Types of changes in the SCN2A gene and how they may affect clinical trial eligibility

About SCN2A and Nav1.2

SCN2A is a gene that tells the body to produce a protein called Nav1.2. 

Nav1.2 is an important sodium channel in the brain. It lets a chemical called sodium into and out of brain cells (neurons). 

The movement of sodium tells the neurons to ‘fire’, which sends messages between neurons and to the rest of the body. 

Changes (variants) in the SCN2A gene affect the way the Nav1.2 sodium channel works. A wide range of changes in the SCN2A gene have been seen. These have been broadly grouped into two different types: gain of function and loss of function variants.

Gain of function variants

Gain of function (GOF) variants in the SCN2A gene make Nav1.2 more active than usual. This means more messages are sent between neurons. 

Loss of function variants

Loss of function (LOF) variants make Nav1.2 less active than usual. This means fewer messages are sent between neurons.

Mixed or unclear variants

A small number of variants have been found that show mixed GOF and LOF effects. Others cannot be placed into either category.

Why does it matter whether the variant is gain of function or loss of function?

For some treatments, called antisense oligonucleotides (ASOs), the type of variant matters. This is because in SCN2A, ASOs are specially designed to treat either gain of function or loss of function variants. 

An ASO designed for a gain of function variant will not work for a loss of function variant. Only individuals with gain of function variants will be eligible for a clinical trial testing this type of ASO.

And an ASO designed for a loss of function variant will not work for a gain of function variant. Clinical trials of these ASOs will only allow individuals with loss of function variants to enrol.

How to find out which type of variant it is

Some genetic testing reports will say which type of variant the person has. If not, a clinical geneticist should be able to find out which it is.

The sponsor or investigator of a clinical trial testing an ASO may review existing genetic testing results or organise for more testing to be done to find out which type of variant it is.