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Gene Symbol: SMN1 and SMN2
Chromosomal Locus: 5q13.1
Protein: Survival Motor Neuron 1, telomeric
Pseudonyms: SMA, types I-IV, Werdnig-Hoffmann disease, Kugelberg-Welander disease
TURNAROUND TIME: 8 days
CPT CODES: 81329
TESTING METHODOLOGY: Detection of copy number for exon 7 of SMN1 and SMN2 using Multiplex Ligation-Dependent Probe Amplification (MLPA). This methodology also includes probes for the rare allele of two polymorphisms g.27134T>G and g.27706-27707delAT. The reference sequence used for this assay was NM_000344.3. This test can be used to determine carrier status
SPECIMEN REQUIREMENTS:
- Collect: Prefer two 5ml whole blood EDTA (lavender top) tube.
- Min. Collection: 0.7 ml whole blood EDTA.
- Transport: blood EDTA at Room Temp shipped regular next day air (No Saturday delivery; store specimen at 4°C and ship Monday).
- Stability: Ambient: up to 7 days; Refrigerated: 2 weeks. Frozen: unacceptable
- Unacceptable Conditions: Serum. Frozen or severely hemolyzed blood. Clotted blood.
- Prenatal testing: Direct: 5ml direct unspun amniotic fluid or 15mg CVS tissue with a backup flask growing. Culture: confluent T25 flask. Maternal blood sample is required for maternal cell contamination studies.
* Extracted nucleic acid is accepted as a specimen type. Our laboratory requires that isolation of nucleic acids used for clinical testing occurs in a CLIA-certified laboratory, or a laboratory meeting equivalent requirements such as established standards from a recognized organization, or certified by an appropriate clinical regulatory agency.
A Molecular Genetics Laboratory Test Requisition must accompany the specimen. Contact the Molecular Laboratory at 918-502-1721 to obtain further information.
*Note: Counseling and informed consent are recommended for genetic testing. A consent form is available as a resource but not required.
INTERPRETATIVE DATA:
Incidence: 1 in 10,000 in the USA
Inheritance: Autosomal recessive; 2.5% of cases result from a de novo mutation on one of the alleles.
| Ethnicity | Carrier Frequency | Post-test Carrier Risk |
|---|---|---|
| Caucasian | 1 in 35 | 1 in 3500 |
| Ash Jewish | 1 in 41 | 1 in 4000 |
| Asian | 1 in 53 | 1 in 5000 |
| African American | 1 in 66 | 1 in 3000 |
| Hispanic | 1 in 117 | 1 in 11000 |
Disease Characteristics: Muscle weakness and atrophy due to a loss of motor nerves in the spinal cord and brain stem. Onset of disease ranges from before birth to young adulthood. Weakness is almost always symmetric and progressive, leading to paralysis of the limbs and trunk- eventually resulting in death. Four clinical types of the disease, types I - IV, are defined by decreasing severity of symptoms. SMA, type I (Werdnig-Hoffman syndrome) strikes within the first 6 months of life. Most children with SMA I die before reaching 2 years of age due to respiratory failure. SMN2 harbors a translational silent C > T substitution in a splice enhancer sequence of exon 7, resulting in exon 7 skipping at the mRNA level. The alternatively spliced SMN2 mRNA encodes a truncated, highly unstable, nonfunctional protein. A small fraction of SMN2 transcripts contain exon 7 that encode a full-length, functional SMN protein. which provides both a molecular explanation for phenotypic severity and a target for therapy. SPINRAZA™ is a tailored molecular therapy for SMA that modulates the splicing behavior of the SMN2 gene resulting in more functional SMN protein.
Molecular Genetic Mechanism: Homozygous deletion of exon 7 of the SMN1 gene is responsible for 95-98% of all cases of SMA. Most case with a deletion will have a deletion of exon 8 as well. The presence of SMN2 results in a small amount of full length transcripts. Establishing the number of the SMN2 copy number is important for SMA patients: the more SMN2 copies a patient has, the more functional SMN protein is produced and the milder the SMA phenotype is. The majority of type I SMA patients carry a homozygous deletion of SMN1 and a normal or reduced number of SMN2 copies. The majority of the type II and III SMA patients show homozygous absence of SMN1 and an increased number of SMN2 copies (3–4 copies). A homozygous deletion of SMN2 is found in about 5% of healthy individuals. This has no clinical phenotype when at least one functional SMN1 copy is present. Healthy individuals lacking SMN1 but having five or more SMN2 copies have been described.
Related Tests: Prader Willi Syndrome, Myotonic Muscular Dystrophy, Hypotonia Panel
Clinical Sensitivity: 95-98% **
Analytic Sensitivity: 100%
Test Limitations: ** MLPA cannot detect any changes that lie outside the target sequence of the probes and will not detect copy number neutral inversions or translocations. 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).
INDICATIONS FOR USE:
Confirmation of the diagnosis of SMA.
Determining copy numbers of SMN2 for therapy
Individuals wanting to know carrier status for SMN1
Individuals at risk who wish prenatal diagnosis.
ADDITIONAL RESOURCES:
OMIM - SMN1: www.omim.org/entry/600354
OMIM - SMA1: www.omim.org/entry/253300
Gene Reviews: www.ncbi.nlm.nih.gov/pubmed/20301526
Genetics Home Reference: www.ghr.nlm.nih.gov/condition/spinal-muscular-atrophy