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SMN1, SMN2

Alias

Also known as cenSMN; BCD541; C-BCD541; GEMIN1; SMA; SMA1; SMA2; SMA3; SMA4; SMN; SMNC; SMNT; T-BCD541; TDRD16A; TDRD16B

Associated disorders

The SMN1 gene is associated with autosomal recessive spinal muscular atrophy (SMA) (MedGen UID: 7755). SMN2 can modify the phenotype in individuals with SMN1-related SMA.

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SMN1, SMN2

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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 in 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.


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Invitae tests that include this gene:

The survival of motor neuron protein (SMN) is a amino acid RNA-binding protein that can be translated from either the SMN1 or SMN2 genes. This protein assembles snRNP complexes that can be used to process mRNA needed to make additional proteins that are necessary for proper growth and function of motor neuron cells.

Spinal muscular atrophy

Clinical condition
SMN1 and SMN2 are associated with spinal muscular atrophy (SMA), 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 (tongue fasciculations), tremor, poor weight gain, sleeping difficulties, pneumonia, scoliosis, joint contractures, and congenital heart disease.

Differential diagnosis

  • Infants under 6 months of age: X-linked infantile spinal muscular atrophy (UBA1) (OMIM 301830), spinal muscular atrophy and respiratory distress (SMARD1) (OMIM 604320), Prader-Willi syndrome (OMIM 176270), myotonic dystrophy type 1 (OMIM 160900), congenital muscular dystrophy, Zellweger spectrum disorder (OMIM 21400), congenital myasthenia gravis (OMIM 254210), Pompe disease (OMIM 232300)
  • Early childhood (over 6 months of age): Duchenne muscular dystrophy (OMIM 310200), Tay-Sachs disease (OMIM 272800), congenital muscular dystrophy
  • Later childhood: Riboflavin transporter deficiency neuronopathy (OMIM 613350) (SLC52A2, SLC52A3), monomelic amyotrophy (OMIM 602440)
  • Adolescence/Adult: Spinal and bulbar muscular atrophy (Kennedy disease) (OMIM 301830), amyotrophic lateral sclerosis (OMIM 105400) (PMID: 20301526)

Gene information
Age of onset and severity are variable but symptoms are due to absence of functioning copies of SMN1, which produces the survival motor neuron protein essential for the maintenance of motor neurons.

SMN1-related SMA is the most common form. Loss of SMN1 gene function can occur through at least three different mechanisms: 1) deletion of SMN1, 2) inactivating sequence variants in SMN1, or 3) gene conversion of SMN1 to SMN2.

  • 95% of cases are caused by a homozygous loss of SMN1, which can occur by deletion or gene conversion to SMN2
  • 5% of cases are due to compound heterozygosity in SMN1 with a deletion of SMN1 on one allele and a pathogenic sequence variant on the second allele (PMID: 9345102, 9199562)

SMN2 is located adjacent to SMN1 and highly homologous to SMN1. Among the 882 nucleotides that code for amino acids, only one nucleotide differs between SMN1 and SMN2: in the terminal exon at position c.840, a C nucleotide occurs in the SMN1 gene while a T nucleotide occurs in the SMN2 gene. The variant at position c.840 does not result in a different amino acid being encoded, but causes improper processing of the SMN2 mRNA and consequently reduced protein production.

Although the SMN2 gene produces minimal functional protein, it can significantly modify the severity of SMA, with more copies of SMN2 correlated with decreased SMA severity (PMID: 11839954, 15852397). However, the number of SMN2 genes a person carries varies and the phenotype cannot be predicted with complete accuracy. There are four degrees of SMA severity based on age of onset and motor function achieved. (PMID:9199562, 10405443)

  • Type I: onset < 6 months; SMN2 CN 1 or 2
  • Type II: onset 7-18 months; SMN2 CN 3+
  • Type III: 18+ months; SMN2 CN 3+
  • Type IV: adult onset; SMN2 CN 4+

Inheritance
SMA is inherited in an autosomal recessive manner, with a new mutation rate of up to 2% (PMID:9345102). Some individuals (an estimated 8% of Ashkenazi Jewish carriers) appear to have normal SMN1 results due to two functional copies of SMN1 on one chromosome and zero functional copies on the other chromosome, an allelic combination termed “silent carrier.” (PMID: 9199562, 10405443, 23788250)

Management
The FDA recently approved the first drug therapy for SMA. Nusinersen is an antisense oligonucleotide (ASO), administered intrathecally that alters splicing of SMN2 pre-mRNA in order to increase the production of full length SMN protein (PMID:26515624). Many SMA clinical trials continue to assess the efficacy of various drugs and the potential for gene therapy (PMID 26823478). Clinical management by a multidisciplinary team is recommended (PMID: 17761659).

Review date: April 2017

Assay and technical information

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 in 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.

Test information
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