WHAT IS A CASK GENE MUTATION
OVERVIEW OF THE CASK GENE
The CASK gene is located on the X chromosome and provides instructions for making a protein called calcium/calmodulin-dependent serine protein kinase (CASK). The CASK protein is primarily found in nerve cells (neurons) in the brain, where it helps control the activity (expression) of other genes that are involved in brain development. It also helps regulate the movement of chemicals called neurotransmitters and of charged atoms (ions), which are necessary for signaling between neurons (Medline Plus, 2014).
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Mutations in the CASK gene are associated with two main related disorders that impact brain development: microcephaly with pontine and cerebellar hypoplasia (MICPCH), and X-linked intellectual disability (XL-ID) with or without nystagmus. MICPCH typically causes more severe symptoms than XL-ID. Females have two copies of the X chromosome, whereas males only have one copy; thus, when males have a mutation on their CASK gene, they typically have more severe signs and symptoms than do females. Research suggests that the more severe MICPCH mostly affects females, likely because only a small number of males with MICPCH survive to birth (Medline Plus, 2014). ​
COMMON SYMPTOMS OF A CASK GENE MUTATION
Neurological Symptoms:
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Microcephaly with or without pontine and cerebellar hypoplasia (MICPCH)*
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Seizure disorder/epilepsy (e.g., myoclonic jerks, infantile spasms, and subcortical myoclonus*)
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Hypotonia (Low muscle tone)
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Hypertonia (High muscle tone)
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Intellectual disability, often moderate-to-severe
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Temperature regulation difficulty
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Poor circulation
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Nystagmus
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Optic nerve hypoplasia
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Sensorineural hearing loss
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Sensory processing difficulties
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Cortical visual impairment (CVI)
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Motor Symptoms:
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Delayed gross and fine motor skills
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Dysphagia (Difficulty swallowing)
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Feeding difficulties (May require G-tube placement)
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Ataxia (Impaired coordination)
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Apraxia (Impaired coordination needed for speech)
Additional Physical Symptoms:
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Distinct facial features:
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Rainbow-arched eyebrows
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Large eyes
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Wide nasal bridge
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Long philtrum
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Undeniably beautiful
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Gastrointestinal issues:
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Reflux/GERD
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Constipation
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Slow motility
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Orthopedic issues:
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Scoliosis
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Hip dysplasia/subluxation
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Short stature
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Behavioral Symptoms:
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Self-stimulatory behaviors (e.g., hand flapping, biting)
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Sleep disturbances
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Joyful personality
*macrocephaly and unremarkable head circumference measurements have also been reported
*subcortical myoclonic seizures mimic myoclonic seizures, but do not originate in the brain (or show up on a typical EEG)
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[source: cask.rare-x.org], [parent reported]
COMMON
MISDIAGNOSES
The CASK disorder has been commonly confused with, or misdiagnosed as:
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Angelman Syndrome
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Dandy-Walker Syndrome
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Rett Syndrome
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Cerebral Palsy
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Autism
[source: parent reported]
GENETICS
THE BOOK ANALOGY
FREQUENTLY ASKED QUESTIONS:
CASK GENE MUTATION
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What is a CASK gene disorder
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What are the different types of CASK gene disorders
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How many people are diagnosed with CASK gene mutations
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What test(s) will my child need to confirm a CASK gene mutation
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What type of mutations are seen with CASK gene disorders
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When was the CASK gene discovered
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Why are boys more severely affected than girls
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When do symptoms first present
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Did my child inherit this disorder from me
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What is the likelihood that I will have more than one child with CASK
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What is the life expectancy of those diagnosed
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Is the CASK gene disorder degenerative
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Will my child walk or talk
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Will my child develop epilepsy
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Are there any treatments for CASK gene disorders
What is a CASK gene disorder?
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CASK gene disorders occur when an individual has a pathogenic or disease-causing mutation on their CASK gene. The CASK gene is located on the X-chromosome and is responsible for creating a protein called calcium/calmodulin-dependent serine protein kinase (CASK). For more information on the CASK gene and CASK-related disorders, see section Overview Of The CASK Gene.
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What are the different types of CASK gene disorders?
