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Centronuclear Myopathy, X-Linked via the MTM1 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
4835 MTM1 81406 81406,81405 $640 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
4835MTM181406 81406,81405 $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

X-linked centronuclear myopathy (CNMX; OMIM 310400), also known as X-linked myotubular myopathy-1 (MTM1), is a severe congenital myopathy in affected males and is caused by mutations in the MTM1 gene (Laporte et al. Nature Genet 13:175-182, 1996). Pregnancies involving males with CNMX are complicated by polyhydramnios secondary to decreased fetal swallowing. Decreased fetal movement is also noted, and some newborns are found to have congenital eventration of the diaphragm leading to respiratory failure (Heckmatt et al. Brain 108:941-964, 1985; Moerman et al. Am J Med Genet 27:213-218, 1987). Newborns are extremely hypotonic and require ventilator support to avoid hypoxia. Facial, extraocular, and neck muscles are always affected. Other features seen at birth include body length greater than the 90th percentile, large head circumference, elongated face, and long fingers and toes (Joseph et al. Am J Med Genet 59:168-173, 1995). A review of medical records of 55 male CNMX patients showed that survivability beyond 1 year of age was common (Herman et al. J Pediat 134:206-214, 1999). Most surviving patients (80%) in the study were ventilator-dependent and their muscle symptoms were non-progressive. Other complications observed in the surviving patients included liver dysfunction, rapid growth with advanced bone age, and pyloric stenosis. Muscle biopsies in CNMX reveal centrally placed nuclei, and most patients have reduced myotubilarin protein in a variety of cell types (Laporte et al. Ann Neurol 50:42-46, 2001). Female carriers are usually asymptomatic, however, cases of obligate carriers have been reported with a range of clinical symptoms. Symptoms in mildly affected female carriers include facial weakness and limb-girdle weakness (Wallgren-Pettersson et al. J Med Genet 32:673-679, 1995). Childhood-onset cases generally have skewed X inactivation and manifestations of moderate facial and neck flexor weakness, scapular winging, weakness and wasting of proximal arm muscles, elevated hemidiaphragm, and generalized, slowly progressive weakness in adulthood (Tanner et al. Hum Genet 104:249-253, 1999; Grogan et al. Neurology 64:1638-1640, 2005). In one case of a carrier female with limb-girdle and facial weakness, skewed X inactivation was not observed (Sutton et al. Neurology 57:900-902, 2001). Clinical features of a female with congenital onset of disease include fetal hypokinesia and severe hypotonia at birth. The affected infant also had absent deep tendon reflexes, a weak cry, ptosis, and a high-arched palate (Schara et al. Neurology 60:1363-1365, 2003). The patient later developed limb girdle and facial weakness.

Genetics

Centronuclear myopathy is a genetically heterogeneous disorder. One autosomal recessive form and several autosomal dominant forms are known. MTM1-related centronuclear myopathy is inherited as an X-linked recessive disorder. Over 250 different mutations of the MTM1 gene are reported. The largest class of mutations is substitution of amino acids followed by small deletions, splice site mutations, nonsense mutations, small insertions, and gross deletions (Laporte et al. Hum Mutat 15:393-409, 2000; Zanoteli et al. Am J Med Genet 134A:338-340, 2005).

Clinical Sensitivity - Sequencing with CNV PG-Select

Analytical sensitivity by DNA sequencing will be limited because a significant number of gross deletions of the MTM1 gene are reported. Clinical sensitivity is problematic to predict due to genetic heterogeneity of this disorder. From a cohort of 60 patients, seven were found to have MTM1 mutations (Laporte et al. Nature Genet 13:175-182, 1996).

Testing Strategy

This test provides full coverage of all coding exons of the MTM1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

Indications for Test

Male patients with clinical features of centronuclear myopathy and with centrally placed nuclei in muscle. Female patients with clinical features consistent with those previously reported in obligate carriers.

Gene

Official Gene Symbol OMIM ID
MTM1 300415
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Severe X-Linked Myotubular Myopathy XL 310400

Citations

  • Grogan PM, Tanner SM, Orstavik KH, Knudsen GPS, Saperstein DS, Vogel H, Barohn RJ, Herbelin LL, McVey AL, Katz JS. 2005. Myopathy with skeletal asymmetry and hemidiaphragm elevation is caused by myotubularin mutations. Neurology 64: 1638–1640. PubMed ID: 15883335
  • Heckmatt JZ, Sewry CA, Hodes D, Dubowitz V. 1985. Congenital centronuclear (myotubular) myopathy: a clinical, pathological and genetic study in eight children. Brain 108: 941–964. PubMed ID: 4075080
  • Herman GE, Finegold M, Zhao W, Gouyon B de, Metzenberg A. 1999. Medical complications in long-term survivors with X-linked myotubular myopathy. The Journal of pediatrics 134: 206–214. PubMed ID: 9931531
  • Joseph M, Pai GS, Holden KR, Herman G. 1995. X-linked myotubular myopathy: Clinical observations in ten additional cases. American journal of medical genetics 59: 168–173. PubMed ID: 8588581,
  • Laporte et al. (2000)  MTM1 mutations in X-linked myotubular myopathy. Hum. Mutat. 15:393-409. PubMed ID: 10790201
  • Laporte et al. (2001) Diagnosis of X-linked myotubular myopathy by detection of myotubularin.  Ann. Neurol. 50:42-46.    PubMed ID: 11456308
  • Laporte J, Hu LJ, Kretz C, Mandel JL, Kioschis P, Coy JF, Klauck SM, Poustka A, Dahl N. 1996. A gene mutated in X-linked myotubular myopathy defines a new putative tyrosine phosphatase family conserved in yeast. Nat. Genet. 13: 175–182. PubMed ID: 8640223
  • Moerman P, Fryns J-P, Devlieger H, Assche A Van, Lauweryns J, Opitz JM, Reynolds JF. 1987. Congenital eventration of the diaphragm: an unusual cause of intractable neonatal respiratory distress with variable etiology. American journal of medical genetics 27: 213–218. PubMed ID: 3605197
  • Schara et al. (2003) X-linked myotubular myopathy in a female infant caused by a new MTM1 gene mutation. Neurology 60:1363-1365.  PubMed ID: 12707446
  • Sutton IJ, Winer JB, Norman AN, Liechti-Gallati S, MacDonald F. 2001. Limb girdle and facial weakness in female carriers of X-linked myotubular myopathy mutations. Neurology 57: 900–902. PubMed ID: 11552027
  • Tanner SM, Orstavik KH, Kristiansen M, Lev D, Lerman-Sagie T, Sadeh M, Liechti-Gallati S. 1999. Skewed X-inactivation in a manifesting carrier of X-linked myotubular myopathy and in her non-manifesting carrier mother. Hum. Genet. 104: 249–253. PubMed ID: 10323249
  • Wallgren-Pettersson C, Clarke A, Samson F, Fardeau M, Dubowitz V, Moser H, Grimm T, Barohn RJ, Barth PG. 1995. The myotubular myopathies: differential diagnosis of the X linked recessive, autosomal dominant, and autosomal recessive forms and present state of DNA studies. Journal of medical genetics 32: 673–679. PubMed ID: 8544184
  • Zanoteli et al. (2005)  Deletion of both MTM1 and MTMR1 genes in a boy with myotubular myopathy. Am. J. Med. Genet. 134A:338-340. PubMed ID: 15690409

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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