• Test code: 03374
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top EDTA tube (K2EDTA or K3EDTA)
  • Alternate specimens:
    Saliva, assisted saliva, buccal swab and gDNA
  • Sample requirements
  • Request a sample kit

Invitae Inclusion Body Myopathy Panel

Test description

The Invitae Inclusion Body Myopathy Panel analyzes up to five genes associated with inclusion body myopathy (IBM), which encompasses a group of myopathies that present with characteristic rimmed vacuoles visualized on muscle biopsies. These genes were curated based on current evidence to provide a comprehensive test for the genetic causes of IBM.

Individuals with clinical signs and symptoms of IBM may benefit from diagnostic genetic testing to confirm or establish a differential diagnosis, to provide anticipatory guidance, to help determine which relatives are at risk, or to guide possible enrollment in clinical trials.

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Primary panel (4 genes)
Add-on Preliminary-evidence Gene for Inclusion Body Myopathy (1 gene)

Preliminary-evidence genes currently have early evidence of a clinical association with the specific disease covered by this test. Some clinicians may wish to include a gene which does not currently have a definitive clinical association, but which may prove to be clinically significant in the future. This gene can be added at no additional charge. Visit our Preliminary-evidence genes page to learn more.


Alternative tests to consider

For a broader analysis of genes associated with myopathies, clinicians may consider the Invitae Comprehensive Myopathy Panel. This broader panel can be ordered at no additional charge.

For a broader analysis of genes associated with hereditary neuromuscular disorders (congenital myopathy, muscular dystrophy and myasthenic syndrome), clinicians may consider the Invitae Comprehensive Neuromuscular Panel. This broader panel can also be ordered at no additional charge.

Inclusion body myopathies are a group of disorders characterized by early adulthood onset muscle weakness and the presence of granules or inclusion bodies visualized on muscle biopsies. GNE-related myopathy (IBM2) typically presents in the late teens to early adulthood with slowly progressive distal muscle weakness involving gait disturbance and foot drop secondary to anterior tibialis muscle weakness. The disorder progresses to involve the upper limbs and proximal leg muscles, with marked sparing of the quadriceps. While intellectual functioning, sensation, and coordination remain intact, affected individuals often lose the ability to walk years after onset. Proximal myopathy and ophthalmoplegia (MYPOP) is a relatively mild, slowly progressive muscle disorder primarily characterized by proximal myopathy and external ophthalmoplegia. Onset typically occurs in childhood. Histological findings on muscle biopsy may include absent type 2A fibers, predominance of type 1 fibers, fiber size variability and internal nuclei. Inclusion body myopathy with Paget disease of bone with or without frontotemporal dementia type 1 (IBMPFD1) is characterized by adult-onset proximal and distal muscle weakness, early-onset Paget disease of bone (PDB), and premature frontotemporal dementia (FTD). 90% of affected individuals develop disabling weakness (average onset of 45 years), 51% have osteolytic lesions consistent with PDB, and 32% develop FTD, which manifests with prominent language and behavioral dysfunction (average onset of 54 years). Cardiomyopathy and cardiac failure have been observed in later stages of the disease. Hereditary myopathy with early respiratory failure (HMERF) is characterized by adult-onset distal or proximal skeletal muscle weakness with respiratory muscle weakness involvement early in the disease course. Disease progression may result in the loss of ability to walk and the need for permanent ventilatory support.

GeneInheritanceClinical subtypes of IBM
Autosomal dominantAutosomal recessive
GNE GNE-related myopathy (IBM2)  
HNRNPA2B1* inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 2 (IBMPFD2)
MYH2 proximal myopathy and ophthalmoplegia (MYPOP or IBM3)(inclusion body myopathy 3, IBM3, MYPOP)
TTN hereditary myopathy with early respiratory failure (HMERF)
VCP inclusion body myopathy with early-onset Paget disease of bone with or withoutand/or frontotemporal dementia 1 (IBMPFD1)

*Preliminary-evidence gene

Pathogenic variants in the GNE gene account for 100% of cases of GNE-related myopathy. In the case of IBMPFD1, pathogenic variants in the VCP gene are detected in 100% of cases after sequencing. The proportion of cases of IBM accounted for by MYH2, TTN, VCP, and HNRNPA2B1 is unknown at this time.

IBM associated with the GNE gene is inherited in an autosomal recessive manner. IBM associated with the VCP, TTN, and HNRNPA2B1 genes is inherited in an autosomal dominant manner. IBM associated with the MYH2 gene is typically inherited in an autosomal recessive manner; however, cases of dominant inheritance have also been reported.

