GENE GUIDE

SMARCA4-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 in 2025. 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 SMARCA4-Related Syndrome.
a doctor sees a patient

SMARCA4-related syndrome is also called Coffin-Siris syndrome 4 and otosclerosis-12 (OTSC12). For this webpage, we will be using the name SMARCA4-related syndrome to encompass the wide range of variants observed in the people identified.

SMARCA4-related syndrome happens when there are changes in the SMARCA4 gene. These changes can keep the gene from working as it should.

Key Role

The SMARCA4 gene plays a role in controlling other genes during development.

Symptoms

Because the SMARCA4 gene is important for brain activity, many people who have SMARCA4-related syndrome have:

  • Developmental delay
  • Intellectual disability
  • Behavioral features
  • Motor delays
  • Language impairments
  • Hearing loss
  • Low muscle tone, also called hypotonia
  • Delayed bone development
  • Sideways curve of the spine, also called scoliosis
  • Shorter than average height

SMARCA4-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 SMARCA4 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 SMARCA4 plays a key role in development, de novo variants in this gene can have a meaningful effect. 

Research shows that SMARCA4-related syndrome is often the result of a de novo variant in SMARCA4. Many parents who have had their genes tested do not have the SMARCA4 genetic variant found in their child who has the syndrome. In some cases, SMARCA4-related syndrome happens because the genetic variant was passed down from a parent.

Autosomal dominant conditions

SMARCA4-related syndrome is an autosomal dominant genetic condition. This means that when a person has the one damaging variant in SMARCA4 they will likely have symptoms of SMARCA4-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

No parent causes their child’s SMARCA4-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 foreseen 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 SMARCA4-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 SMARCA4-related syndrome, the sibling’s risk of having a child who has SMARCA4-related syndrome depends on the sibling’s genes and their parents’ genes. 

  • If neither parent has the same genetic variant causing SMARCA4-related syndrome, the symptom-free sibling has a nearly 0 percent chance of having a child who would inherit SMARCA4-related syndrome. 
  • If one biological parent has the same genetic variant causing SMARCA4-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 SMARCA4-related syndrome, the risk of having a child who has the syndrome is about 50 percent.

As of 2024, at least 50 people with SMARCA4-related syndrome have been identified in a medical clinic.

People who have SMARCA4-related syndrome may look different. Appearance can vary and can include some but not all of these features:

  • Skeleton — Certain fingers and toes, most often the fifth finger and toe, might be unusually short. In some people, the inner forearm bone, also called radius, might be out of place at the elbow. The connection between the hip and thighbones might be misshaped. Some people might have very small or absent kneecaps.
  • Facial features — Some people have unusually large or small heads, a wide mouth with full lips, a broad nasal tip, a low nasal bridge, and a long vertical groove between the nose and the upper lip.
  • Other features might include thick eyebrows, long eyelashes, and excessive hair growth, also called hypertrichosis, except on the scalp where hair tends to be thin.

Scientists and doctors have only just begun to study SMARCA4-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 SMARCA4-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/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

The majority of people with SMARCA4-related syndrome had global developmental delay or intellectual disabilities, ranging from mild to severe, and speech delays. Sometimes people were non-verbal.

  • 37 out of 39 people had global developmental delay or intellectual disability (95 percent)
  • 33 out of 35 people had speech delays (94 percent)

Behavior

People with SMARCA4-related syndrome had behavioral issues, such as autism and attention-deficit/hyperactivity disorder (ADHD).

  • 23 out of 32 people had other behavioral issues (72 percent)

Brain

People with SMARCA4-related syndrome had seizures, brain changes seen on magnetic resonance imaging (MRI), lower than average muscle tone (hypotonia), and a smaller than average head size (microcephaly).

  • 7 out of 29 people had seizures (24 percent)
  • 22 out of 33 people had brain changes seen on MRI (67 percent)
  • 13 out of 40 people had hypotonia (33 percent)
  • 12 out of 32 people had microcephaly (38 percent)
24%
7 out of 29 people had seizures.
67%
22 out of 33 people had brain changes seen on MRI.
33%
13 out of 40 people had hypotonia.
38%
12 out of 32 people had microcephaly.

Physical findings

People with SMARCA4-related syndrome had heart defects, such as mild patent foramen ovale, single ventricle, and tetralogy of Fallot.

  • 16 out of 39 people had heart defects (41 percent)

Immune system

About one-half of people with SMARCA4-related syndrome had frequent infections.

  • 11 out of 23 people had frequent infections (48 percent)

Where can I find support and resources?

Coffin-Siris Syndrome Foundation

To connect, support, and inform the Coffin Siris Syndrome community and to promote related research.

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 SMARCA4-related syndrome.

  • Qian, Y., Zhou, Y., Wu, B., Chen, H., Xu, S., Wang, Y., Zhang, P., Li, G., Xu, Q., … & Wang, H. (2022). Novel variants of the SMARCA4 gene associated with autistic features rather than typical Coffin-Siris syndrome in eight Chinese pediatric patients. Journal of Autism and Developmental Disorders, 52(11), 5033-5041. https://pubmed.ncbi.nlm.nih.gov/34813034/
  • Vergano, S. S., Santen, G., Wieczorek, D., Wollnik, B., Matsumoto, N., & Deardorff, M. A. Coffin-Siris syndrome. 2021 Aug 12. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK131811/
  • Vasko, A., Drivas, T. G., & Schrier Vergano, S. A. (2021). Genotype-phenotype correlations in 208 individuals with Coffin-Siris syndrome. Genes (Basel), 12(6). 937. https://pubmed.ncbi.nlm.nih.gov/34205270/

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