Understanding the Complex Inheritance of Spinal Muscular Atrophy

Spinal muscular atrophy is one of the most common recessive genetic conditions, yet it can be challenging to interpret genetic carrier screen results. Let’s review the unique considerations for spinal muscular atrophy when determining carrier risk and unravel this mystery.

What is spinal muscular atrophy?

Spinal muscular atrophy, or SMA, is a genetic condition that leads to damaged motor nerve cells in the spinal cord that eventually deteriorate, impairing movement and physical strength. It ultimately impacts the ability to move, walk, eat, and breathe. SMA affects about 1 in 11,000 babies born each year, regardless of sex or ethnicity. SMA is often thought of as a childhood condition. However, symptoms may present at different times throughout life, from gestation through infancy and into adulthood. The younger the age of onset, the more severe the condition and prognosis. This is reflected in the four subtypes of the disease, from SMA type I (most severe) to type IV (least severe). Early diagnosis is critical to allow for treatments that may improve survival and help achieve motor milestones.

What causes SMA?

SMA is caused by having no working copies of the SMN1 gene. There are 2 main considerations to assess if someone is at risk for having a child with SMA: how many working copies of the SMN1 gene do they have, and how are those copies arranged on their chromosomes? 

Carriers, including silent carriers, are generally healthy themselves, but are at risk of having a child affected with SMA. Approximately 1 in 54 Americans is a carrier of SMA. If both reproductive partners are carriers of SMA, they have a 1 in 4, or 25%, chance of having a child affected with SMA in every pregnancy.

It is important to know that in addition to the SMN1 gene, we have an almost identical gene, called SMN2, which produces about 10% to 15% of the product of SMN1. For affected individuals who have 0 working copies of SMN1, the higher the number of copies of the SMN2 gene that are present, the milder the symptoms of disease may potentially be. In fact, there are people who have 0 copies of SMN1 and enough copies of SMN2 to compensate so they present with no symptoms at all.

How is SMA carrier screening done?

Carrier screening at Quest Diagnostics for SMA looks for 2 things: the total number of SMN1 genes that a person has and the presence or absence of the “2+0” variant. If a person has a result of SMN1: 1 copy, they are a confirmed carrier of SMA. Typically, if someone is found to have 2 copies of the SMN1 gene, it is not possible to determine if they are on the same or different chromosomes. The “2+0 variant” is a change in the genetic code that doesn’t affect the gene function itself; however, the presence of the “2+0” variant increases the chance that an individual is a silent carrier of SMA. Those risks vary by ethnicity and can be found on the individual’s carrier screening report. Testing of additional family members may be able to clarify an individual’s “2+0” carrier status. Patients who are found to have 2 copies of SMN1 and are positive for the “2+0” variant should be treated as potential carriers of SMA and testing of their reproductive partner should be considered.

This type of carrier screening only detects the specific common deletion in the gene and does not detect other variants. This method of testing detects about 95% of carriers.

Why have carrier screening for SMA?

Saving time, saving neurons. Carrier screening can identify at-risk individuals and gives the option of fetal diagnostic testing through amniocentesis or chronic villi sampling. Some individuals will decide not to do prenatal testing but may elect postnatal testing as soon as the baby is born. Both prenatal and postnatal genetic testing after carrier screening allows for early intervention through treatment. Children of individuals who did not complete carrier testing may still be identified through newborn screening programs, which have been implemented in some states for SMA. Treatments have the best chance of success the earlier they are begun, and early identification of people affected with SMA can make a difference in their lives and the lives of their families.

For more information about SMA and genetic testing for SMA:

• Learn more at QuestSMA.com
• Quest Diagnostics offers multiple test codes for SMA. See the Quest Test Directory listing for Spinal Muscular Atrophy Carrier Screen (test code 39445), Spinal Muscular Atrophy, Diagnostic (16869) and Spinal Muscular Atrophy, Fetus (91619)
• Contact Quest’s genetic specialists at 1.866.GENE.INFO (1.866.436.3463) or GeneInfo@QuestDiagnostics.com for more information and to discuss which test is best

References

1. Sugarman EA, Nagan N, Zhu H, et al. Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72 400 specimens. Eur J Hum Genet. 2012;20:27-32.
2. Lefebvre S, Burglen L, Reboullet S, et al. Identification and characterization of a spinal muscular atrophy‐determining gene. Cell. 1995;80:155–165.
3. Prior TW, Leach ME, and Finanger E. Spinal Muscular Atrophy. In: Adam MP, Mizraa GM, Pagon RA, et al, eds. GeneReviews® [Internet]. 1993-2023. Accessed June 20, 2023. https://www.ncbi.nlm.nih.gov/books/NBK1352/
4. The American College of Obstetricians and Gynecologists (ACOG). Carrier screening for spinal muscular atrophy; frequently asked questions. Accessed June 1, 2023. https://www.acog.org/patient-resources/faqs/pregnancy/carrier-screening-for-spinal-muscular-atrophy
5. What is spinal muscular atrophy (SMA)? Biogen. Accessed June 1, 2023. https://www.togetherinsma.com/en_us/home/introduction-to-sma/smn1-gene.html