Diagnostic testing to confirm a suspected diagnosis of spinal muscular atrophy (SMA). Prenatal or preconception carrier screening for SMA in the general population. Carrier screening for reproductive partner of known SMA carrier. Carrier screening for parents of a child with a deletion of the SMN1 gene or other family history of SMA.
- Patient Preparation
- Lavender (EDTA), Pink (K2EDTA), or Yellow (ACD Solution A or B).
- Specimen Preparation
- Transport 3 mL whole blood. (Min: 2 mL)
- Storage/Transport Temperature
- Unacceptable Conditions
- Ambient: 72 hours; Refrigerated: 1 week; Frozen: Unacceptable
Characteristics: 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 (zero) functioning copies of the SMN1 gene that produces survival motor neuron protein; most (95 percent) have homozygous loss of SMN1 due to deletion or gene conversion, while some (5 percent) have a sequence variant in one remaining copy of SMN1. 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, but phenotype cannot be predicted with certainty. SMN2 copy number will be reported for individuals with zero copies of SMN1 or symptomatic individuals with one copy of SMN1. Two variants that are part of a haplotype associated with SMN1 duplication in silent carriers (2 copies of SMN1 on one chromosome with zero copies on the other) will be reported if detected with 2 or more copies of SMN1 in the context of carrier screening. The presence of these variants, particularly in Ashkenazi Jews and Asians, increases the likelihood that 2 copies of SMN1 are on the same chromosome but this is not definitive.
Inheritance: Autosomal recessive
Cause: Pathogenic mutations in the SMN1 gene.
Variants Tested: For copy number: SMN1 (NM_000344.3) exon 7 c.840C and exon 8 c.*239G, and SMN2 (NM_017411.3) exon 7 c.840T. For haplotype associated with SMN1 duplication (silent carriers): SMN1 c.*3+80T>G (rs143838139) and c.*211_*212del (rs200800214).
Clinical sensitivity: 95-98 percent in individuals affected with SMA. Detection rate for carrier screening is 95 percent in Caucasians, 94 percent in Ashkenazi Jewish, 93 percent in Asians, 71 percent in African Americans, and 91 percent in Hispanics.
Methodology: Multiplex probe ligation-dependent amplification (MLPA)
Analytical sensitivity and specificity: 99 percent.
Limitations: Diagnostic errors can occur due to rare sequence variations. Single base pair substitutions, small deletions/duplications, regulatory region mutations, and deep intronic mutations will not be detected. This test is unable to determine chromosomal phase of SMN1 or SMN2 copies. Even if the variants associated with SMN1 duplication are detected, the test cannot definitively differentiate individuals with one or more copies of SMN1 on each chromosome from individuals with two or more copies of SMN1 on one chromosome and zero on the other (silent carriers).
Counseling and informed consent are recommended for genetic testing. Consent forms are available online at www.aruplab.com.
|Component Test Code*||Component Chart Name||LOINC|
|2013437||SMA Copy Number, Specimen||31208-2|
|2013438||SMA Copy Number, Symptoms||75325-1|
|2013439||SMA Copy Number, SMN1 Copies||35462-1|
|2013440||SMA Copy Number, SMN2 Copies||54449-4|
|2013441||SMA Copy Number, Linked Variant||82155-3|
|2013442||SMA Copy Number, Int||49857-6|
- Spinal Muscular Atrophy