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Neurogenic Arthrogryposis Multiplex Congenita-1 with Myelin Defect via the LGI4 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
13305 LGI4 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
13305LGI481479 81479,81479 $890 Order Options and Pricing

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).

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

Fetal akinesia (FA) describes a clinical syndromic entity characterized by reduced or absent fetal movements resulting in multiple phenotypic abnormalities. These secondary defects may include intrauterine growth restriction (IUGR), craniofacial dysmorphic features (cleft palate or retromicrognathia), limb pterygia, pulmonary hypoplasia, and arthrogryposis. This group of disorders contains several overlapping conditions ranging from distal arthrogryposis, multiple pterygium syndrome, arthrogryposis multiplex congenita (AMC), to the more severe lethal congenital contracture syndrome and fetal akinesia deformation sequence (FADS) (Beecroft et al. 2018. PubMed ID: 29959180; Pergande et al. 2020. PubMed ID: 31680123). 

AMC is defined by congenital, non-progressive contractures in more than two joints and in multiple body areas. These contractures and reduced fetal movement can lead to secondary polyhydramnios or fetal hydrops. The underlying defect can be genetic or environmental. Causes can include muscle disorders, neurological disorders, connective tissue disorders, fetal vascular compromise, uterine space limitations, and maternal disease or drug use. The overall incidence of AMC ranges from 1/3,000 to 1/5,000 live births (Beecroft et al. 2018. PubMed ID: 29959180; Pergande et al. 2020. PubMed ID: 31680123). 

Autosomal recessive neurogenic arthrogryposis multiplex congenita-1 with myelin defect (AMC1) is a severe neurogenic disorder with onset typically occurring in utero (Karakaya et al. 2018. PubMed ID: 29858556; Xue et al. 2017. PubMed ID: 28318499). At least 10 individuals with AMC1 have been described in the literature with the majority of cases not surviving past infancy. Clinical features include distal arthrogryposis and fetal akinesia sequence with camptodactyly, adduction of thumbs, clubfeet, flexion of feet, knees, wrists, and elbows, microretrognathia, and pulmonary hypoplasia. One 6 year old patient that survived also presented with verbal developmental delay, onset of seizures at age 1 year,  prominent ears, narrow forehead, high-arched palate, reduced mouth opening, dental crowding, esotropia, strabismus, and ptosis. Genetic testing may aide in establishing a differential diagnosis and may assist reproductive planning.

Genetics

Pathogenic variants in LGI4 are associated with autosomal recessive neurogenic arthrogryposis multiplex congenita-1 with myelin defect (AMC1). Splice variants, missense variants, and nonsense variants have been reported in 10 individuals with AMC1 from 5 families (Karakaya et al. 2018. PubMed ID: 29858556; Xue et al. 2017. PubMed ID: 28318499). All of these cases were either homozygous or compound heterozygous for LGI4 variants. To date, all pathogenic variants have been inherited from a carrier parent. No structural variants have been reported.

The LGI4 gene encodes the leucine-rich glioma-inactivated 4 protein which is a ligand secreted by Schwann cells and regulates peripheral nerve myelination. This ligand binds to the cell surface receptor Adam22, which is expressed in neurons and drive myelin formation. LGI4 deficient mice exhibit an arthrogryposis phenotype due to peripheral hypomyelination (Nishino et al. 2010. PubMed ID: 21068328). LGI4 has been cited as a non-essential 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 (Karakaya et al. 2018. PubMed ID: 29858556; Xue et al. 2017. PubMed ID: 28318499). Analytical sensitivity should be high as all pathogenic variants reported to date are detectable by sequencing.

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 LGI4 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 consistent with a diagnosis of arthrogryposis multiplex congenita. Targeted testing is indicated for family members of patients who have known pathogenic variants in LGI4. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in LGI4.

Gene

Official Gene Symbol OMIM ID
LGI4 608303
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Citations

  • Beecroft et al. 2018. PubMed ID: 29959180
  • Karakaya et al. 2018. PubMed ID: 29858556
  • Nishino et al. 2010. PubMed ID: 21068328
  • Online Gene Essentiality.
  • Pergande et al. 2020. PubMed ID: 31680123
  • Xue et al. 2017. PubMed ID: 28318499

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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