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Congenital Myasthenic Syndrome 21 via the SLC18A3 Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
5229 SLC18A3 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
5229SLC18A381479 81479,81479 $890 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing backbone).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing backbone).

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Turnaround Time

18 days on average for standard orders or 13 days on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Angela Gruber, PhD

Clinical Features and Genetics

Clinical Features

Congenital myasthenic syndromes (CMS) are disorders of the neuromuscular junction resulting from abnormalities of presynaptic, synaptic, or post synaptic proteins. CMS are characterized by fatigable weakness affecting limb, ocular, facial, and bulbar muscles. Neonates present with feeding problems, choking, feeble cry, and muscle weakness (Vanhaesebrouck and Beeson. 2019. PubMed ID: 31361628; Abicht et al. 2016. PubMed ID: 20301347). Some neuromuscular junction genes can result in a more severe presentation of fetal akinesia, intrauterine growth retardation, arthrogryposis, lung hypoplasia, cleft palate, and cryptorchidism (Pergande et al. 2020. PubMed ID: 31680123). Patients presenting in later childhood are seen with abnormal exercise-induced fatigue and difficulty running. Most patients present prior to 2 years of age, although rare exceptions have been reported (Vanhaesebrouck and Beeson. 2019. PubMed ID: 31361628; Abicht et al. 2016. PubMed ID: 20301347). Symptoms are extremely variable, and are in some cases induced by febrile illness, infection, or excitement. Life-threatening respiratory crises may occur in affected neonates or older children. CMS may be differentiated from myasthenia gravis, an acquired autoimmune disorder, by earlier age at onset and by negative serology tests for anti-acetylcholine receptor (AchR) and anti-Musk antibodies.

Congenital myasthenic syndrome 21 or related disorders have been described in at least six different families with varied severity in presentation. The first two described cases include typical myasthenic clinical features of exercise intolerance, ptosis, ophthalmoplegia, hypotonia, feeding difficulties and facial weakness (O'Grady et al. 2016. PubMed ID: 27590285). However, a more severe presentation was observed in two siblings with retrognathia, severe hypotonia and distal arthrogryposis in all extremities, dislocated hips, respiratory failure, and genital abnormalities including undescended testes and micropenis (Aran et al. 2017. PubMed ID: 28188302). Prenatal onset was also described in two fetuses that were homozygous for a nonsense variant and presented with fetal akinesia, arthrogryposis, edema, and partial cleft palate (Hakonen et al. 2019. PubMed ID: 31059209). An additional two unrelated patients with biallelic variants in SLC18A3 presented with hypotonia, ptosis, poor weight gain, and apneic episodes (Lamond et al. 2021. PubMed ID: 33462016). Genetic testing may aid in establishing a differential diagnosis and may assist reproductive planning.

Genetics

Pathogenic variants in the SLC18A3 gene are associated with autosomal recessive congenital myasthenic syndrome 21. Missense variants and at least one nonsense variant have been reported to date; all variants were inherited from a carrier parent. Two large deletions encompassing the SLC18A3 gene and additional surrounding genes have also been reported (O'Grady et al. 2016. PubMed ID: 27590285). SLC18A3 is relatively intolerant to loss of function variants (Genome Aggregation Database).

The SLC18A3 gene encodes the vesicular acetylcholine transporter (VAChT), which transports acetylcholine into vesicles. Acetylcholine release from vesicles at the neuromuscular junction is necessary for both the central and peripheral nervous systems. Knockdown of VAChT in mice leads to myasthenic symptoms and cognitive defects (Prado et al. 2006. PubMed ID: 16950158), whereas knockout of VAChT in mice is lethal soon after birth due to cyanosis (de Castro et al. 2009. PubMed ID: 19635813). SLC18A3 has been cited as a nonessential gene for growth of human tissue culture cells (Online Gene Essentiality).

Clinical Sensitivity - Sequencing with CNV PGxome

The clinical sensitivity is difficult to estimate, as to date, a limited number of cases have been described in the literature. Analytical sensitivity should be high as all pathogenic variants reported to date are detectable by sequencing and NGS copy number variant analysis.

Testing Strategy

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the SLC18A3 gene plus 10 bases flanking noncoding DNA in all available transcripts in addition to non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).

Indications for Test

Candidates for this test are patients with clinical features of congenital myasthenic syndrome or fetal akinesia. Targeted testing is indicated for family members of patients who have known pathogenic variants in SLC18A3. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in SLC18A3.

Gene

Official Gene Symbol OMIM ID
SLC18A3 600336
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Myasthenic syndrome, congenital, 21, presynaptic AR 617239

Citations

  • Abicht et al. 2016. PubMed ID: 20301347
  • Aran et al. 2017. PubMed ID: 28188302
  • de Castro et al. 2009. PubMed ID: 19635813
  • Genome Aggregation Database (gnomAD).
  • Hakonen et al. 2019. PubMed ID: 31059209
  • Lamond et al. 2021. PubMed ID: 33462016;
  • O'Grady et al. 2016. PubMed ID: 27590285
  • Online GEne Essentiality Database (OGEE).
  • Pergande et al. 2020. PubMed ID: 31680123
  • Prado et al. 2006. PubMed ID: 16950158
  • Vanhaesebrouck and Beeson. 2019. PubMed ID: 31361628

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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ORDER OPTIONS

View Ordering Instructions

1) Select Test Method (Backbone)


1) Select Test Type


2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

No Additional Test Options are available for this test.

Note: acceptable specimen types are whole blood and DNA from whole blood only.
Total Price: $
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