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Dystroglycanopathy via the LARGE1/LARGE 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
7029 LARGE1 81479 81479,81479 $640 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
7029LARGE181479 81479,81479 $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

  • Angela Gruber, PhD

Clinical Features and Genetics

Clinical Features

Variants in the LARGE1/LARGE gene (OMIM 603590) cause muscular dystrophies in the dystroglycanopathy spectrum. Walker-Warburg syndrome (WWS), a severe congenital muscular dystrophy with defective neuronal migration and associated structural brain and eye abnormalities, is the most severe manifestation (Godfrey et al. Brain 130:2725-2735, 2007; van Reeuwijk et al. Hum Genet 121:685-690, 2007; Mercuri et al. Neurology 72:1802-1809, 2009). Patients with the congenital muscular dystrophy, structural brain abnormalities, and severe mental retardation have also been confirmed to have variants in the LARGE1 gene (Longman et al. Hum Mol Genet 12:2853-2861, 2003; Clement et al. Ann Neurol 64:573-582, 2008). The enzyme encoded by LARGE1, N-acetylglucosaminyltransferase, is necessary for proper posttranslational processing of the protein alpha dystroglycan (ADG). In the absence of this enzyme, ADG remains hypoglycosylated and diverse pathologies follow (Barresi and Campbell. J Cell Science 119:199-207, 2006). Molecular diagnosis (and classification) of the dystroglycanopathy subtypes is complex because extensive locus heterogeneity exists for each disorder (Godfrey et al. Brain 130:2725-2735, 2007), and because the phenotypes caused by the six demonstrated and putative glycosyltransferase genes continue to expand (eg. van Reeuwijk et al. Hum Mutat 27:453-459, 2006).

Genetics

The dystroglycanopathies are inherited in an autosomal recessive manner. It should be noted that six other genes (POMT1, POMT2, ISPD, POMGNT1, FKRP, and FKTN) encode proteins required for processing of ADG. The small numbers of LARGE1 gene variants thus far reported include missense, single nucleotide duplication, nonsense, and partial gene deletions.

Clinical Sensitivity - Sequencing with CNV PG-Select

LARGE1 variants are an infrequent finding in patients with congenital muscular dystrophy and ADG hypoglycosylation. In a study including 91 patients with demonstrated ADG hypoglycosylation, one patient was found to have LARGE1 variants (Godfrey et al. Brain 130:2725-2735, 2007). In a second cohort of 81 patients with congenital muscular dystrophy and ADG hypoglycosylation, a single patient was found to have LARGE1 variants (Mercuri et al. Neurology 72:1802-1809, 2009). Similarly, within a cohort of 36 patients with clinical signs of congenital muscular dystrophy, one patient with LARGE1 variants was found (Longman et al. Hum Mol Genet 12:2853-2861, 2003). Because dystroglycanopathies exhibit extensive locus and allelic heterogeneity, a negative LARGE1 sequence result does not rule out a diagnosis of a one of these disorders when classic clinical findings are present. Evaluation of a patient’s muscle biopsy by immunofluorescence can detect abnormal glycosylation of ADG and can, therefore, help direct a diagnostic evaluation.

Testing Strategy

This test provides full coverage of all coding exons of the LARGE1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Indications for Test

Individuals with severe congenital muscular dystrophy and immunofluorescence results demonstrating hypoglycosylation of ADG in muscle. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in LARGE1.

Gene

Official Gene Symbol OMIM ID
LARGE1 603590
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Citations

  • Barresi, R. and Campbell, K. P. (2006). "Dystroglycan: from biosynthesis to pathogenesis of human disease." J Cell Sci 119(Pt 2): 199-207. PubMed ID: 16410545
  • Clement, E., et.al. (2008). "Brain involvement in muscular dystrophies with defective dystroglycan glycosylation." Ann Neurol 64(5): 573-82. PubMed ID: 19067344
  • Godfrey C, Clement E, Mein R, Brockington M, Smith J, Talim B, Straub V, Robb S, Quinlivan R, Feng L, Jimenez-Mallebrera C, Mercuri E, et al. 2007. Refining genotype phenotype correlations in muscular dystrophies with defective glycosylation of dystroglycan. Brain 130: 2725–2735. PubMed ID: 17878207
  • Longman, C., et.al. (2003). "Mutations in the human LARGE gene cause MDC1D, a novel form of congenital muscular dystrophy with severe mental retardation and abnormal glycosylation of alpha-dystroglycan." Hum Mol Genet 12(21): 2853-61. PubMed ID: 12966029
  • Mercuri, E., et.al. (2009). "Congenital muscular dystrophies with defective glycosylation of dystroglycan: a population study." Neurology 72(21): 1802-9. PubMed ID: 19299310
  • Reeuwijk J van, Maugenre S, Elzen C van den, Verrips A, Bertini E, Muntoni F, Merlini L, Scheffer H, Brunner HG, Guicheney P, Bokhoven H van. 2006. The expanding phenotype of POMT1 mutations: from Walker-Warburg syndrome to congenital muscular dystrophy, microcephaly, and mental retardation. Human Mutation 27: 453–459. PubMed ID: 16575835
  • van Reeuwijk, J., et.al. (2007). "Intragenic deletion in the LARGE gene causes Walker-Warburg syndrome." Hum Genet 121(6): 685-90. PubMed ID: 17436019

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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