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Limb Girdle Muscular Dystrophy Type 2B and Miyoshi Myopathy via the DYSF 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
3123 DYSF 81408 81408,81479 $640 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
3123DYSF81408 81408,81479 $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

The dysferlinopathies encompass two primary phenotypes. Limb girdle muscular dystrophy type 2B (LGMD2B; OMIM 253601) is characterized by atrophy and weakness of proximal muscles with onset in adolescence or young adulthood. Miyoshi myopathy (MM; OMIM 254130) affects distal leg muscles initially with atrophy and weakness spreading to the thighs and gluteal muscles (Miyoshi et al. Brain 109:31-54, 1986). Marked inflammatory changes are sometimes seen in muscle biopsies from MM patients. Age of onset of MM is late teens (Aoki et al. Neurology 57:271-278, 2001) and, as in LGMD2B, progression is slow. Both phenotypes exhibit massive elevations of serum CpK. Distal myopathy with anterior tibial onset (DMAT; OMIM 606768) is a third DYSF association. This phenotype has been described in a single Spanish family (Illa et al. Ann Neurol 49:130-134, 2001). It should be noted that intrafamilial variability spanning all three phenotypes has been reported (Weiler et al. Am J Hum Genet 59:872-878, 1996; Liu et al. Nat Genet 20:31-36, 1998). Approximately half of a cohort of forty dysferlinopathy patients reviewed by Nguyen et al. (Arch Neurol 64:1176-1182, 2007) had MM or LGMD2B. Another one-third of the cohort had atypical phenotypes with mixed proximal and distal weakness. Distal painful leg swelling without muscle weakness occurred in 10%. The same study reported that 25% of the patients were initially misdiagnosed as having polymyositis.

Genetics

Dysferlin-related disorders are inherited in an autosomal recessive manner. Variants are distributed throughout the gene (http://www.dmd.nl/). Nonsense, missense, small insertions and deletions, and splice site variants have been reported. Dysferlin appears to function in calcium-dependent membrane repair of skeletal muscle fibers (Bansal and Campbell Trends Cell Biol 14:206-213, 2004). Evaluation of muscle biopsies shows that most dysferlinopathy patients have complete deficiency of the protein although individuals with partial dysferlin deficiency have been reported (Piccolo et al. Ann Neurol 48:902-912, 2000). Dysferlin deficiency can also occur secondary to variants in the genes for caveolin-3 or calpain-3. Patients with MM who have negative DYSF tests may have variants in the ANO5 gene (Bolduc et al. Am J Hum Genet 86:213-221, 2010).

Clinical Sensitivity - Sequencing with CNV PG-Select

Nguyen et al. (Hum Mutat 26:165-175, 2005) found two DYSF variants in 23 of 34 dysferlinopathy patients and one variant in the remaining 11 patients. The patients were from various ethnic backgrounds and unrelated to one another. In a large cohort of North American LGMD patients, Moore et al. (J Neuropathol Exp Neurol 65:995-1003) made a diagnosis of dysferlinopathy in 18% of the cohort using a combined immuno and molecular approach, making DYSF the most common cause of LGMD in this mixed population. Dysferlinopathy is also prevalent in certain ethnic groups. For example, a c.1624delG variant underlies the high (1:1300) prevalence for LGMD2B in Libyan Jews (Argov et al. Brain 123:1229-1237, 2000) and in Sueca, Spain, a founder variant has been found in 2% of the population (Vilchez et al. Arch Neurol 62:1256-1259, 2005). In 20 of 25 Japanese patients with a clinical diagnosis of MM, 6 different DYSF variants were identified (Takahashi et al. Neurology 60:1799-1804, 2003).

Testing Strategy

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

Indications for Test

Individuals with clinical symptoms consistent with LGMD, MM, or DMAT. Individuals with absent staining of dysferlin in muscle or peripheral blood monocytes. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in DYSF.

Gene

Official Gene Symbol OMIM ID
DYSF 603009
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Citations

  • Aoki, M., et.al. (2001). "Genomic organization of the dysferlin gene and novel mutations in Miyoshi myopathy." Neurology 57(2): 271-8. PubMed ID: 11468312
  • Argov, Z., et.al. (2000). "Muscular dystrophy due to dysferlin deficiency in Libyan Jews. Clinical and genetic features." Brain 123 ( Pt 6): 1229-37. PubMed ID: 10825360
  • Bansal, D., Campbell, K. P. (2004). "Dysferlin and the plasma membrane repair in muscular dystrophy." Trends Cell Biol 14(4): 206-13. PubMed ID: 15066638
  • Bolduc, V. et.al. (2010). "Recessive mutations in the putative calcium-activated chloride channel Anoctamin 5 cause proximal LGMD2L and distal MMD3 muscular dystrophies." Am J Hum Genet 86(2): 213-221. PubMed ID: 20096397
  • Illa, I., et.al. (2001). "Distal anterior compartment myopathy: a dysferlin mutation causing a new muscular dystrophy phenotype." Ann Neurol 49(1): 130-4. PubMed ID: 11198284
  • Liu, J., et.al. (1998). "Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy." Nat Genet 20(1): 31-6. PubMed ID: 9731526
  • Miyoshi, K., et.al. (1986). "Autosomal recessive distal muscular dystrophy as a new type of progressive muscular dystrophy. Seventeen cases in eight families including an autopsied case." Brain 109 ( Pt 1): 31-54. PubMed ID: 3942856
  • Moore SA, Shilling CJ, Westra S, Wall C, Wicklund MP, Stolle C, Brown CA, Michele DE, Piccolo F, Winder TL, Stence A, Barresi R, King N, King W, Florence J, Campbell KP, Fenichel GM, Stedman HH, Kissel JT, Griggs RC, Pandya S, Mathews KD, Pestronk A, Serrano C, Darvish D, Mendell JR. 2006. Limb-girdle muscular dystrophy in the United States. J Neuropathol Exp Neurol 65: 995-1003. PubMed ID: 17021404
  • Nguyen, K., et.al. (2005). "Dysferlin mutations in LGMD2B, Miyoshi myopathy, and atypical dysferlinopathies." Hum Mutat 26(2): 165. PubMed ID: 16010686
  • Nguyen, K., et.al. (2007). "Phenotypic study in 40 patients with dysferlin gene mutations: high frequency of atypical phenotypes." Arch Neurol 64(8): 1176-82. PubMed ID: 17698709
  • Piccolo, F., et.al. (2000). "Intracellular accumulation and reduced sarcolemmal expression of dysferlin in limb--girdle muscular dystrophies." Ann Neurol 48(6): 902-12. PubMed ID: 11117547
  • Takahashi, T., et.al. (2003). "Dysferlin mutations in Japanese Miyoshi myopathy: relationship to phenotype." Neurology 60(11): 1799-804. PubMed ID: 12796534
  • Vilchez, J. J., et.al. (2005). "Identification of a novel founder mutation in the DYSF gene causing clinical variability in the Spanish population." Arch Neurol 62(8): 1256-9. PubMed ID: 16087766
  • Weiler, T., et.al. (1996). "Limb-girdle muscular dystrophy and Miyoshi myopathy in an aboriginal Canadian kindred map to LGMD2B and segregate with the same haplotype." Am J Hum Genet 59(4): 872-8. PubMed ID: 8808603

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

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