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Microcephaly with pontine and cerebellar hypoplasia (MICPCH):
This is the most commonly occurring CASK-related disorder seen in our community and is associated with pathogenic loss-of-function mutations on the CASK gene (Moog et al., 2020). Individuals with MICPCH will have MRI findings that include underdevelopment of the cerebellum and pons. MICPCH affects females more frequently than males, likely due to the fact that males with MICPCH rarely survive birth.
Females with the MICPCH subtype of CASK may exhibit intellectual disability (often moderate to severe), global developmental delay, axial hypotonia and appendicular hypertonia, and movement disorders (e.g., dystonia; Moog et al., 2020). Research suggests that most affected individuals will be able to sit independently, but only ~25% will be able to walk. Language is thought to be absent in most, however, anecdotal evidence suggests that children learn how to communicate in a variety of non-verbal ways.
MICPCH in males may have a comorbidity of severe epileptic encephalopathy in addition to severe-to-profound developmental delay (Moog et al., 2020). Males with the MICPCH subtype often experience infantile spasms early in life that are difficult to treat.
Most affected males and females with MICPCH will have the disorder as a result of a de novo pathogenic variant (i.e., they did not inherit the variant from a parent; Moog et al., 2020).
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X-linked intellectual disability (XL-ID) with or without nystagmus:
XL-ID with or without nystagmus is thought to be the more mild subtype of CASK-related disorders and is associated with milder hypomorphic pathogenic variants.
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Males with XL-ID may have mild-to-severe intellectual disability, with or without nystagmus and other ocular abnormalities. Females will typically have normal intelligence, however, some may exhibit mild-to-severe intellectual disability with or without additional ocular abnormalities (Moog et al., 2020).
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How many people are diagnosed with CASK gene mutations?
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Currently, there are 277 known individuals diagnosed with a CASK gene mutation worldwide (Source: CASK Gene Foundation). However, many factors – such as the availability of testing, age of affected individuals, etc. – may impact these numbers.
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What test(s) will my child need to confirm a CASK gene mutation?
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Only a genetic test can confirm if your child has a CASK gene mutation. There are various types of genetic tests:
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Single nucleotide polymorphism (SNP) microarray: This test detects variations in a person’s DNA, such as large deletions or duplications on each chromosome. The majority of CASK gene mutations cannot be detected on a microarray test and require further testing for proper diagnosis, however, some community members report that their child was diagnosed through a microarray analysis. Microarrays can be performed through blood or saliva.
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Whole Exome Sequencing (WES): This test detects variants in protein-coding regions of the genome to uncover genetic influences on disease. WES is able to take a more in-depth, intricate look at each chromosome. The majority of CASK gene mutations are detected via WES. Exome sequencing can be performed through blood or saliva.
Other tests that may be performed prior to, or after, genetic testing include*:
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MRI: Brain MRIs are commonly performed once a child receives a diagnosis of microcephaly. Common abnormalities seen on MRIs among those diagnosed with a CASK gene mutation include pontine and cerebellar hypoplasia. This means that two areas of the brain, the pons and cerebellum, are underdeveloped and thus smaller than normal. This MRI finding, called microcephaly with pontine and cerebellar hypoplasia (MICPCH), is the most common form of a CASK gene disorder noted in our community.**
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*A diagnosis of MICPCH alone does not mean the child has a CASK gene mutation. The child will still require genetic testing for confirmation.
**MICPCH occurs on a spectrum of severity. Some individuals have a more severely impacted cerebellum and pons, whereas others may only have a portion of their cerebellum underdeveloped.
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What type of mutations are seen with CASK gene disorders?
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To understand the types of variants seen with CASK gene disorders, it’s important to have a basic understanding of genetics. See our Genetics 101: The Book Analogy for an easy-to-understand overview of genes, chromosomes, and the genome alphabet!
There are a variety of mutations, or variants, seen in our community. Typically, no two individuals will have the same mutation unless they inherited the gene from their mother.
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CASK gene deletion:
Deletions involve the loss of one or more nucleotides from a DNA segment. Any number of nucleotides can be deleted from a DNA segment, from one single nucleotide to an entire piece of a chromosome (NIH.gov, 2024). Many individuals with CASK gene mutations have deletions of some, or a large portion, of their CASK gene.
