SMA Screening: A Practical Approach

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Faculty

Melissa Gibbons, MS, CGC

Samone Masters, MS, CGC

Tamar Ailenberg, MS, CHC, CCG

Melissa Gibbons, a certified genetic counselor, is an associate professor in the Department of Pediatrics- Genetics at the University of Colorado School of Medicine and Children’s Hospital Colorado in Aurora, CO

Samone Masters is the Supervising Genetic Counselor in the Department of Obstetrics and Gynecology at Jacobi Medical Center in Bronx, NY

Tamar Ailenberg is a certified genetic counsellor with both the American Board of Genetic Counselors and the Canadian Association of Genetic Counsellors. She is a practicing genetic counselor in Ontario, Canada

SUMMARY:

Spinal Muscular Atrophy (SMA) is an autosomal recessive condition that is characterized by the loss of motor neurons that leads to the weakening and wasting of skeletal muscle.  Because the carrier frequency is generally high across most ethnicities and because of the potential severity, carrier screening should be offered to anyone considering pregnancy or who is currently pregnant (ACOG, ACMG recommendations).  A panethnic screening approach has now been widely adopted within the medical community. Since the release of these guidelines, new medical therapies have received FDA approval, further making SMA screening in the prenatal and newborn period compelling.

Carrier Screening Recommendations

ACOG

ACOG recommends offering screening for SMA to all individuals who are currently pregnant or considering pregnancy due to
- High carrier frequency
- Severity of disease: life expectancy ≤2 years old in untreated type 1 SMA

ACMG

In November 2008, ACMG started recommending that SMA carrier screening be offered to all pregnant couples or those considering pregnancy
ACMG (2021) currently recommends that screening for autosomal recessive conditions with a carrier frequency ≥1/200 (including SMA) be offered to all pregnant couples or those considering pregnancy

SMA and Newborn Screening

The goal of newborn screening (NBS) is to allow for newborns to be identified and treated prior to irreversible changes that may take place
As of July 2018, SMA was included on the Recommended Uniform Screening Panel (RUSP) due to meeting the following criteria
- Ability to screen for SMA: Evaluates for homozygous deletion of exon 7 in the SMN1 gene (see SMA Carrier Screening Technologies below)
- Available treatments: See Spinal Muscular Atrophy: An Overview of the Natural History and Available Therapies, linked at the top of this page
- Potential net benefits of screening: Early treatment is met with more success

Interpreting SMA Carrier Screening Results

The Genetics You Need to Understand the Results

SMA is an autosomal recessive condition impacted by two separate genes – SMN1 and SMN2
SMN1 is the causative gene
- The most common mutation in the SMN1 gene is a deletion in exon 7 | 95% of individuals with SMA are homozygotes for this deletion
- The remainder are mostly heterozygotes for an SMN1 exon 7 deletion and a point mutation in SMN1
SMN2 is a modifier gene (can impact the severity of the disease in an affected individual)
A higher number of SMN2 gene copies is thought to correlate with a milder clinical phenotype in those affected with SMA
However, the number of SMN2 gene copies alone is not sufficient to accurately predict the SMA phenotype

Information Included on an SMA Carrier Screening Report

SMN1 gene analysis (dosage)
- The number of SMN1 gene copies (0 to 3+ copies) determines carrier status
g.27134T>G
- A SNP that does not impact the function of the gene | Rather, it is a marker for the possible presence of a pathogenic variant
- The presence of this polymorphism is therefore linked with being a 2+0 carrier known as a “silent carrier”
- The risk of being a silent carrier is determined by an individual’s ancestry
- Presence of g.27134T>G polymorphism increases silent carrier risk
- Absence of g.27134T>G polymorphism decreases silent carrier risk

SMN2
- The number of SMN2 gene copies does not impact carrier status
- Not all labs perform SMN2 gene analysis as part of SMA carrier screening
Additional considerations
- Negative carrier screening does not guarantee an unaffected child
- 98% of individuals with SMA inherited the SMN1 gene mutation from their parents | There is a 2% de novo rate
- In 95% of SMA cases, a homozygous deletion of exon 7 is identified | Many carrier screens only detect this deletion of exon 7 | Residual carrier risks take these limitations into consideration and should be presented to patients

