Özge’s background is in research; she holds a MSc. in Molecular Genetics from the University of Leicester and a PhD. in Developmental Biology from the University of London. Özge worked as a bench scientist for six years in the field of neuroscience before embarking on a career in science communication. She worked as the research communication officer at MDUK, a UK-based charity that supports people living with muscle-wasting conditions, and then a research columnist and the managing editor of resource pages at BioNews Services before joining Rare Disease Advisor.
Most cases of spinal muscular atrophy (SMA) are caused by mutations in the SMN1 gene that encode for the survival motor neuron (SMN) protein.1 This protein is essential for the health of motor neurons that control the movement of skeletal muscles. When there is not enough functional SMN protein, motor neurons die, leading to muscle weakness and atrophy.
The most common form of SMA (types 1-4) is inherited in an autosomal recessive manner.3 Two SMA carriers have a 25% chance of having a child affected by the disease, a 50% chance of having a child who is also a carrier, and a 25% chance of having an unaffected child.
It is estimated that as many as 1 in 35 people in the US are carriers of SMA.4
SMA Carrier Testing Guidelines
People who have a family member affected by SMA may consider carrier testing to determine their carrier status and calculate their risk of passing the disease onto the next generation. Those with a family member who has SMA or is a carrier of it are at an increased risk of being a carrier of the disease. The risk of being a carrier of SMA is not affected by ethnicity.5
Because the carrier frequency of SMA is high, carrier testing should be offered to all couples planning a family, regardless of ethnicity.6 Patients identified as carriers may consider genetic counseling to evaluate the risk of passing the disease onto future children, and to the fetus, in cases where the couple has already conceived.6
Carrier testing is voluntary and there are caveats to address, such as confidentiality, paternity issues, discrimination, self-esteem, and cost.6
Carrier Testing Specifics
Carrier testing involves a simple blood test that can detect the most common mutations that cause SMA, which is a homologous deletion in the SMN1 gene. Most carriers will have one intact SMN1 gene and one gene with a deletion. In some instances, there is a point mutation in the SMN1 gene, wherein the SMN protein synthesized from this gene is not functional. Carrier testing does not identify point mutations in the SMN1 gene, so it is not 100% accurate. However, testing has been found to detect approximately 90% of carriers.5
In some cases, a de novo mutation occurs during the formation of a sperm or egg cell.7 Some couples, where only one partner is a carrier of SMA, can have a child with SMA due to a mutation that occurs during gametogenesis in the other partner. A negative carrier test does not, therefore, eliminate the risk of having a child with SMA.
Some types of SMA are caused by mutations in genes other than SMN1.8 Carrier testing looking for mutations in these genes is available, but the causative mutation responsible for SMA in that particular family must be known, for these genes to be tested.
Limitations of Carrier Testing
The main limitation of carrier testing is the risk of de novo mutations, which primarily occur during paternal meiosis. It is estimated that approximately 2% of SMA cases are the result of de novo mutations, which is higher than for most autosomal recessive disorders.6
Another limitation is that the copy number of the SMN1 gene can vary from person to person, with 5% of the population having 3 copies of the gene. In these cases, 2 of the SMN1 genes are found on one chromosome 5 and one copy is on the other chromosome 5. Such a carrier will have the same dosage result as a noncarrier with one SMN1 gene on each chromosome 5. So, even though a normal SMN1 copy dosage reduces the risk of being a carrier, there is still a risk of being a carrier and passing the disease onto the next generation. Bayesian analysis should be done to calculate this risk and provide proper genetic counseling to families.6
Carrier testing is also not able to predict the severity of the disease in the offspring, which is dependent on other genetic factors.
Reviewed by Michael Sapko, MD on 7/1/2021
- De Holanda Mendonça R, Matsui C, Polido GJ, et al. Intragenic variants in the SMN1 gene determine the clinical phenotype in 5q spinal muscular atrophy. Neurol Genet. 2020;1;6(5):e505. doi:10.1212/NXG.0000000000000505
- Carrier. National Human Genome Research Institute. Accessed June 1, 2021.
- Causes/Inheritance. Muscular Dystrophy Association. Accessed June 1, 2021.
- Chong JX, Oktay AA, Dai Z, Swoboda KJ, Prior TW, Ober C. A common spinal muscular atrophy deletion mutation is present on a single founder haplotype in the US Hutterites. Eur J Hum Genet. 2011;19(10):1045–1051. doi:10.1038/ejhg.2011.85
- Carrier testing for spinal muscular atrophy FAQ. University of California San Francisco Health. Accessed June 1, 2021.
- Prior TW. Carrier screening for spinal muscular atrophy. Genet Med. 2008;10(11):840–842. doi:10.1097/GIM.0b013e318188d069
- Spinal muscular atrophy. Medline Plus. Accessed June 1, 2021.
- Darras BT. Non-5q spinal muscular atrophies: the alphanumeric soup thickens. Neurology. 2011;26;77(4):312-4. doi:10.1212/WNL.0b013e3182267bd8