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CASK gene missense mutation:
Missense mutations occur when a single nucleotide base in a DNA sequence is swapped for another, resulting in a different codon and, therefore, a different amino acid (Elsevier, 2024). The severity of the missense mutation is dependent upon which amino acid it codes for. Recent research suggests that missense mutations on the CASK gene can impact interactions with other important proteins (LaConte et al., 2018).
CASK gene nonsense mutation:
Nonsense mutations occur in DNA when a sequence change replaces an amino acid with a stop codon rather than a codon specifying an amino acid. The stop codon results in the production of a shortened protein that is likely non-functional (NIH.gov, 2024).
CASK gene frameshift mutation:
A frameshift mutation is caused by the insertion or deletion of nucleotide bases in numbers that are not multiples of three. This is important because cells read a gene’s code in groups of three bases when making a protein, and each of these “triplet codons” corresponds to one of 20 amino acids used to build a protein. Thus, if a mutation disturbs this normal reading of the gene’s code, then the entire gene sequence following the mutation cannot be read. As a result, frameshift mutations often result in the addition of the wrong amino acids to the protein, and/or they may create a stop codon similar to a nonsense mutation (NIH.gov, 2024).
CASK gene duplication:
Duplications occur when one or more copies of a DNA segment is produced. These copies, or duplications, can be as small as a few bases or may be a duplication of the entire gene.
CASK gene insertion:
Insertions involve the addition of one or more nucleotides into a segment of DNA. Any number of nucleotides can be added, or inserted, into a segment of DNA. The effect of an insertion varies, but can disrupt the function of a gene (NIH.gov, 2024).
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When was the CASK gene discovered?
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1998: The first reported associated between a deletion of the CASK gene and clinical phenotype of optic atrophy (Dimitratos et al., 1998)
2007: The first reported case of a female patient with a large deletion on her CASK gene causing microcephaly and intellectual disability. This was the first time it was suggested that the CASK gene is involved in X-linked intellectual disability (Froyen et al., 2007)
2008: Confirmation of associations between CASK gene mutations and MICPCH and XLID in five patients (Najm et al., 2008)
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Why are boys more severely affected than girls?
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The CASK gene is located on the X-chromosome, which is one of two sex chromosomes. Females inherit two X-chromosomes (one from their mother and one from their father). However, all female cells go through a process called x inactivation when, one X- chromosome is silenced, which is thought to ensure that females do not experience overexpression of the X-chromosome. X inactivation occurs at random and while it is hypothesized that 50% of the paternal X-chromosomes and 50% of the maternal X-chromosomes are silenced, that is not always the case. When the CASK gene mutation occurs on the maternal X-chromosomes, females have the paternal “back-up” X-chromosomes that are still producing functional protein. In addition, females can experience a phenomenon called “skewing” in which more of either the paternal or maternal X-chromosomes are silenced. If a female has 70% of her maternal X-chromosomes silenced, and the CASK gene mutation occurs on the maternal X-chromosome, that person will produce more functional CASK protein and may display a milder form of the CASK gene disorder than if she had 50% of her maternal chromosomes silenced.
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Males, on the other hand, inherit one X-chromosome from their mother and one Y-chromosome from their father. Thus, when a CASK gene mutation occurs in males, it occurs on the entire X chromosome, which causes more severe symptoms, as there is no “back up” X-chromosome that produces functional CASK protein.
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It should be noted, however, that not all males with CASK gene mutations are more severely affected than females. There are additional factors that may impact severity, such as the type of mutation, which may allow for some functional or partially functional CASK protein to be produced. More research is needed to better understand why some individuals are more severely affected compared to others. ​
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When do symptoms first present?
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Symptom presentation varies person to person. Some parents report that symptoms, such as slow growth or a small head circumference, were noted during the prenatal period. Other parents report that symptoms became noticeable within the first six months of life.
The most commonly reported first symptom is microcephaly that often progresses over time. Anecdotal evidence suggests that developmental delay becomes prominent within the first 6-12 months of life.
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Did my child inherit this disorder from me?
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The majority of cases occur de novo, meaning the variant is a random occurrence and was not inherited from either parent. However, it is possible for females to be carriers of their child’s CASK gene mutation, which would be detected via genetic testing, and thus have a 50% chance of transmitting the disorder in each pregnancy. Males who inherit the pathogenic variant will be affected due to only having one X-chromosome, however, females who inherit the pathogenic variant may be asymptomatic or display a range of symptom presentation (Moog et al., 2020). This is more common with the XL-ID subtype compared to MICPCH.
