The Invitae Spinal Muscular Atrophy test analyzes SMN1, which is known to cause spinal muscular atrophy (SMA), and SMN2, which can modify the phenotype in individuals with SMN1-related SMA. The presence of multiple copies of the SMN2 gene is associated with a milder phenotype or, rarely, non-penetrance (PMID: 15378550, 11839954).
Individuals with clinical signs and symptoms of SMA may benefit from diagnostic genetic testing to confirm the diagnosis, provide anticipatory guidance, help determine which relatives are at risk, and to guide treatment and enrollment in certain clinical trials.
For a broader analysis of the genetics of hereditary neuropathies or neuromuscular disease:
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, tremor, 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.
SMA is inherited in an autosomal recessive manner. Up to 2% of SMA occurs de novo (PMID: 9345102). 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” (PMID: 9199562, 10405443).
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 (PMID: 745211), and the incidence of severe infantile acute SMA type I is estimated to be 4-10 individuals per 100,000 live births (PMID: 1608493, 8478016, 745211).
Approximately 1 in 50 individuals are carriers of a single SMN1 deletion or pathogenic variant.
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 performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) 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 (typically referred to as exon 7). This assay unambiguously detects SMN1 exon 8 copy number and sequence variants. Sequence variants outside of exon 8 will also be detected, but this assay cannot determine whether the variant is located in SMN1 or SMN2. SMN2 exon 8 copy number will be reported for individuals with a positive result in SMN1. CNVs of exons 1-7 of SMN1 or SMN2 (typically referred to as exons 1-6 in the literature) will not be reported. This assay cannot 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). The SMA-STAT test does not detect sequence variants in SMN1 or SMN2, and therefore cannot be used to identify compound heterozygotes.