How ALS Genetic Mutations Are Inherited
Genes are found on long twisted strings of DNA called chromosomes. Each cell in the body (except sperm and eggs) has 46 chromosomes, arranged in pairs, that contain an estimated 20,000 to 25,000 genes. Chromosomes, and the genes they carry, are passed from parents to children. A child inherits one chromosome in each pair from the father, and the other chromosome in each pair from the mother.
Genes, Mutations and ALS
Genes serve as instruction manuals for cells, telling each cell’s protein-making machinery how to assemble all the proteins it needs to work and stay healthy. Sometimes these instructions are different from the instructions needed to make a healthy protein. This happens because of a gene change, also called a gene mutation. When mutations change genes in a way that is harmful to the cell, they can cause diseases like ALS. Click here to learn more about ALS genes and mutations.
Once an ALS-associate gene is mutated, it can be passed from parents to their children. This is known as inheritance.
Because chromosomes occur in pairs, every cell (except sperm and eggs) has two copies of almost every gene. For instance, the C9orf72 gene, which has been linked to ALS, is located on chromosome 9. Since there are two copies of this chromosome, each cell carries two copies of the C9orf72 gene.
If at least one copy of the C9orf72 gene is mutated, it can lead to ALS. This is true for most ALS genes – inheriting one mutated copy is enough to cause or increase a person’s risk of developing the disease. When having just one copy of a mutated gene can cause disease, it is known as a dominant mutation. When both copies of a gene must be mutated to cause disease, it is called a recessive mutation.
Just because a person inherits an ALS-linked gene mutation does not automatically mean they will develop the disease. Penetrance refers to the likelihood that someone carrying a disease-causing mutation will go on to develop the disease.
Some gene mutations cause such a significant change in cell function that anyone who inherits it is almost certain to develop ALS at some point during their life. Examples of these include the C9orf72 gene mutation and many SOD1 mutations. Other ALS gene mutations show reduced (or incomplete) penetrance, which means that not everyone with the mutation will develop ALS. These mutations increase the risk of the disease but may not cause it without other contributing factors.
The penetrance of most ALS gene mutations increases with age, so the likelihood of developing ALS generally increases as a person gets older. For example, the penetrance of the A4V mutation in SOD1, the most common SOD1 mutation in North America, is estimated to be at least 90% by age 70. This means that at least 90% of people with the A4V mutation develop ALS symptoms by age 70.
Probability, Chance and Genetic Inheritance
During the formation of eggs and sperm, chromosome pairs split up, so an egg or sperm each contains only one chromosome from each pair, incorporated at random. This means that a parent has a 50-50 chance of passing any specific gene along to their child.
Nearly all the ALS-associated genes that have been identified are located on autosomes, which are non-sex chromosomes (not the X and Y chromosomes). So, for example, if a man has one normal copy of the C9orf72 gene and one mutated copy, about half his sperm will contain the normal gene and the other half will contain the mutated gene. This means there is a 50% chance he will pass the mutated gene on to any of his children. The chances of passing it on to successive children are not affected by whether previous children received it; the chance is still 50% for each child. This would be the same for a woman carrying the mutation and passing it on in her eggs.
The same calculation holds true for almost all ALS genes. However, one ALS gene, UBQLN2, is found on the X chromosome, which changes the odds of inheritance since females inherit two X chromosomes and males inherit one X chromosome and one Y chromosome.
If the mother has a mutated UBQLN2 gene and the father does not, there is a 50% chance that any of her children will inherit a mutated copy. Fathers, on the other hand, cannot pass a mutated UBQLN2 gene on to their sons, but all their daughters will get a mutated copy.
Determining Your Genetic Status
The only way to know for sure if you carry a mutation in a gene associated with ALS is to get a genetic test. The decision whether to get tested or not is a very personal one. Genetic testing comes with many benefits, but also some risks, and may not be right for you. Click here to learn more about the benefits and risks of genetic testing for people currently living with ALS. If you haven’t been diagnosed with ALS but have family members with the disease, click here to explore the potential benefits and risks of genetic testing.
To learn more about ALS genetics, check out these resources provided by the International Alliance of ALS/MND Associations and watch this video from experts through our collaboration with the Alliance.