GENE GUIDE

SIN3A-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 SIN3A-Related Syndrome.
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SIN3A-related syndrome is also called Witteveen-Kolk syndrome (WITKOS). For this webpage, we will be using the name SIN3A-related syndrome to encompass the wide range of variants observed in the people identified.

SIN3A-related syndrome happens when there are changes to the SIN3A gene. These changes can keep the gene from working as it should.

Key Role

The SIN3A gene plays a key role in controlling other genes, especially in a region of the brain called the cerebral cortex.

Symptoms

Because the SIN3A gene is important for brain activity, many people who have SIN3A-related syndrome have:

  • Mild intellectual disability or developmental delay
  • Motor delays
  • Small head
  • Short height
  • Hyperactivity
  • Limb defects
  • Birth defects, including in the heart, eye, or intestinal tract
  • Behavioral issues
  • Seizures

SIN3A-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 SIN3A 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 SIN3A plays a key role in development, de novo variants in this gene can have a meaningful effect.

Research shows that SIN3A-related syndrome is often the result of a de novo variant in SIN3A. Many parents who have had their genes tested do not have the SIN3A genetic variant found in their child who has the syndrome. In some cases, SIN3A-related syndrome happens because the genetic variant was passed down from a parent.

Autosomal dominant conditions

SIN3A-related syndrome is an autosomal dominant genetic condition. This means that when a person has the one damaging variant in SIN3A they will likely have symptoms of SIN3A-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 SIN3A gene?

No parent causes their child’s SIN3A-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 SIN3A-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 SIN3A-related syndrome, the sibling’s risk of having a child who has SIN3A-related syndrome depends on the sibling’s genes and their parents’ genes.

  • If neither parent has the same genetic variant causing SIN3A-related syndrome, the symptom-free sibling has a nearly 0 percent chance of having a child who would inherit SIN3A-related syndrome.

As of 2024, about 87 people with SIN3A-related syndrome have been identified in a medical clinic. The first case of SIN3A-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 SIN3A-related syndrome may look different. Appearance can vary and can include some but not all of these features:

  • Long face
  • Tall, broad forehead
  • Small mouth with thin upper lip
  • Eyes that slant downwards
  • Smaller than average head
  • Short height

Scientists and doctors have only just begun to study SIN3A-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 SIN3A-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 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.

Learning

Many with SIN3A-related syndrome had developmental delay or intellectual disability. Some people had speech delays.

  • 31 out of 43 people had developmental delay or intellectual disability (72 percent)

Behavior

Behavioral disorders occurred in people with SIN3A-related syndrome, including features of autism, aggressive behavior, hyperactivity, and obsessive-compulsive disorder.

  • 18 out of 34 people had behavioral issues (53 percent)

Brain

Some people with SIN3A-related syndrome had seizures, brain changes seen on magnetic resonance imaging (MRI), or a smaller than average head size, also called microcephaly.

  • 7 out of 42 people had seizures (17 percent)
  • 13 out of 35 people had brain changes on MRI (37 percent)
  • 18 out of 40 people had microcephaly (45 percent)
17%
7 out of 42 people had seizures.
37%
13 out of 35 people had brain changes on MRI.
45%
18 out of 40 people had microcephaly.

Vision and hearing

People with SIN3A-related syndrome had hearing and vision loss. Vision issues included strabismus (crossed eyes), nystagmus (eyes that move rapidly without control), and colobomas in both eyes (area of missing tissue in the eye).

Growth

Fewer than one-half of people with SIN3A-related syndrome had lower than average muscle tone, also called hypotonia. About 1 in 3 had short height. Some had hypermobile joints.

  • 15 out of 38 people had hypotonia (39 percent)
  • 12 out of 41 people had short height (29 percent)

Facial features

All people had facial features, such as a high forehead, down-slanting outer side of the eyes, a small pointed chin, and a thin upper lip.

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.”

Sources and References

  • Witteveen JS. et al. Nature Genetics, 48, 877-887, (2016). Haploinsufficiency of MeCP2-interacting transcriptional co-repressor SIN3A causes mild intellectual disability by affecting the development of cortical integrity, pubmed.ncbi.nlm.nih.gov/27399968/.
  • Balasubramanian M. et al. European Journal of Human Genetics, Epub ahead of print, (2021). Comprehensive study of 28 individuals with SIN3A-related disorder underscoring the associated mild cognitive and distinctive facial phenotype, pubmed.ncbi.nlm.nih.gov/33437032/.
  • Narumi-Kishimoto Y. et al. European Journal of Medical Genetics, 62, 103547, (2019). Novel SIN3A mutation identified in a Japanese patient with Witteveen-Kolk syndrome, pubmed.ncbi.nlm.nih.gov/30267900/.
  • van Dongen LCM. et al. American Journal of Medical Genetics Part A, 182, 2384-2390, (2020). Behavior and cognitive functioning in Witteveen-Kolk syndrome, pubmed.ncbi.nlm.nih.gov/32783353/.
  • Correa Brito, L., Keselman, A., Villegas, F., Scaglia, P., Esnaola Azcoiti, M., Castro, S., Sanguineti, N., Izquierdo, A., Maier, M., … & Ropelato, M. G. (2024). Case report: Novel SIN3A loss-of-function variant as causative for hypogonadotropic hypogonadism in Witteveen-Kolk syndrome. Frontiers in Genetics, 15, 1354715. https://pubmed.ncbi.nlm.nih.gov/38528912/
  • Jacobson, A., & Bohnsack, B. L. (2022). Anterior megalophthalmos in sisters with Witteveen-Kolk syndrome. Journal of the American Association for Pediatric Ophthalmology and Strabismus, 26(3), 148-150. https://pubmed.ncbi.nlm.nih.gov/35144002/
  • Latypova, X., Vincent, M., Mollé, A., Adebambo, O. A., Fourgeux, C., Khan, T. N., Caro, A., Rosello, M., Orellana, C., … & Isidor, B. (2021). Haploinsufficiency of the SIN3/HDAC corepressor complex member SIN3B causes a syndromic intellectual disability/autism spectrum disorder. American Journal of Human Genetics, 108(5), 929-941. https://pubmed.ncbi.nlm.nih.gov/33811806/
  • Penon-Portmann, M., Carlston, C. M., Martin, P. M., & Slavotinek, A. (2022). Exome sequencing identifies a novel SIN3A variant in a patient with Witteveen-Kolk syndrome. Molecular Syndromology, 13(4), 337-342. https://pubmed.ncbi.nlm.nih.gov/36158056/

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