GENE GUIDE

CASK1-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 CASK1-Related Syndrome.
a doctor sees a patient

CASK-related syndrome is also called FG syndrome 4, intellectual developmental disorder and microcephaly with pontine and cerebellar hypoplasia, and intellectual developmental disorder, with or without nystagmus. For this webpage, we will be using the name CASK-related syndrome to encompass the wide range of variants observed in the people identified. 

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

Key Role

The CASK gene plays a key role in the development of the brain and the function of brain cells. It’s especially important in controlling the connections between brain cells. 

Symptoms

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

  • Developmental delay 
  • Intellectual disability 
  • Small head size 
  • Motor difficulties or movement disorders 
  • Lower than average muscle tone 
  • Speech difficulties 
  • Autism 
  • Repeated hand movements 
  • Seizures 
  • Repetitive eye movements, also called nystagmus 
  • Hyperactivity 
  • Aggression

CASK-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. Genes are arranged in structures in our cells called chromosomes. Chromosomes and genes usually come in pairs, with one copy from the mother’s egg, and one copy from the father’s sperm. 

We each have 23 pairs of chromosomes. One pair, called the X and Y chromosomes, differs between biological males and biological females. Biological females have two copies of the X chromosome and all its genes, one inherited from their mother and one inherited from their father. Biological males have one copy of the X chromosome and all its genes, inherited from their mother, and one copy of the Y chromosome and its genes, inherited from their father. 

In most cases, parents pass on exact copies of the gene to their child. But the process of making the sperm and egg is not perfect. A variant in the genetic code can lead to physical issues, developmental issues, or both. 

The CASK gene is located on the X chromosome, therefore variants in this gene can affect biological males and biological females in different ways. Biological males who have variants in this gene will likely have CASK-related syndrome. 

Biological females who have variants in this gene may or may not have symptoms of CASK-related syndrome. Biological females who have one working copy of the gene and one non-working copy are considered to be ‘carriers’. Even if a biological female does not have signs or symptoms of the syndrome, they can pass it along to their children.

X-linked dominant conditions

CASK-related syndrome usually results from a spontaneous variant in the CASK gene in the sperm or egg during development. When a brand new genetic variant happens in the genetic code it is called a ‘de novo’ genetic variant. The child can be the first in the family to have the gene 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 CASK plays a key role in development, de novo variants in this gene can have a meaningful effect. Many parents who have had their genes tested do not have the CASK gene variant found in their child who has the syndrome.In some cases, CASK-related syndrome is inherited. Biological females who inherit the CASK gene variant tend to have milder symptoms than those who have a de novo variant.

X-Linked Dominant Genetic Syndrome

Sex chromosomes
Non-carrier father
Non-carrier mother
Sex chromosomes
Genetic variant happens in X-chromosome in sperm or egg, or after fertilization
Non-carrier female
Female child with X-linked genetic condition
Male child with X-linked
genetic condition
Non-carrier
male

Why does my child have a change in the CASK gene?

No parent causes their child’s CASK-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 CASK-related syndrome depends on the genes of both biological parents. 

  • For a biological female parent who does not have 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 increased 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. 
  • For a biological female parent who has the same CASK variant and is pregnant with a daughter, there is a 50 percent chance of passing on the same genetic variant and a 50 percent chance of passing on the working copy of the gene without the same CASK genetic variant. 
  • If they are pregnant with a son, there is a 50 percent chance of passing on the same genetic variant and the syndrome.  

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

  • If neither parent has the same genetic variant causing CASK-related syndrome, the symptom-free sibling has a nearly 0 percent chance of having a child who would inherit CASK-related syndrome.
  • If the biological mother has the same genetic variant causing CASK-related syndrome, the symptom-free daughter has a 50 percent chance of also having the same genetic variant. If the symptom-free daughter has the same genetic variant as their sibling who has the syndrome, the symptom-free sibling’s chance of having a son who has CASK-related syndrome is 50 percent. 

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

As of 2024, about 207 people with CASK-related syndrome have been identified in a medical clinic. 

