Genetic Testing for Spinal Muscular Atrophy

Crystal Proud, MD: Now we've talked quite a bit about genetic testing, and so why don’t we focus for a moment on the genes that we've been referring to, the SMN1 and the SMN2 genes, and how these genes play a role in our patients impacted by spinal muscular atrophy [SMA]. John, I was hoping you could take us through the different functions of the SMN1 and SMN2 genes.

John Brandsema, MD: We started with the discussion of this survival motor neuron gene and what it does. Both these SMN1 and SMN2 genes are located on the long arm of chromosome 5. It depends a little bit when you're trying to look at a family in terms of when you’re going to be able to make this diagnosis. There's also the option to do prenatal testing. Sometimes, parents, when they're pregnant, will choose to be tested for carrier status.

There is quite a high carrier rate in the population, about 1 in 50 or so, depending on which study you look at. But in that context, there is a false-negative risk, both from those compound heterozygote situations that Nancy was referring to. If it's not a deletion, it's not going to pick it up. But also, some people will have 2 SMN1s on 1 allele and zero on the other. They can still pass that zero copy allele to their child and have a 1 in 4 risk, just like anyone else with this autosomal recessive disorder, of having an affected child.

But the test sees those 2 copies on the other allele and thinks that you're not a carrier. It can be misleading, this prenatal testing. It’s rare for this to happen, but it does happen with varying frequency in different ethnicities. Then you get to newborn screening, again, looking for the double deletion. You're going to miss those who have a sequence change, or some sort of inversion or something else is the reason why their SMN1 gene isn't working. And then, you have patients who present symptomatically.

If you're in a situation where you already have a newborn screen done that was negative, you're really obligated to sequence the SMN1 gene in that situation to look for whether there is a mutation or some other genetic explanation for why 1 of their copies of SMN1 isn't working. Then you could also test them for whether they have a carrier status of 1 and zero and then that compound heterozygous mutation is why they're presenting the symptoms.

Some of our patient populations even that have had an established diagnosis for several years needed to be retested in the era of therapies because we only did the deletion testing to see if they had SMA. But we didn't look at their SMN2 copy number at the time because establishing the diagnosis was sufficient to do their supportive care. But in today's age, we really need to also know the SMN2 copy number in terms of making decisions around initiation of treatments.

The reason the SMN2 copy number is important is because patients are completely missing the SMN1 genes so they're relying on SMN2 to make their survival motor neuron protein. And the SMN2 gene can make the protein but only at about 10% of the efficiency of the SMN1

gene. The more copies of the SMN2 gene you have, the more likely it is that you’ll have milder symptoms with SMA. This rule is pretty accurate at the extreme, so if you have only 1 copy of SMN2, you're likely to present very severely.

If you have more than 4 copies of SMN2, you're likely to present with a mild walking type of SMA. But in the middle there’s a little bit more ambiguity. And there are also clear violations of this rule on both ends due to genetic modifiers, that there are people with more copies who will present more severely, and those with fewer copies who will present with a milder phenotype.

This is why we're all working so hard to try to identify other biomarkers of how severe somebody will be with SMA because, especially in the context of identifying people pre-symptomatically with either prenatal or newborn screening, we need to be able to make a decision about when to start to intervene with some of these new treatments that we have for SMA and when that might be the most appropriate for an individual.

Right now, the SMN2 copy number is the best prognostic marker that we have, but we’re looking at a lot of other things like neural filaments and other possible indicators of disease severity to help us in the decision-making over time and possibly also to assess response to these treatments once they're initiated.

Crystal Proud, MD: My next question for you is going to be whether you can tell that someone has a phenotype based on their SMN2 copy number. It's not uncommon for a parent to call and say, “My child has 2 copies of SMN2 and that means that he's a type II, or he has 3 copies of SMN2 and so he must be a type III.” How you go about addressing that kind of confusion with your parents and families?

John Brandsema, MD: I think that's a really important point of distinguishing that we can't be absolutely sure based on any 1 piece of information. This conversation is very nuanced when you're talking with a prenatal consult, when somebody has had carrier testing for both parents. They've tested their fetus because both parents were identified as carriers, and they're even sometimes trying to make decisions about their pregnancy at the time that you're talking to them.

You're using their SMN2 copy number to try to give some guidance. But it's really important to distinguish that error that we have both in the accuracy of the SMN2 copy number test itself, and also in how well it correlates to the phenotype that somebody is going to present with. But then also to bring in the discussion of all of the treatments that are now modifying the experience of SMA even if people present early.

We have the ability to change their experience of the disease, which we're going to talk about later. That conversation is nuanced in the prenatal context. It's nuanced in the newborn screening context when most times you have a totally normal appearing baby in the clinic with you and parents who have just been through a very stressful time in terms of the delivery.

Now you're throwing the information at them that they're facing a degenerative disease, but we might be able to treat it, and here's some options. Trying to navigate this together really takes a lot of discussion and expertise from multiple perspectives to be able to put that into context. Then we also have our patients who have been living with SMA for a while, and they have the opportunity to be treated.

And it's still important to consider when they first presented with symptoms thus far when we're trying to think about the appropriate treatments for them. It really is context dependent, and we try to use all the information that we have available to us clinically, sometimes also adding factors in like electrophysiology and other things in our decision making to be as clear as possible with families.