If the CASK pathogenic variant cannot be detected in the mother’s DNA, there is still a chance of germline mosaicism that could cause pathogenic variants in additional children (Moog et al., 2020). This means that the mutation is only present in the mother’s eggs and cannot be detected through genetic testing.
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What is the likelihood that I will have more than one child with CASK?
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If genetic testing confirmed your child’s mutation is de novo (i.e., occurred at random; not inherited from either parent), then it is very unlikely that any additional children will also have a CASK gene mutation. Germline mosaicism (i.e., the mutation only occurs in the sex cells) is unlikely, but possible, and is unable to be detected via genetic testing.
If genetic testing confirmed that either parent is a carrier of the mutation, we recommend speaking with a genetic counselor for further information that will be specific to your family.
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What is the life expectancy of those diagnosed?
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To date, no research has been conducted regarding life expectancy among those diagnosed with a CASK gene mutation. Unfortunately, the CASK community has lost a number of members of various ages. Research suggests that males diagnosed with MICPCH, the more severe form of CASK, rarely make it to birth or pass within the first year. More research is needed to better understand mortality and prognosis among individuals diagnosed with CASK gene mutations.
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Is the CASK gene disorder degenerative?
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While initial research suggested that CASK gene disorders were neurodevelopmental in nature, more recent evidence suggests that the disorder is neurodegenerative. Results from a study conducted by Muhkerjee et al. (2022) show that complete loss of the CASK gene in males leads to unconstrained degeneration and encephalopathy. However, x-inactivation in females results in a non-progressive pathology. More research is needed to further explain if, and to what extent, CASK gene mutations are neurodegenerative.
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Will my child walk or talk?
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Research suggests that about 25-50% of affected individuals gain the ability to walk (Moog et al., 2020). While research also suggests that language is absent among most of our children, data from the RARE-X CASK data collection program show that children learn to use a variety of non-verbal communication methods, such as gestures or AAC devices, to effectively communicate with their parents and caregivers. More research is needed in this area to better discern how individuals with CASK communicate wants and needs.
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Will my child develop epilepsy?
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Epilepsy is a common comorbidity of CASK-related disorders, with affected individuals showing a range of seizure types such as infantile spasms, absence seizures/atypical absence seizures, myoclonic jerks, focal seizures, and subcortical myoclonus. Research suggests that between 40-50% of individuals with CASK gene disorders develop epilepsy (Giacomini et al., 2021). Some research asserts that 40% of affected individuals will develop epilepsy by the age of 10-years-old (Moog et al., 2020).
Overall developmental disability does not seem to be related to development of epilepsy or specific epilepsy/EEG characteristics (Giacomini et al., 2021). Per anecdotal data from our community, epilepsy in CASK is often difficult to treat and requires a combination of treatments.
Project CASK, in conjunction with Dr. Asim Shahid at New York Presbyterian Hospital, is proud to report that we are launching the first-ever comprehensive study on epilepsy in CASK in Summer 2024. We hope that this study will provide additional insight on which variants are more likely to develop epilepsy, best treatment options available, and provide overall clarity on this important and devastating symptom.
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Are there any treatments for CASK gene disorders?
Currently, there are no disorder-specific treatments for CASK gene disorders. Affected individuals are supported through frequent therapies, nutritional support, and pharmaceutical support to lessen symptoms. More research is needed, and is on its way, to develop targeted disorder-specific treatments for the CASK community.
In December 2023, Project CASK hosted the CASK Think Tank in partnership with the Orphan Disease Center at University of Pennsylvania. This was the first time that CASK experts from around the world came together with other rare disease experts, including translational and basic researchers, to discuss CASK and help us pave the path towards efficacious treatments, including gene therapy and small molecule treatments, as quickly as possible. Following the Think Tank, Project CASK opened our Grants Program for the first time and received 18 applications for both basic and translational research. Results from this RFA will be available shortly, and we are eager to jumpstart therapeutic development for CASK to get some research funded!
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Questions?
Do you have a question not listed here? You can CASK Us Anything! Just send an email to hello@projectcask.org and one of our team members will respond as soon as we are able.
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