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

  • Well-drawn arched eyebrows 
  • Broad nasal bridge and broad nasal tip 
  • Small or short nose 
  • Long philtrum (space between the nose and lip) 
  • Protruding maxilla (prominent top teeth and bone) 
  • Small chin 
  • Large ears

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

The CASK gene is on the X chromosome. Pathogenic or likely pathogenic variants in CASK affect females and males differently. The information below is divided by females and males. 

Females with CASK-related syndrome

Two identified conditions in females included X-linked intellectual disability, with or without nystagmus, and microcephaly with pontine and cerebellar hypoplasia (MICPCH). Females with X-linked intellectual disability, with or without nystagmus are usually relatives of more severely affected males, and have a missense genetic variant. These females usually have normal intelligence, mild vision issues, no other neurological symptoms, and normal MRI findings. 

Females with MICPCH usually have a loss-of-function genetic variant. The information below mostly includes females with MICPCH.

Learning  

Females with CASK-related syndrome had developmental delay or intellectual disability. Most females with CASK-related syndrome were able to sit between 7 and 36 months, and most females were not able to speak. 

  • 124 out of 129 people had moderate to severe intellectual disability (96 percent) 

Brain 

Some females with CASK-related syndrome had seizures. Females with MICPCH had a smaller than average head size, microcephaly, and pontine and cerebellar hypoplasia, which is an underdevelopment of part of the brain stem and lower back part of the brain. Hypoplasia of the pontine and cerebellar ranged from mild to severe. Some of the seizure types reported included late-onset drug-resistant spasms, some of which developed into developmental and epileptic encephalopathy; Ohtahara syndrome; West syndrome; absence seizures; Lennox-Gastaut syndrome; and myoclonic seizures. 

  • 44 out of 122 people had seizures (36 percent)
  • 107 out of 122 people had microcephaly (88 percent)
Human head showing brain outline
36%
44 out of 122 people had seizures.
88%
107 out of 122 people had microcephaly.

Other medical features 

Short height was common by the age of 4. Other features included hearing loss in about 1 in 3 females; a curvature of the spine, also called scoliosis; and vision issues, including optic nerve hypoplasia, retinopathy, nystagmus (eyes that move rapidly without control), and strabismus (crossed eyes).

Males with CASK-related syndrome 

Two identified conditions in males included X-linked intellectual disability, with or without nystagmus, and microcephaly with pontine and cerebellar hypoplasia (MICPCH). 

Males with X-linked intellectual disability, with or without nystagmus usually have a missense genetic variant. Males with MICPCH usually have a loss-of-function genetic variant. In general, males with either genetic condition have very similar medical features, but, males with X-linked intellectual disability, with or without nystagmus may have mild intellectual disability and no pontine and cerebellar hypoplasia.

Learning 

Males with CASK-related syndrome had developmental delay or intellectual disability. Males with MICPCH usually had severe to profound developmental delay. 

  • 58 out of 62 people had intellectual disability (94 percent) 

Brain 

Over one-half of males with CASK-related syndrome had seizures. Males with MICPCH had a smaller than average head size, microcephaly, and pontine and cerebellar hypoplasia, which is an underdevelopment of part of the brain stem and lower back part of the brain. Hypoplasia of the pontine and cerebellar ranged from mild to severe. Some of the seizure types reported included late-onset drug-resistant spasms, some of which developed into developmental and epileptic encephalopathy; Ohtahara syndrome; West syndrome; absence seizures; Lennox-Gastaut syndrome; and myoclonic seizures.  

  • 33 out of 61 people had seizures (54 percent)
  • 35 out of 46 people had microcephaly (76 percent)
54%
33 out of 61 people had seizures.
76%
35 out of 46 people had microcephaly.

Other medical features  

Some males with CASK-related syndrome had movement issues, such as ataxia or dystonia; vision issues, including nystagmus (eyes that move rapidly without control); and heart defects.

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

The content in this guide comes from published studies about CASK-related syndrome. Below you can find details about each study, as well as links to summaries or, in some cases, the full article.

  • Moog, U., & Kutsche, K. CASK disorders. 2020 May 21. 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/NBK169825/
  • Mori, T., Zhou, M., & Tabuchi, K. (2023). Diverse clinical phenotypes of CASK-related disorders and multiple functional domains of CASK protein. Genes (Basel), 14(8), 1656. https://pubmed.ncbi.nlm.nih.gov/37628707/

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