Interpreting an SMA Carrier Screening Report

1 SMN1 Copy: SMA Carrier

Carrier screening of reproductive partner is recommended

2 SMN1 Copies: Further Interpretation of g.27134T>G Polymorphism Needed to Access Carrier Risk

g.27134T>G polymorphism: Present
- Increased risk of being a silent carrier
- Carrier risk based on ancestry, which will be included in the report
- Carrier screening of reproductive partner is recommended
g.27134T>G polymorphism: absent
- Decreased carrier risk
- Carrier risk based on ancestry, which will be included in the report

Ethnicity-Based Risks

Ashkenazi Jewish
- Carrier frequency: 1/41
- Detection rate: 90%
- Residual risk after negative result (no SNP testing): 1/345
- Residual risk after negative SNP result: 1/580
- Residual risk after positive SNP result: Carrier

Asian
- Carrier frequency: 1/53
- Detection rate: 92.6%
- Residual risk after negative result (no SNP testing): 1/628
- Residual risk after negative SNP result: 1/702
- Residual risk after positive SNP result: Carrier

African American
- Carrier frequency: 1/66
- Detection rate: 71.1%
- Residual risk after negative result (no SNP testing): 1/121
- Residual risk after negative SNP result: 1/395.7
- Residual risk after positive SNP result: 1/34

Hispanic
- Carrier frequency: 1/117
- Detection rate: 90.6%
- Residual risk after negative result (no SNP testing): 1/1061
- Residual risk after negative SNP result: 1/1762
- Residual risk after positive SNP result: 1/140

Caucasian
- Carrier frequency: 1/35
- Detection rate: 94.9%
- Residual risk after negative result (no SNP testing): 1/632
- Residual risk after negative SNP result: 1/769
- Residual risk after positive SNP result: 1/29

Genetic Counseling

SMA is inherited in an autosomal recessive pattern
If both partners are carriers
- Risk of the fetus of being affected: 25%
- Risk of the fetus being an asymptomatic carrier: 50%
- Risk of the fetus being unaffected and not a carrier: 25%
Above risks are the same for each pregnancy
If only one partner is a carrier following comprehensive testing of the couple (deletion and sequencing analysis), risk of an affected fetus is very low but not zero because of a small chance of a de novo deletion in one of the fetus’ alleles or a parent being a silent carrier
If one partner is a carrier and the other partner is not tested, genetic counselors can use the above carrier frequencies based on ethnicity to calculate potential risk to the fetus

Determination of SMA Status in Offspring

Preimplantation genetic screening: An option in the setting of preconception counselling and carrier screening or for couples with previous pregnancy affected with SMA
Prenatal Diagnostic testing: Amniocentesis and chorionic villus sampling (CVS)
Newborn Screening: Has become widely adopted for the identification of SMA due to therapies that can potentially improve outcome if administered early in life

Learn More – Primary Sources

ACOG Committee Opinion 691: Carrier Screening for Genetic Conditions

Prevalence, incidence and carrier frequency of 5q–linked spinal muscular atrophy – a literature review | Orphanet Journal of Rare Diseases | Full Text (biomedcentral.com)

Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics (ACMG) (Gregg et al. Genet Med, 2021)

An Ashkenazi Jewish SMN1 haplotype specific to duplication alleles improves pan-ethnic carrier screening for spinal muscular atrophy

Newborn Screening for Spinal Muscular Atrophy – Cure SMA

GeneReviews: Spinal Muscular Atrophy – GeneReviews®

Faculty Disclosures

Melissa Gibbons has participated in Taysha Gene Therapy Advisory Board

Samone Masters has no relevant financial relationships to disclose

Tamar Ailenberg has no relevant financial relationships to disclose

Commercial Support

11/2023 US-UNB-23-0002