Penetrance is gene-specific. The GNE gene has moderate-high penetrance. The VCP gene has complete penetrance, although there is marked phenotypic variability across age groups. MYH2 penetrance is high for the recessive form of MYPOP. TTN and HNRNPA2B1 have an unknown penetrance at this point.

The overall prevalence of inclusion body myopathies is unknown at this point, but is thought to be relatively low.

To date, more than 200 individuals with GNE-related myopathy have been identified worldwide. Among these, about 160 are of Iranian-Jewish descent and were identified to have a founder mutation (p.Met712Thr) (PMID: 19596068).

The clinical spectrum of inclusion body myopathies is broad. Genetic testing may confirm a suspected diagnosis, narrow down the diagnosis to a specific type of inclusion body myopathy, or rule out disorders with similar symptoms. A genetic diagnosis may also help predict disease progression and inform recurrence risk.

  1. O’Ferrall, EK, Sinnreich, M. GNE-Related Myopathy. 2004 Mar 26. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301439
  2. Kimonis, V, et al. Inclusion Body Myopathy with Paget Disease of Bone and/or Frontotemporal Dementia. 2007 May 25. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301649
  3. Kim, HJ, et al. Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature. 2013; 495(7442):467-73. PMID: 23455423
  4. Lossos, A, et al. A novel autosomal recessive myopathy with external ophthalmoplegia linked to chromosome 17p13.1-p12. Brain. 2005; 128(Pt 1):42-51. PMID: 15548556
  5. Tajsharghi, H, et al. Recessive myosin myopathy with external ophthalmoplegia associated with MYH2 mutations. Eur. J. Hum. Genet. 2014; 22(6):801-8. PMID: 24193343
  6. Ohlsson, M, et al. Hereditary myopathy with early respiratory failure associated with a mutation in A-band titin. Brain. 2012; 135(Pt 6):1682-94. PMID: 22577218
  7. Pfeffer, G, et al. Titin mutation segregates with hereditary myopathy with early respiratory failure. Brain. 2012; 135(Pt 6):1695-713. PMID: 22577215
  8. Huizing, M, Krasnewich, DM. Hereditary inclusion body myopathy: a decade of progress. Biochim. Biophys. Acta. 2009; 1792(9):881-7. PMID: 19596068
  9. Nishino, I, et al. GNE myopathy: current update and future therapy. J. Neurol. Neurosurg. Psychiatr. 2015; 86(4):385-92. PMID: 25002140
  10. Eisenberg, I, et al. Mutations spectrum of GNE in hereditary inclusion body myopathy sparing the quadriceps. Hum. Mutat. 2003; 21(1):99. PMID: 12497639
  11. Darin, N, et al. Autosomal dominant myopathy with congenital joint contractures, ophthalmoplegia, and rimmed vacuoles. Ann. Neurol. 1998; 44(2):242-8. PMID: 9708547
  12. D'Amico, A, et al. A new de novo missense mutation in MYH2 expands clinical and genetic findings in hereditary myosin myopathies. Neuromuscul. Disord. 2013; 23(5):437-40. PMID: 23489661
  13. Weihl, CC, et al. Valosin-containing protein disease: inclusion body myopathy with Paget's disease of the bone and fronto-temporal dementia. Neuromuscul. Disord. 2009; 19(5):308-15. PMID: 19380227
  14. Nalbandian, A, et al. The multiple faces of valosin-containing protein-associated diseases: inclusion body myopathy with Paget's disease of bone, frontotemporal dementia, and amyotrophic lateral sclerosis. J. Mol. Neurosci. 2011; 45(3):522-31. PMID: 21892620
  15. Kimonis, VE, et al. Clinical and molecular studies in a unique family with autosomal dominant limb-girdle muscular dystrophy and Paget disease of bone. Genet. Med. 2000; 2(4):232-41. PMID: 11252708
  16. Pfeffer, G, et al. Titin founder mutation is a common cause of myofibrillar myopathy with early respiratory failure. J. Neurol. Neurosurg. Psychiatr. 2014; 85(3):331-8. PMID: 23486992

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
GNE NM_001128227.2
HNRNPA2B1 NM_031243.2
MYH2 NM_017534.5
TTN* NM_001267550.2
VCP NM_007126.3

TTN: Deletion/duplication and sequencing analysis is not offered for exons 153-155 (NM_133378.4). Variants are named relative to the NM_001267550.2 (meta) transcript, but only variants in the coding sequence and intronic boundaries of the clinically relevant NM_133378.4 (N2A) isoform are reported (PMID: 25589632).