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Lafora Disease via the NHLRC1 Gene

Summary and Pricing

Test Method

Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
9009 NHLRC1 81403 81403,81479 $640 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
9009NHLRC181403 81403,81479 $640 Order Options and Pricing

Pricing Comments

This test is also offered via our exome backbone with CNV detection (click here). The exome-based test may be higher priced, but permits reflex to the entire exome or to any other set of clinically relevant genes.

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

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

  • Eric Bend, PhD

Clinical Features and Genetics

Clinical Features

Lafora disease (LD) is a form of progressive myoclonic epilepsy. During adolescence, LD patients present with myoclonic seizures, headaches, dysarthria, ataxia and hallucinations (Turnbull et al. 2012). Seizures, though at first controlled by anticonvulsants, soon become drug resistant and increase in frequency and severity. Rapid neurodegeneration occurs within 10 years of seizure onset resulting in dementia (Gomez-Abad et al. 2005). Patients are eventually reduced to a vegetative state due to severe myoclonus. LD can be distinguished from other progressive myoclonic epilepsies by the presence of intracellular Lafora bodies, insoluble glycogen aggregates, in neurons and other cells. Lafora bodies can be detected via axillary skin biopsy.

Genetics

Lafora disease is inherited in an autosomal recessive manner and is caused by loss-of-function mutations in the NHLRC1/EPM2B or EPM2A genes. Mutations in either NHLRC1 or EPM2A result in similar LD phenotypes, with NHLRC1 mutations resulting in a slower clinical progression (Criado et al. 2011; Franceschetti et al. 2006). Missense, nonsense and frameshift mutations in NHLRC1 as well as deletions encompassing the entire NHLRC1 gene have been reported in LD patients (Singh and Ganesh 2009; Kecmanovic et al. 2013; Lohi et al. 2007).

Under normal cellular conditions, glycogen assembles into soluble, spherical polyglucosan structures. In LD patients, polyglucosan structure is disrupted, resulting in the formation of insoluble aggregates, known as Lafora bodies. Whether Lafora bodies are the cause of LD or a symptom is unclear, though the number of Lafora bodies in neurons correlates with increased neurodegeneration (Criado et al. 2011).

EPM2A encodes the phosphatase, laforin. NHLRC1 encodes malin, a ubiquitin ligase. Laforin and malin localize to the endoplasmic reticulum where they physically interact. Laforin and malin normally prevent the accumulation of Lafora bodies by regulating enzymes involved in glycogen metabolism and by promoting autophagy and the degradation of Laflora bodies (Liu et al. 2013). Studies in mouse models demonstrate that loss of either laforin or malin results in an accumulation of Lafora bodies in neurons and subsequent neurodegeneration (Turnbull et al. 2011).

Clinical Sensitivity - Sequencing with CNV PG-Select

Mutations in the NHLRC1 gene account for ~30% of LD cases (Gomez-Abad et al. 2005).

Testing Strategy

This test provides full coverage of all coding exons of the NHLRC1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Indications for Test

Candidates for NHLRC1 testing include patients with symptoms of Lafora disease and for which mutations in EPM2A were not found. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in NHLRC1.

Gene

Official Gene Symbol OMIM ID
NHLRC1 608072
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Lafora Disease AR 254780

Related Test

Name
Lafora Disease via the EPM2A Gene

Citations

  • Criado O, Aguado C, Gayarre J, Duran-Trio L, Garcia-Cabrero AM, Vernia S, San Millan B, Heredia M, Roma-Mateo C, Mouron S, Juana-Lopez L, Dominguez M, et al. 2011. Lafora bodies and neurological defects in malin-deficient mice correlate with impaired autophagy. Human Molecular Genetics 21: 1521–1533. PubMed ID: 22186026
  • Franceschetti S, Gambardella A, Canafoglia L, Striano P, Lohi H, Gennaro E, Ianzano L, Veggiotti P, Sofia V, Biondi R. 2006. Clinical and genetic findings in 26 Italian patients with Lafora disease. Epilepsia 47: 640–643. PubMed ID: 16529633
  • Gomez-Abad C, Gomez-Garre P, Gutierrez-Delicado E, Saygi S, Michelucci R, Tassinari CA, Rodriguez de Cordoba S, Serratosa JM. 2005. Lafora disease due to EPM2B mutations: A clinical and genetic study. Neurology 64: 982–986. PubMed ID: 8651643
  • Kecmanovic M, Jovic N, Čukic M, Keckarevic-Markovic M, Keckarevic D, Stevanovic G, Romac S. 2013. Lafora disease: Severe phenotype associated with homozygous deletion of the NHLRC1 gene. Journal of the Neurological Sciences 325: 170–173. PubMed ID: 23317923
  • Liu Y, Zeng L, Ma K, Baba O, Zheng P, Liu Y, Wang Y. 2013. Laforin–Malin Complex Degrades Polyglucosan Bodies in Concert with Glycogen Debranching Enzyme and Brain Isoform Glycogen Phosphorylase. Molecular Neurobiology. PubMed ID: 24068615
  • Lohi H, Turnbull J, Zhao XC, Pullenayegum S, Ianzano L, Yahyaoui M, Mikati MA, Quinn NP, Franceschetti S, Zara F, Minassian BA. 2007. Genetic diagnosis in Lafora disease: Genotype-phenotype correlations and diagnostic pitfalls. Neurology 68: 996–1001. PubMed ID: 17389303
  • Singh S, Ganesh S. 2009. Lafora progressive myoclonus epilepsy: A meta-analysis of reported mutations in the first decade following the discovery of the EPM2A and NHLRC1 genes. Human Mutation 30: 715–723. PubMed ID: 19267391
  • Turnbull J, DePaoli-Roach AA, Zhao X, Cortez MA, Pencea N, Tiberia E, Piliguian M, Roach PJ, Wang P, Ackerley CA, Minassian BA. 2011. PTG Depletion Removes Lafora Bodies and Rescues the Fatal Epilepsy of Lafora Disease. PLoS Genetics 7: e1002037. PubMed ID: 21552327
  • Turnbull J, Girard J-M, Lohi H, Chan EM, Wang P, Tiberia E, Omer S, Ahmed M, Bennett C, Chakrabarty A, Tyagi A, Liu Y, et al. 2012. Early-onset Lafora body disease. Brain 135: 2684–2698. PubMed ID: 22961547

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

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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.
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