GENE GUIDE

TRIP12-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 TRIP12-Related Syndrome.
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TRIP12-related syndrome is also called Intellectual developmental disorder, autosomal dominant 49. For this webpage, we will be using the name TRIP12-related syndrome to encompass the wide range of variants observed in the people identified.

TRIP12-related syndrome happens when there are changes to the TRIP12 gene. These changes can keep the gene from working as it should.

Key Role

The TRIP12 gene plays a key role in the basic function of the cell.

Symptoms

Because the TRIP12 gene is important in brain development and function, many people who have TRIP12-related syndrome have:

  • Developmental delay
  • Intellectual disability
  • Autism or features of autism
  • Behavioral issues
  • Seizures
  • Anxiety
  • Obesity
  • Vision issues
  • Defects of the cardiac, renal, genital, or skeletal system

TRIP12-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 TRIP12 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 TRIP12 plays a key role in development, de novo variants in this gene can have a meaningful effect. 

Research shows that TRIP12-related syndrome is often the result of a de novo variant in TRIP12. Many parents who have had their genes tested do not have the TRIP12 genetic variant found in their child who has the syndrome. In some cases, TRIP12-related syndrome happens because the genetic variant was passed down from a parent.

Autosomal dominant conditions

TRIP12-related syndrome is an autosomal dominant genetic condition. This means that when a person has the one damaging variant in TRIP12 they will likely have symptoms of TRIP12-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 TRIP12 gene?

No parent causes their child’s TRIP12-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 TRIP12-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 TRIP12-related syndrome, the sibling’s risk of having a child who has TRIP12-related syndrome depends on the sibling’s genes and their parents’ genes. 

  • If neither parent has the same genetic variant causing TRIP12-related syndrome, the symptom-free sibling has a nearly 0 percent chance of having a child who would inherit TRIP12-related syndrome. 
  • If one biological parent has the same genetic variant causing TRIP12-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 TRIP12-related syndrome, the risk of having a child who has the syndrome is about 50 percent.

As of 2024, at least 88 people with TRIP12-related syndrome have been identified in a medical clinic. The first case of TRIP12-related syndrome was described in 2012. Scientists expect to find more people who have the syndrome as access to genetic testing improves.

People who have TRIP12-related syndrome may look different. Appearance can vary and can include some but not all of these features:

  • Deep-set eyes
  • Fullness of the upper eyelids
  • Small opening space between the upper and lower eyelids
  • Broader than average nasal tip
40%
40 percent of people have differences in the shape of the ear, such as large lobes.
33%
33 percent of people have differences in the shape of the eye, such as a skin fold of the upper eyelid that covers the inner corner, known as an epicanthic fold.
30%
30 percent of people have a wide mouth.

Scientists and doctors have only just begun to study TRIP12-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 TRIP12-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.

Speech and Learning

All people with TRIP12-related syndrome had developmental delay and intellectual disability, as well as language delay. Intellectual disability ranged from mild to severe.

  • 58 out of 58 people had developmental delay and intellectual disability (100 percent)
  • 54 out of 54 people had language delay (100 percent)

Behavior

Many people with TRIP12-related syndrome had autism and behavioral issues. Behavioral issues included attention deficit hyperactivity disorder, or ADHD, aggression, and anxiety. Some people had developmental regression.

  • 30 out of 55 people had autism (55 percent)
  • 39 out of 52 people had behavioral issues (75 percent)
  • 8 out of 52 people had developmental regression (15 percent)
55%
30 out of 55 people had autism.
75%
39 out of 52 people had behavioral issues.
15%
8 out of 52 people had developmental regression.

Brain

Some people with TRIP12-related syndrome had seizures in infancy or childhood. Some people had brain changes seen on magnetic resonance imaging (MRI).

  • 9 out of 58 people had seizures (16 percent)
  • 13 out of 42 people had abnormal MRI findings (31 percent)
16%
9 out of 58 people had seizures.
31%
13 out of 42 people had abnormal MRI findings.

Mobility

People who have TRIP12-related syndrome had impaired motor skills, although most people were able to walk unassisted after the age of 2 years, and many people had low muscle tone. Some people had a movement disorder, such as tremor or stereotypies.

  • 43 out of 54 people had impaired motor skills (80 percent)
  • 55 out of 56 people were able to walk unassisted after the age of 2 (98 percent)
  • 23 out of 47 people had low muscle tone (49 percent)
  • 6 out of 37 people had a movement disorder (16 percent)

Weight issues

People with TRIP12-related syndrome were at risk of developing obesity and had feeding difficulties.

  • 23 out of 53 people had obesity (43 percent)
  • 10 out of 36 people had feeding difficulties (28 percent)

Other findings

Some people with TRIP12-related syndrome had sleep and vision issues or recurrent infections. Other findings included joint laxity and hand and foot defects.

  • 8 out of 38 people had sleep issues (21 percent)
  • 20 out of 50 people had vision issues (40 percent)
  • 12 out of 47 people had recurrent infections (26 percent)
21%
8 out of 38 people had sleep issues.
40%
20 out of 50 people had vision issues.
26%
12 out of 47 people had recurrent infections.

Where can I find support and resources?

TRIP12 Gene Community 

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 TRIP12-related syndrome. Below you can find details about each study, as well as links to summaries or, in some cases, the full article.

  • Bramswig NC. et al. Human Genetics, 136, 179-192, (2017). Identification of new TRIP12 variants and detailed clinical evaluation of individuals with non-syndromic intellectual disability with or without autism www.ncbi.nlm.nih.gov/pmc/articles/PMC5821420
  • Zhang J. et al. Human Genetics, 136, 377-386, (2017). Haploinsufficiency of the E3 ubiquitin- protein ligase gene TRIP12 causes intellectual disability with or without autism spectrum disorders, speech delay, and dysmorphic features www.ncbi.nlm.nih.gov/pmc/articles/PMC5543723
  • Donoghue T. et al. American Journal of Medical Genetics Part A, 182, 1801-1806, (2020). Novel de novo TRIP12 mutation reveals variable phenotypic presentation while emphasizing core features of TRIP12 variations www.pubmed.ncbi.nlm.nih.gov/32424948
  • Louie, R. J., Friez, M. J., Skinner, C., Baraitser, M., Clark, R. D., Schwartz, C. E., & Stevenson, R. E. (2020). Clark-Baraitser syndrome is associated with a nonsense alteration in the autosomal gene TRIP12. American Journal of Medical Genetics Part A, 182(3), 595-596. https://pubmed.ncbi.nlm.nih.gov/31814248/
  • Aerden, M., Denommé-Pichon, A. S., Bonneau, D., Bruel, A. L., Delanne, J., Gérard, B., Mazel, B., Philippe, C., Pinson, L., … Van Esch, H. (2023). The neurodevelopmental and facial phenotype in individuals with a TRIP12 variant. European Journal of Human Genetics, 31(4), 461-468. https://pubmed.ncbi.nlm.nih.gov/36747006/

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