Spinal Muscular Atrophy

  • Order to confirm a suspected diagnosis of SMA or for carrier screening
  • SMN1 and SMN2 copy number and the linked variant c.*3+80T>G (rs143838139) will be reported

Order for prenatal diagnosis of SMA when both parents carry a known deletion of SMN1 or have a previous child with SMA caused by two SMN1 deletions

  • Rare pathogenic SMN1 sequence variants will not be detected
  • SMN1 and SMN2 copy number will be reported but the linked variant will not
Related Tests
  • Reproductive carrier screening for cystic fibrosis (CF), fragile X syndrome (FXS), and SMA
  • Recommended for carrier screening in women who are pregnant or planning a pregnancy
  • Not recommended for men, as FXS carrier screening is not indicated
  • Do not use for diagnostic testing in patients with symptoms of CF, FXS, or SMA
  • Not recommended for diagnostic testing for CF, FXS, or SMA

Spinal muscular atrophy (SMA) is the most common lethal genetic disease in children and is characterized by progressive muscle weakness due to degeneration of the lower motor neurons. Onset ranges from before birth to adulthood and severity is highly variable. Individuals with SMA have no functioning copies of the SMN1 gene. Most (95%) have a loss of both copies of the SMN1 gene due to deletion or gene conversion, while a minority (5%) have a deletion of SMN1 on one chromosome and a SMN1 sequence variant on the other. The SMN2 gene, adjacent and highly homologous to SMN1, produces lower levels of survival motor neuron protein compared to SMN1. Disease severity has been shown to be modified by SMN2 gene copy number in some cases, though phenotype cannot be predicted with certainty. An SMN1 variant, c.*3+80T>G, that is part of a haplotype associated with SMN1 duplication in silent carriers (two copies of SMN1 on one chromosome and no copies on the other), particularly in individuals of Ashkenazi Jewish descent, increases the likelihood that two copies of SMN1 are on the same chromosome.

Disease Overview

Incidence

~1/12,000 live births in the U.S.

  • Carrier rate varies by ethnicity: ~1/54 overall in the U.S.
  • See SMA Carrier Risk table for ethnicity-specific posttest carrier risk

Symptoms

  • Progressive muscle weakness due to degeneration of lower motor neurons
    • Clinical findings of affected individuals fall on a spectrum
    • Most common symptoms: difficulty breathing, swallowing, and walking
  • SMA subtypes are distinguished by age of onset and severity for purposes of prognosis and management
    • SMA 0: prenatal onset
      • Most severe form, survival is typically <6 months
    • SMA 1: onset at 0-6 months
      • Most common subtype;  severe muscle weakness, survival <2 years
    • SMA 2: onset at 6-12 months
      • Child usually cannot walk without assistance
    • SMA 3: onset after 12 months
      • Milder muscle weakness, child usually can walk and stand without assistance
    • SMA 4: adult onset
      • Mild muscle weakness, normal life span

Diagnostic Testing

  • Diagnosis is based on clinical findings and molecular genetic testing
    • Electromyography (EMG), nerve conduction velocities (NCV), and muscle/nerve histology may aid in diagnosis
  • 95-98% of individuals with SMA have a homozygous loss of SMN1 (zero copies of SMN1)
  • 2-5% of individuals with SMA have loss of SMN1 on one chromosome and a pathogenic sequence variant in the remaining copy of SMN1 (not detected by this test)
  • Not possible to definitively predict clinical subtype based on genotype
    • Higher SMN2 copy number may correlate with milder disease severity in affected individuals

Carrier Testing

  • Presence of two or more copies of SMN1 usually indicates patient is not a carrier, although residual carrier risk exists
    • Test is unable to determine if SMN1 copies are on the same or opposite chromosomes
  • Test is unable to identify pathogenic sequence variants in the SMN1 gene(s) that are present
  • 3-4% of general population has both copies of SMN1 on the same chromosome (also known as SMN1 duplication)
    • If paired with SMN1 loss (zero copies) on the opposite chromosome, these individuals are “silent carriers” or “2+0 carriers”
  • Two or more copies of SMN1 on the same chromosome is rare but more frequent in certain populations such as African American and Ashkenazi Jewish
  • A linked variant, c.*3+80T>G, often associated with SMN1 gene duplication on the same chromosome, is tested
    • Presence of two SMN1 copies and linked variant increases risk of being silent carrier, especially in Ashkenazi Jewish individuals
  • SMN2 copy number is relevant only for affected individuals

Pathophysiology

  • SMA is caused by low levels of survival motor neuron (SMN) protein essential for motor neurons
  • Majority of functional SMN protein is produced by SMN1 gene
  • Only about 10% of functional SMN protein is produced by SMN2 gene
    • May be multiple copies of SMN2 per chromosome
      • In affected individuals with two missing or mutated copies of the SMN1 gene, SMN protein produced by SMN2 may reduce the severity of symptoms
  • Spinraza (nusinersen) is an FDA-approved drug that can be used to treat SMA by increasing the amount of functional SMN protein produced from SMN2

Genetics

Genes

SMN1, SMN2

Inheritance

Autosomal recessive

De novo Mutation Rate

2% of affected alleles

Test Interpretation

Sensitivity/Specificity

  • Clinical sensitivity for diagnostic testing  
    • 95-98% of individuals with SMA have no copies of SMN1
    • 2-5% of affected individuals have one copy of SMN1 plus a pathogenic sequence variant
  • Detection rate for carrier screening
  • See SMA Carrier Risk table for ethnicity-specific carrier risk

Results

  • Diagnostic test results
    • Zero copies of SMN1 detected
      • Consistent with diagnosis of SMA
    • One copy of SMN1 detected
      • Individual is at least a carrier of SMA and may be affected if a pathogenic sequence variant is present
    • Two copies of SMN1 detected
      • Greatly reduced risk to be affected with SMA
    • SMN2 copy number will be reported but cannot be used to predict disease severity with certainty
  • Carrier screening results
    • One copy of SMN1 detected
      • Individual is carrier of SMA
    • Two or more copies of SMN1 detected
      • Carrier risk is reduced but not eliminated (both SMN1 copies may be on same chromosome or may have a pathogenic sequence variant in one chromosome)
    • Two copies of SMN1 detected and linked variant present
      • Increased risk to be a silent carrier (both SMN1 copies on same chromosome, no copies on the other chromosome)
    • See SMA Carrier Risk table for ethnicity-specific residual carrier risk
SMA Carrier Risk Based on Ethnicity and Test Result
Ethnicity Carrier Frequency  Detection Rate Using SMN1 Copy No. and Linked Varianta   Posttest (Residual) Carrier Risk If 2 Copies of SMN1 and Absence of Linked Varianta   Posttest Carrier Risk If 2 Copies of SMN1 and Linked Variant Presenta  
African American 1 in 72 90% 1 in 375 1 in 39
Ashkenazi Jewish 1 in 67 93% 1 in 918 Likely carrier
Asian 1 in 59 93% 1 in 907 1 in 61
White 1 in 47 95% 1 in 921 1 in 69
Hispanic 1 in 68 3% 1 in 906 1 in 99

aLinked variant is SMN1 c.*3+80T>G.

Sources: Feng, 2017 ; Sugarman, 2012 

Limitations

  • Diagnostic errors can occur due to rare sequence variations
  • Single base pair substitutions, small deletions/duplications, regulatory region and deep intronic variants will not be detected
  • Test is unable to determine:
    • Whether SMN1 copies are on the same or opposite chromosomes
    • Whether SMN1 and SMN2 copies are on the same or opposite chromosomes
Additional Resources