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 Genes | Test CPT Code | Gene CPT Codes Copy CPT Code | Base Price | |
|---|---|---|---|---|---|
| 9009 | NHLRC1 | 81403 | 81403,81479 | $990 | Order Options and Pricing |
Pricing Comments
Testing run on PG-select capture probes includes CNV analysis for the gene(s) on the panel but does not permit the optional add on of exome-wide CNV analysis. Any of the NGS platforms allow reflex to other clinically relevant genes, up to whole exome or whole genome sequencing depending upon the base platform selected for the initial test.
An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.
This test is also offered via a custom panel (click here) on our exome or genome backbone which permits the optional add on of exome-wide CNV or genome-wide SV analysis.
Turnaround Time
3 weeks on average for standard orders or 2 weeks 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.
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.
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, ?ukic 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
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Requisition Form
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For Requisition Forms, visit our Forms page
If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.
Specimen Types
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