GENE GUIDE

KCNB1-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 KCNB1-Related Syndrome.
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KCNB1-related syndrome is also called developmental and epileptic encephalopathy, 26. For this webpage, we will be using the name KCNB1-related syndrome to encompass the wide range of variants observed in the people identified.

KCNB1-related syndrome happens when there are changes to the KCNB1 gene. These changes can keep the gene from working as it should.

Key Role

The KCNB1 gene plays a key role in communication between brain cells.

Symptoms

Because the KCNB1 gene is important in the development and function of brain cells, many people who have KCNB1-related syndrome have:

  • Seizures
  • Developmental delay
  • Behavior issues
  • Intellectual disability
  • Poor or absent speech

Genes make proteins that do the work inside of cells. Different changes to a gene can cause different symptoms. One study showed that 4 of 6 people who had gene changes that produce a shorter protein had a milder developmental delay than people who had gene changes that produce a protein with other kinds of changes.

Our genes contain the instructions, or code, that tell our cells how to grow, develop, and work. Every child gets two copies of the KCNB1 gene: one copy from their mother, from the egg, and one copy from their father, from the sperm. In most cases, parents pass on exact copies of the gene to their child. But the process of copying genes is not perfect. A change in the genetic code can lead to physical issues, developmental issues, or both.

Sometimes a random change happens in the sperm or egg. This change to the genetic code is called a ‘de novo’, or new, change. The child can be the first in the family to have the gene change.

De novo changes can take place in any gene. We all have some de novo changes, most of which don’t affect our health. But because KCNB1 plays a key role in development, de novo changes in this gene can have a meaningful effect.

Research shows that KCNB1-related syndrome is often the result of a de novo change in KCNB1. Many parents who have had their genes tested do not have the KCNB1 gene change found in their child who has the syndrome. In some cases, KCNB1-related syndrome happens because the gene change was passed down from a parent. This is called dominant inheritance.

Dominant inheritance

Children have a 50% chance of inheriting the genetic change.

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 KCNB1-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 KCNB1-related syndrome depends on the genes of both birth parents.

  • If neither birth parent has the same gene change 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 change in the gene.
  • If one birth parent has the same gene change found in their child, the chance of having another child who has the syndrome is 50 percent.

For a symptom-free sibling, a brother or sister, of someone who has KCNB1-related syndrome, the risk of having a child who has the syndrome depends on the symptom-free sibling’s genes and their parents’ genes.

  • If neither parent has the same gene change found in their child who has the syndrome, the symptom-free sibling has a nearly 0 percent chance of having a child who has KCNB1-related syndrome.
  • If one birth parent has the same gene change found in their child who has the syndrome, the symptom-free sibling has a small chance of also having the same gene change. If the symptom-free sibling has the same gene change as their sibling who has the syndrome, the symptom-free sibling’s chance of having a child who has KCNB1-related syndrome is 50 percent.

For a person who has KCNB1-related syndrome, the risk of having a child who has the syndrome is about 50 percent.

As of 2024, 119 people with KCNB1-related syndrome have been identified in a medical clinic. The first case of KCNB1-related syndrome was described in 2014.

People who have KCNB1-related syndrome do not look different.

Scientists and doctors have only just begun to study KCNB1-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 KCNB1-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 a major published article. It highlights how many people have different symptoms. To learn more about the article, see the Sources and references section of this guide.

Speech and Learning

Everyone with KCNB1-related syndrome had intellectual disability or developmental delay. More than one-half had severe developmental delay. Speech delay and speech issues were common.

  • 20 out of 61 people had mild to moderate intellectual disability (33 percent)
  • 41 out of 61 people had severe to profound intellectual disability (67 percent)
  • 37 out of 70 people were non-verbal (53 percent)
  • 13 out of 49 people had some words in their vocabulary (27 percent)
  • 11 out of 49 people were able to speak in short sentences (23 percent)
33%
20 out of 61 people had mild to moderate intellectual disability.
67%
41 out of 61 people had severe to profound intellectual disability.
53%
37 out of 70 people were non-verbal.
27%
13 out of 49 people had some words in their vocabulary.
23%
11 out of 49 people were able to speak in short sentences.

Behavior

Some people with KCNB1-related syndrome had autism or features of autism. Many people had behavior issues, including attention deficit hyperactivity disorder (ADHD) or aggression.

  • 45 out of 75 people had features of autism (60 percent)
  • 28 out of 75 people had ADHD (37 percent)
  • 22 out of 57 people had aggression (39 percent)
60%
45 out of 75 people had features of autism.
37%
28 out of 75 people had ADHD.
39%
22 out of 57 people had aggression.

Brain

Most people with KCNB1-related syndrome had seizures, with the average age of onset at 13 months old. The most common seizure types were generalized onset seizures, generalized tonic-clonic seizures, and focal onset seizures. Seizures were more likely in people who had KCNB1 missense variants than in those who had KCNB1 truncating variants.

In a case series of people between the ages of 1 and 34, there was no history of sudden unexpected death in epilepsy (SUDEP).

  • 81 out of 93 people had seizures (87 percent)

Sitting and walking

About one-half of people had low muscle tone, and some had movement difficulties, including but not limited to involuntary movements. The majority of people walked independently and were walking by 2 years of age.

  • 32 out of 62 people had low muscle tone (52 percent)
  • 14 out of 62 people had a movement disorder called ataxia (23 percent)
  • 10 out of 62 people had a movement disorder called dystonia (16 percent)
  • 36 out of 50 people walked independently (72 percent)

Other issues

Many people with KCNB1-related syndrome had sleep disorders.

  • 12 out of 36 people had sleep disorders (33 percent)

Where can I find support and resources?

KCNB1.org

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 a published study about KCNB1-related syndrome. Below you can find details about the study, as well as a link to the full article.

  • Torkamani A. et al. Annals of Neurology, 76, 529-540, (2014). De novo KCNB1 mutations in epileptic encephalopathy
    www.ncbi.nlm.nih.gov/pmc/articles/PMC4192091
  • Bar, C., … Nabbout, R. (2020). Developmental and epilepsy spectrum of KCNB1 encephalopathy with long-term outcome. Epilepsia, 61(11), 2461-2473. https://pubmed.ncbi.nlm.nih.gov/32954514/
  • Bar, C., Breuillard, D., Kuchenbuch, M., Jennesson, M., Le Guyader, G., Isnard, H., Rolland, A., Doummar, D., Fluss, J., Afenjar, A., Berquin, P., De Saint Martin, A., Dupont, S., Goldenberg, A., Lederer, D., Lesca, G., Maurey, H., Meyer, P., Mignot, C., Nica, A., Odent, S., Poisson, A., Scalais, E., Sekhara, T., Vrielynck, P., Barcia, G., & Nabbout, R. (2022). Adaptive behavior and psychiatric comorbidities in KCNB1 encephalopathy. Epilepsy & Behavior, 126, 108471. https://pubmed.ncbi.nlm.nih.gov/34915430/
  • Lu, J. M., Zhang, J. F., Ji, C. H., Hu, J., & Wang, K. (2021). Mild phenotype in a patient with developmental and epileptic encephalopathy carrying a novel de novo KCNB1 variant. Neurological Sciences, 42(10), 4325-4327. https://pubmed.ncbi.nlm.nih.gov/34176003/

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