How is muscular dystrophy inherited?

What is Muscular Dystrophy?

Muscular dystrophy can be defined as a group of disorders that cause progressive muscle weakness. This would mean the muscles in the body lose function and eventually stop being able to work. Currently, there are about 30 known types of muscular dystrophy. The most common type of muscular dystrophy is called Duchenne Muscular Dystrophy.

For the sake of this article, we will go into more depth with Duchenne Muscular Dystrophy (DMD).  DMD is an X-linked recessive condition caused by variants in the DMD gene. Symptoms for DMD can start with a waddling gait, or way of walking, as well as frequent falls at around 2-3 years old. The progression of DMD can occur quite quickly with wheelchair dependency occurring by age ten and assisted ventilation needed by age 20. 

DMD Variants

DMD is the largest known gene in the genome to date. Typically, variants that cause DMD are ones that disrupt the reading frame, meaning they will alter how the entire gene is read after the variation. A majority of these variants involve deletions in specific spots in the gene’s code, which are called exons. An exon is the part of DNA that is used to code proteins, which in turn help the body to grow, function, and develop. Exons 45-55 or 3-9 are known to have the most frequent deletions that result in DMD.¹ 

Carrier Status

Sometimes it is possible for us to harbor a genetic variant, without us actually showing symptoms for the condition. This is called being a carrier. Typically this occurs for conditions that have autosomal recessive inheritance, which is when individuals need to harbor two variants in order to be symptomatic.

This can also occur with X-linked conditions, which are conditions caused by variants on the X chromosome. Individuals with two X chromosomes (XX) may carry a variant for a condition on one X chromosome, but either show little or no symptoms. This is because their other X chromosome overtakes the one with a variant. In individuals that have one X and one Y chromosome (XY), they will be impacted by a condition if their X chromosome has the variant, because it is their only copy.

While more males are typically impacted by DMD, females can also be affected. Females typically only carry one variant in DMD, making them carriers. It is possible for them to harbor two variants, but less likely. The result of their carrier status typically leaves them asymptomatic, however, they can display Becker Muscular Dystrophy (BMD) symptoms.² BMD is another type of muscular dystrophy that is known to be a less severe and slower progressive version of DMD. Females that carry a DMD variant and are symptomatic would still be considered to be affected by DMD, it is just often less severe and more comparable to the symptoms of BMD.

Children inherit half of their genes from each parent. Which copy of your genes you pass down to your children is random. So, if you carry a gene variant for a condition, you have a 50% chance of passing down that variant to a child, even if you do not have any symptoms of the condition! If the child’s other parent is also a carrier, this means the child has a 25% chance of being affected by the condition.

Inheritance

When it comes to X-linked recessive conditions, affected males will have a 50% chance of passing down their affected gene. This means that all of their genetically female offspring will be carriers of the condition. However, none of their genetically male offspring will be affected, because they will have received the parents Y chromosome, which does not carry the X-linked condition.

A female's risk for passing down the trait depends on if she is affected in both copies of the gene, or if she is a carrier. If she is a carrier, she has a 50% chance of passing down the gene. However, this is a 50% chance for either male or female offspring. If she is affected in both copies of the gene, she has a 100% chance of passing down an affected copy. This would make all male offspring affected, and would make female offspring carriers.

However, not everyone affected by DMD inherited it from a parent. It is also possible that they are the first person in their family to have this variant, making it a de novo variant. About 33% of variants in DMD are de novo, meaning their variant is novel to their family.³ There are a number of reasons this can occur, but it is really just a random change in DNA that occurs either before or right at conception.

Predictive Genetic Testing

Let’s take a look at your family tree, or pedigree. Your sister is a carrier for muscular dystrophy, and her sons are affected by it. Now, it’s possible that your sister’s variant is de novo, meaning that she is the first person in your family to carry the variant and that it was not passed down from either of your parents. But for the sake of understanding genetics, let’s assume one of your parents passed it down to her. This could have come from either of your parents. Therefore, you have a 50% chance that you inherited this variant as well.

Reproductive Options

There are multiple genetic tests that can be done before or during pregnancy. First, carrier status may be tested. If you are only interested in finding out your status for muscular dystrophy, a genetic counselor can order single gene testing for you in the DMD gene. This may be easier if other affected family members, such as your sister or her sons, have previously had genetic testing. This allows the lab to look for the specific variant in your family.

If you are interested in finding out more prior to family planning, you can also talk to a prenatal genetic counselor about carrier panels. This comprehensive panel is a genetic test that aims to check if you carry any autosomal recessive variants that may be passed down to your child. This is typically done along with your child’s other parent to see if the two of you harbor any of the same variants.

After testing, preimplantation genetic testing (PGT) could be a next step if you are interested in ensuring that your child does not harbor a particular genetic condition. Let’s say you did not want to pass down the muscular dystrophy gene; PGT could be used in tandem with in vitro fertilization (IVF). Here, embryos would be tested to see if they harbor the variant. You could then choose to implant embryos with or without the variant.

Conclusion

Overall, while we are able to predict risk for individuals to be affected by muscular dystrophy, it is best to speak with a genetics professional to talk about your own personal risk. This can take place in a genetic counseling session, where the genetic counselor can discuss what genetic testing might look like for you. It is always best to seek the advice of a professional when considering serious medical questions.