The Science

Your genetics is not your destiny

George M. Church (Geneticist)

What is CASK?

CASK is a protein (a molecule that ‘does stuff’) found in the human body. The CASK gene is the section of DNA that codes for the protein (has the recipe on how to make it). The gene is very large being 404,253 bases (letters) long. To put it into perspective, the average size of a human gene is 28,000 bases (Ref: Bionumbers). The CASK protein plays an important role in the brain, allowing brain cells (neurones) to work properly. It also interacts with a large number of other proteins, making its role wide-ranging and important. Research has also shown that the protein is involved in metabolic pathways (Srivastava et al 2016) and that some of the symptoms of CASK gene mutation may be a result of metabolic stress on the body (Patel et al. 2020).

The Swiss army knife of proteins

The CASK protein is a large protein that can do many jobs. It is best to think of it as a swiss army knife. Depending on the mutation, the swiss army knife can do all of its jobs, most of its jobs, a few jobs, or none of them.

The most serious mutations tend to be deletions or additions. It generally means that some or all of the tools on the knife are broken. If you have been told that your child has a frameshift mutation, then this will have been the result of a ‘letter’ in the DNA being deleted or accidently added.

A substitution or duplication on the CASK gene can mean that a few of the tools are damaged, but not broken. Maybe a knife got a bit rusty or the corkscrew a bit bent. So it can still do the job but it may struggle , be inefficient or just be a bit ‘hit or miss’. Your geneticist may have told you your child has a missense mutation. This will have been caused by a substitution. Occasionally, however, a substitution can cause a nonsense mutation. This is a serious type of mutation since it means the knife is likely to be completely broken, or only has some of its tools.

Some people are found to be mosaic for the mutation. This means that the faulty genes are only found in some parts of the body. People with mosaicism tend to have less severe symptoms.

Is it inherited?

CASK gene mutation is a dominant mutation, which means only one faulty copy of the gene is needed to cause the disease. It also means that it is not normally heritable. The condition is caused by a ‘de novo’ mutation – a random occurrence. There is nothing that the parent could have altered or done differently to avoid their child having the condition. This is good news for family planning because there is no reason any future children should have the condition. The geneticist assigned to the family should explain this (or any exceptions to this rule) and reassure the family. Never-the-less the NHS are increasing their genetic testing tools and couples may be able to request a blood test in the early stages of future pregnancies to find out whether the same mutation has occurred again.

Boys versus girls

Cask gene mutation is an X-linked disease. This means that the gene is found on the X chromosome and so boys and girls will be affected differently.

All boys’ cells contain an X and a Y chromosome (along with 22 pairs of other chromosomes). Girls’ cells contain two X chromosomes. Since the CASK gene is found on the X chromosome, girls have two CASK genes in every one of their cells. One will be functional and the other will be faulty. The body automatically inactivates one X chromosome in each cell, but this is completely random as to which X chromosome gets inactivated. On average it means that, in girls, 50% of their cells have the healthy CASK gene activated (and so can make a perfect CASK protein), and 50% of their cells have their faulty gene activated.

Boy’s cells only contain one X chromosome, and therefore only one CASK gene per cell. Therefore, if they have CASK disease, they have no healthy copy of the CASK gene in any cell. Sadly, this means the child is very sick and normally passes away soon after birth.

There are, however, exceptions and there are a number of boys in the world with CASK gene mutation who, possibly due to mosaicism (Burglen et al. 2012), have a mild version of the condition.

MICPCH and X-linked intellectual disability

The brains of children with CASK gene mutation often fall into two categories. From an MRI it can be seen that the cerebellum is underdeveloped, causing the microcephaly associated with the disease. If the pons (part of the brain stem) is also small or misfigured then the child is said to have pontocerebellar hypoplasia (PCH) and, specifically, MICPCH. This is the more severe form of the disease. If the brain stem is healthy then the condition is called XL-ID. Again, not every child fits neatly into one of these two groups and some specialists see it more as a scale, with MICPCH associated with intractable epilepsy at one end and XL-ID at the other.