent)
- 19 out of 21 people had macrocephaly (90 percent)
Medical and physical concerns linked to gain-of-function TRIO-related syndrome
Other medical findings
People with gain-of-function TRIO-related syndrome had growth issues, gastrointestinal issues, skeletal issues, or dental issues. Skeletal issues included defects in the curvature of the spine, also called scoliosis. Dental issues included crowded teeth and delayed eruption of the teeth.
- 7 out of 12 people had infant feeding difficulties (58 percent)
- 8 out of 12 people had intrauterine growth restriction (67 percent)
- 4 out of 9 people had constipation (44 percent)
- 4 out of 12 people had scoliosis (33 percent)
- 2 out of 9 people had dental crowding (22 percent)
- 1 out of 9 people had delayed eruption of the teeth (11 percent)
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Where can I find support and resources?
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.”
- Learn more about Simons Searchlight – www.simonssearchlight.org/frequently-asked-questions
- Simons Searchlight webpage with more information on TRIO – www.simonssearchlight.org/research/what-we-study/trio
- Simons Searchlight TRIO Facebook community – Simons Searchlight TRIO Facebook community
Sources and references
The content in this guide comes from a published review about TRIO-related syndrome. Below you can find details about the review, as well as a link to the full article.
- Hiraide, T., Hayashi, T., Yamoto, K., Masunaga, Y., Asahina, M., Ogata, T., Saitsu, H., & Fukuda, T. (2025). An atypical case of macrocephaly and severe intellectual disability associated with a missense variant in the guanine nucleotide exchange factor-1 domain of TRIO. Brain & Development, 47(5), 104405. doi:10.1016/j.braindev.2025.104405
- Mehta, N. H., Dennis, E., Allington, G., Mekbib, K. Y., Hale, A. T., Davalan, W. C., Duy, P. Q., Zilla, E., Fan, B., … & Kahle, K. T. (2026). De novo TRIO missense variants disrupt Ras-GEF domains and cause congenital ventriculomegaly and hydrocephalus. Human Mutation, 2026, 8870037. doi:10.1155/humu/8870037
- Schwartzmann, S., Zhao, M., Sczakiel, H. L., Hildebrand, G., Ehmke, N., Horn, D., Mensah, M. A., & Boschann, F. (2024). RNA analysis and computer-aided facial phenotyping help to classify a novel TRIO splice site variant. American Journal of Medical Genetics Part A, 194(7), e63599. doi:10.1002/ajmg.a.63599
- Zhang, S. Y., Jin, J. Y., Zeng, L., Niu, R. C., & Wang, X. (2026). Identification and growth features of developmental delay with macrocephaly caused by a novel TRIO variant affecting the second SH3 domain. BMC Medical Genomics. doi:10.1186/s12920-026-02422-6