α-Actin (Skeletal Muscle Form)-Related Myopathy via the ACTA1 Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
8813 ACTA1 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8813ACTA181479 81479(x2) $890 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.

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

Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing backbone).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing backbone).

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

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

Clinical Features and Genetics

Clinical Features

Nemaline myopathy (NEM) is a genetically and clinically heterogeneous disorder characterized by muscle weakness, hypotonia, and the presence of nemaline bodies in skeletal muscle fibers. Muscle weakness is typically observed in affected neonates or infants, although later-onset cases are reported (Ryan et al. Ann Neurol 50:312-320, 2001). The most severely affected muscle groups are proximal limb, facial, bulbar, and respiratory muscles. Deep tendon reflexes are absent or depressed. Histologically, NEM is characterized by type 1 fiber predominance and the presence of rodlike structures called nemaline bodies with Gomori trichrome staining of skeletal muscle (Ryan et al. Neurol 60:665-673, 2003). Six clinical types of NEM have been delineated based on age of onset, severity and distribution of weakness, and respiratory function (Ryan et al. 2001; North and Ryan. GeneReviews. 2010). Overlap among the six groups is significant, and adults are sometimes diagnosed only after a family member has presented with typical signs. Congenital fiber-type disproportion (CFTD) usually presents with hypotonia and varying degrees of skeletal muscle weakness affecting the limbs. Symptoms appear at birth or within the first year of life and, in the majority of cases, remain stable over time or improve with age. The diagnosis relies on histological observation of type 1 fibers that are at least 12% smaller than the mean diameter of type 2A or type 2B fibers in the absence of other significant pathologic findings, most notably nemaline bodies. Actinopathies are reviewed by Goebel and Laing (Brain Pathology 19:516-522, 2009).

Genetics

Variants in the skeletal muscle form of α-actin (ACTA1; OMIM #102610) are one cause of nemaline myopathy (NEM3; OMIM #161800) and congenital fiber-type disproportion (CFTD1; OMIM #255310). Nearly 200 unique variants are known (Laing et al. Hum Mutat 30:1267-1277, 2009). NEM3 is most often inherited as an autosomal dominant condition, and most patients have de novo variants (Laing et al. 2009). Parental mosaicism for ACTA1 variants is documented (e.g. Nowak et al. Nat Genet 23:208-212, 1999). Recessive inheritance of NEM3 is rare and all such variants manifest as null alleles. Although CFTD is a genetically heterogeneous condition that can be inherited in an autosomal recessive, autosomal dominant, or X-linked manner, the three reported cases of ACTA1-related CFTD have been caused by autosomal dominant variants (Laing et al. Ann Neurol 56:689-694, 2004).

Clinical Sensitivity - Sequencing with CNV PGxome

ACTA1 variants account for 15%-25% of all cases of nemaline myoapthy (e.g. Nowak et al. 1999; Ryan et al. 2001) and possibly up to 50% of the severe, congenital-onset form (Agrawal et al. Ann Neurol 56:86-96, 2004). Five other genes (NEB, TPM3, TNNT1, TPM2, and CFL2) are associated with NEM; however, the fraction of cases attributed by them is small. Laing et al. (2004) found heterozygous ACTA1 variants in 6% (three unrelated individuals) of a CFTD cohort from Japan and Australia.

Testing Strategy

This test provides full coverage of all coding exons of the ACTA1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).

Indications for Test

Individuals with clinical symptoms consistent with NEM and muscle biopsy studies showing nemaline bodies. Individuals with clinical symptoms consistent with CFTD and muscle biopsy studies showing type 1 fibers that are smaller than type 2 fibers. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in ACTA1.

Gene

Official Gene Symbol OMIM ID
ACTA1 102610
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Diseases

Name Inheritance OMIM ID
Congenital Fiber Type Disproportion AR, AD 255310
Nemaline Myopathy 3 AR, AD 161800

Related Tests

Name
Comprehensive Cardiology Panel
Myopathy, Congenital via the TPM3 Gene

Citations

  • Agrawal PB, Strickland CD, Midgett C, Morales A, Newburger DE, Poulos MA, Tomczak KK, Ryan MM, Iannaccone ST, Crawford TO, Laing NG, Beggs AH. 2004. Heterogeneity of nemaline myopathy cases with skeletal muscle alpha-actin gene mutations. Ann Neurol 56: 86-96. PubMed ID: 15236405
  • Goebel, H. H., Laing, N. G. (2009). "Actinopathies and myosinopathies." Brain Pathol 19(3): 516-22. PubMed ID: 19563543
  • Kathryn North, Monique M Ryan (2010). "Nemaline Myopathy."
  • Laing NG, Clarke NF, Dye DE, Liyanage K, Walker KR, Kobayashi Y, Shimakawa S, Hagiwara T, Ouvrier R, Sparrow JC, Nishino I, North KN, et al. 2004. Actin mutations are one cause of congenital fibre type disproportion. Annals of Neurology 56: 689–694. PubMed ID: 15468086
  • Laing NG, Dye DE, Wallgren-Pettersson C, Richard G, Monnier N, Lillis S, Winder TL, Lochmüller H, Graziano C, Mitrani-Rosenbaum S, Twomey D, Sparrow JC, Beggs AH, Nowak KJ. 2009. Mutations and polymorphisms of the skeletal muscle alpha-actin gene (ACTA1). Hum Mutat 30: 1267-1277. PubMed ID: 19562689
  • Nowak, K. J., et.al. (1999). "Mutations in the skeletal muscle alpha-actin gene in patients with actin myopathy and nemaline myopathy." Nat Genet 23(2): 208-12. PubMed ID: 10508519
  • Ryan MM, Ilkovski B, Strickland CD, Schnell C, Sanoudou D, Midgett C, Houston R, Muirhead D, Dennett X, Shield LK, Girolami U De, Iannaccone ST, Laing NG, North KN, Beggs AH. 2003. Clinical course correlates poorly with muscle pathology in nemaline myopathy. Neurology 60: 665–673. PubMed ID: 12601110
  • Ryan MM, Schnell C, Strickland CD, Shield LK, Morgan G, Iannaccone ST, Laing NG, Beggs AH, North KN. 2001. Nemaline myopathy: a clinical study of 143 cases. Ann. Neurol. 50: 312–320. PubMed ID: 11558787

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

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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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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