The Invitae Spinal Muscular Atrophy STAT test analyzes the copy number of SMN1, which is known to cause spinal muscular atrophy (SMA). SMN2 copy number, which can modify the phenotype in individuals with SMN1-related SMA, is reported for individuals with a homozygous deletion of SMN1. This test does not detect SMN1 sequence variants.
This test provides an accelerated 4 day turnaround time (TAT), which can facilitate urgent management and treatment decisions. Identification of homozygous deletion of SMN1 combined with determination of SMN2 copy number is a predictor of disease severity and identifies those that would benefit from new and emerging therapies. Early intervention is critical to modulate the progressive degeneration seen in SMA.
This test analyzes SMN1 and SMN2 copy number but does not detect SMN1 sequence variants, which are found in 2-5% of individuals affected with SMA. If there is reason to suspect a patient carries a sequence variant, the Invitae Spinal Muscular Atrophy Panel should be considered instead:
Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by the loss of motor neurons within the spinal cord, which results in progressive muscle weakness and atrophy. Other features of SMA may include muscle fasciculations, tremors, poor weight gain, sleeping difficulties, pneumonia, scoliosis, joint contractures, and congenital heart disease. Four clinical SMA subtypes have been distinguished: severe infantile acute SMA type I (also referred to as Werdnig-Hoffman disease), infantile chronic SMA type II, juvenile SMA type III (also referred to as Wohlfard-Kugelberg-Welander disease), and adult-onset SMA type IV.
Type I infants are hypotonic and have severe proximal muscle wasting due to a loss of motor neurons in the anterior horn of the spinal cord. These individuals are diagnosed prenatally or within 6 months after birth. They never sit unaided and usually succumb to the disease within the first 2 years, most often due to respiratory muscle weakness. Individuals with intermediate SMA type II develop the disease before 18 months of age, are able to sit unaided, but do not stand or walk. Individuals with SMA type III are diagnosed after 18 months, are able to walk and often live at least into the second or third decade. Individuals with SMA Type IV walk during adult years and are typically diagnosed in the second or third decade. The age of onset, phenotype, prognosis, and life expectancy display marked inter- and intrafamilial variability.
Approximately 95%-98% of individuals with SMA are homozygous for a deletion or gene conversion of SMN1 to SMN2 and about 2%-5% are compound heterozygotes for an SMN1 deletion or conversion mutation and an SMN1 pathogenic sequence variant. This test analyzes SMN1 and SMN2 copy number but does not detect sequence variants and has a reduced clinical sensitivity compared to the Invitae Spinal Muscular Atrophy Panel.
SMA is inherited in an autosomal recessive manner. Up to 2% of pathogenic SMN1 alleles occur de novo. Some heterozygous carriers (an estimated 8% of Ashkenazi Jewish carriers) appear to have normal SMN1 genetic testing results due to two functional copies of SMN1 on one chromosome and a deletion on the other chromosome, a situation referred to as “silent carrier”. This assay does not detect silent carriers.
On its own, homozygous deletion of SMN1 has high penetrance. However, penetrance is complicated by modifying effects of SMN2 copy number. Unaffected individuals with five copies of SMN2 and a homozygous deletion in SMN1 have been reported, suggesting that five copies of SMN2 may compensate for the lack of SMN1 expression (PMID: 15378550).
The prevalence of SMA I, II and III is estimated to be <2 per 100,000 in the general population, and the incidence of severe infantile acute SMA type I is estimated to be 4-10 individuals per 100,000 live births.
Genetic testing may confirm a suspected diagnosis or rule out disorders with similar symptoms. A genetic diagnosis may also help predict disease progression, inform recurrence risk, and guide treatment and enrollment in clinical trials.
For management guidelines please refer to:
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory.
SMN1 copy number is detected by multiplex ligation-dependent probe amplification and sequencing of the ligation products using Illumina technology (MLPA-seq). Deletions and duplications are called using an algorithm that was developed and its performance characteristics validated by the laboratory to determine copy number at each target by comparing the read counts for the proband sequence with a distribution of read counts derived from a set of clinical samples. SMN1 exon 8 copy number calling has been validated. Reported variants are not confirmed by an orthogonal technology.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for SMN1 exon 8 deletions. Mosaic copy-number deletions and duplications may not be detected. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases (such as circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion, or maternal cell contamination), the analyzed DNA may not represent the patient's constitutional genome.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|
|SMN1, SMN2*||SMN1: NM_000344.3, SMN2: NM_017411.3|
SMN1, SMN2: The SMN1 gene is identical to the SMN2 gene with the exception of exon 8 (also known as exon 7). This assay detects SMN1 and SMN2 exon 8 copy number, which is used to infer the copy number of the entire SMN1 gene. SMN2 exon 8 copy number is only reported for individuals with a homozygous deletion of SMN1 exon 8. This test does not detect sequence variants in SMN1 or SMN2, and therefore cannot be used to identify compound heterozygotes. This test also does not detect silent carriers (individuals that have 2 functional copies of SMN1 on one chromosome and zero copies on the other). Therefore a negative result for carrier testing greatly reduces but does not eliminate the chance that a person is a carrier. For individuals with 2 copies of SMN1, the residual risk of being a carrier has been reported to be 1 in 121 in African Americans, 1 in 345 in Ashkenazi Jewish individuals, 1 in 628 in Asians, 1 in 632 in Caucasians, and 1 in 1061 in Hispanic individuals (PMID: 23788250).