GENE GUIDE

PACS2-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 PACS2-Related Syndrome.
a doctor sees a patient

PACS2-related syndrome happens when there are changes in the PACS2 gene. These changes can keep the gene from working as it should.

Key Role

The PACS2 gene plays an important role in the life cycle of cells, and it is important for communication for different structures within cells.

Symptoms

Because the PACS2 gene is important for many parts of the body, some people may have:

  • Seizures
  • Developmental delay
  • Intellectual disability
  • Autism
  • Delayed walking and speech
  • Low muscle tone
  • Heart defects
  • Genital issues in males

PACS2-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 PACS2 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 PACS2 plays a key role in development, de novo variants in this gene can have a meaningful effect. 

Research shows that PACS2-related syndrome is often the result of a de novo variant in PACS2. Many parents who have had their genes tested do not have the GENE genetic variant found in their child who has the syndrome. In some cases, PACS2-related syndrome happens because the genetic variant was passed down from a parent.

Autosomal dominant conditions

PACS2-related syndrome is an autosomal dominant genetic condition. This means that when a person has the one damaging variant in PACS2 they will likely have symptoms of PACS2-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 PACS2 gene?

No parent causes their child’s PACS2-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 PACS2-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 PACS2-related syndrome, the sibling’s risk of having a child who has PACS2-related syndrome depends on the sibling’s genes and their parents’ genes. 

  • If neither parent has the same genetic variant causing PACS2-related syndrome, the symptom-free sibling has a nearly 0 percent chance of having a child who would inherit PACS2-related syndrome. 
  • If one biological parent has the same genetic variant causing PACS2-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 PACS2-related syndrome, the risk of having a child who has the syndrome is about 50 percent.

As of 2024, about 32 people with PACS2-related syndrome have been described in medical research.

People who have PACS2-related syndrome may look different. Appearance can vary and can include some but not all of these features:

  • Wide-set eyes
  • Uncontrollable eye movements
  • Thin upper lip
  • Wide mouth
  • Fifth finger that curves

Scientists and doctors have only just begun to study PACS2-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 PACS2-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: epilepsy.com/…t-is-epilepsy/seizure-types

This section includes a summary of information from published articles that describe 32 people with changes in the PACS2 gene. It highlights how many people have different symptoms. To learn more about the articles, see the Sources and references section of this guide.

Learning

Most people with PACS2-related syndrome had developmental delay or intellectual disability. Some people had autism or features of autism.

  • 24 out of 28 people had developmental delay or intellectual disability (86 percent)
  • 5 out of 32 people had autism (16 percent)
  • 2 out of 15 people had features of autism (13 percent)
86%
24 out of 28 people had developmental delay or intellectual disability.
16%
5 out of 32 people had autism.
13%
2 out of 15 people had features of autism.

Brain

Speech delay was common, and seizures were the most common medical issue for people with PACS2-related syndrome, which often occurred within the first few weeks or months after birth.

  • 13 out of 15 people had speech delay (87 percent)
  • 32 out of 32 people had seizures (100 percent)
87%
13 out of 15 people had speech delay.
100%
32 out of 32 people had seizures.

Studies have shown that about one-half of people with PACS2-related syndrome were able to treat seizures with either valproate or levetiracetam. Combining medications was often needed. Brain imaging through magnetic resonance imaging (MRI) often showed developmental abnormalities.

  • 25 out of 32 people had abnormalities on brain imaging (78 percent)

Other features

Some people had low muscle tone or vision issues. Vision issues included but were not limited to myopia (nearsightedness), strabismus (crossed eyes), and astigmatism (an imperfection of the eye that causes blurred distance and near vision).

  • 13 out of 22 people had low muscle tone (59 percent)
  • 7 out of 22 people had vision issues (32 percent)

Where can I find support and resources?

PACS2 Research Foundation

The non-profit organization dedicated to drive first-ever treatment development for ultra-rare neurodevelopmental disorder (Development and Epileptic Encephalopathy 66) caused by mutation in PACS2 gene. We strive to enhance the quality of life for affected patients and their families. We anchor our efforts on interdisciplinary and international cooperation, buidling and fortifying patient-scientists-clinicists partnership and sharing experience with other research foundations.

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

  • Chou, I. J., Hou, J. Y., Fan, W. L., Tsai, M. H., & Lin, K. L. (2023). Long-term outcome of neonatal seizure with PACS2 mutation: Case series and literature review. Children (Basel), 10(4), 621. https://pubmed.ncbi.nlm.nih.gov/37189870/
  • Mizuno, T., Miyata, R., Hojo, A., Tamura, Y., Nakashima, M., Mizuguchi, T., Matsumoto, N., & Kato, M. (2021). Clinical variations of epileptic syndrome associated with PACS2 variant. Brain & Development, 43(2), 343-347. https://pubmed.ncbi.nlm.nih.gov/33243487/
  • Olson, H. E., … Thauvin-Robinet, C. (2018). A recurrent de novo PACS2 heterozygous missense variant causes neonatal-onset developmental epileptic encephalopathy, facial dysmorphism, and cerebellar dysgenesis. American Journal of Human Genetics, 103(4), 631. https://pubmed.ncbi.nlm.nih.gov/30290155/

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