Invitae Congenital Myopathy Panel

Ordering
  • Test code: 03362
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit
Billing

Test description

The Invitae Congenital Myopathy Panel analyzes up to 27 genes associated with congenital myopathies, a heterogeneous group of neuromuscular disorders with widely variable symptom severity. These genes were curated based on current available evidence to provide a comprehensive test for the genetic causes of congenital myopathies.

Given that congenital myopathies are a heterogeneous group of disorders, identification of the underlying genetic cause can help predict outcome for the patient, and inform recurrence risk.

Order test

Primary panel (25 genes)

ACTA1 BIN1 CCDC78 CFL2 CNTN1 COL6A1 COL6A2 COL6A3 DNM2 FKBP14 KBTBD13 KLHL40 KLHL41 LMOD3 MEGF10 MTM1 MYH7 NEB RYR1 SEPN1 STAC3 TNNT1 TPM2 TPM3 TTN

NEB: This assay detects the exon 55 deletion found in Ashkenazi Jewish individuals in association with nemaline myopathy. Exons 82-105 contain a large triplicated region. Deletion/duplication analysis excludes this region. Sequence changes in this region can be detected, but this assay cannot determine which of the three repeat units is affected (and zygosity is often ambiguous). All variants in this region are reported relative to the exon 82-89 repeat.
RYR1: Deletion/duplication analysis is not offered for exons 48 or 49.
SEPN1: Analysis includes the NM_20451.2:c.*1107T>C variant in the 3' UTR.
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).

Add-on preliminary-evidence gene (2 genes)

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 genes which do not currently have a definitive clinical association, but which may prove to be clinically significant in the future. These genes can be added at no additional charge. Visit our Preliminary-evidence genes page to learn more.

COL12A1 MYF6

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. In some cases, congenital myopathies may have overlapping features with congenital muscular dystrophies. If a congenital muscular dystrophy is suspected, clinicians may consider the Invitae Congenital Muscular Dystrophy Panel, or the Invitae Comprehensive Muscular Dystrophy panel. Congenital myopathies may also have nonspecific or overlapping features with other neuromuscular disorders, in which case clinicians may consider Invitae’s Comprehensive Neuromuscular panel, which includes genes associated with myopathies, muscular dystrophies, and congenital myasthenic syndrome.

Congenital myopathies are a heterogeneous group of inherited neuromuscular disorders, features of which typically present between the neonatal period and early childhood. The most common presenting symptoms are hypotonia and muscle weakness. Congenital myopathies can be divided into subtypes based on histopathologic muscle biopsy findings, such as central cores, central nuclei, fiber-type disproportion, multiminicores, and nemaline bodies. Overall, central core disease is the most common subtype of congenital myopathy, and accounts for approximately 40% of individuals with a congenital myopathy.

Symptoms and disease severity vary depending on the causative gene; however, the majority of individuals with a form of congenital myopathy can achieve independent ambulation, despite having delayed motor development. Some affected individuals who achieve independent ambulation may later lose the ability to walk independently. Respiratory involvement of variable severity is observed in approximately two-thirds of individuals with a congenital myopathy. Cardiac involvement is rare. In approximately 10% of cases, congenital myopathy is lethal in infancy or early childhood.

GeneInheritanceAssociated subtypes of congenital myopathy
Autosomal dominantAutosomal recessiveX-linked
ACTA1 nemaline myopathy-3, congenital fiber-type disproportion
BIN1 centronuclear myopathy-2
CCDC78 centronuclear myopathy-4
CFL2 nemaline myopathy-7
CNTN1 Compton-North congenital myopathy
COL12A1* Bethlem myopathy-2, Ullrich congenital muscular dystrophy-2
COL6A1 Bethlem myopathy-1, Ullrich congenital muscular dystrophy-1
COL6A2 Bethlem myopathy-1, Ullrich congenital muscular dystrophy-1
COL6A3 Bethlem myopathy-1, Ullrich congenital muscular dystrophy-1
DNM2 DNM2-associated centronuclear myopathy
FKBP14 Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss
KBTBD13 nemaline myopathy-6
KLHL40 nemaline myopathy-8
KLHL41 nemaline myopathy-9
LMOD3 nemaline myopathy-10
MEGF10 early-onset myopathy with minicores, areflexia, respiratory distress, and dysphagia
MTM1 X-linked centronuclear myopathy
MYF6* centronuclear myopathy-3
MYH7 myosin storage myopathy, Laing distal myopathy, congenital fiber-type disproportion
NEB nemaline myopathy-2
RYR1 central core disease, centronuclear myopathy, congenital fiber-type disproportion, multiminicore disease
SEPN1 congenital fiber-type disproportion, multiminicore disease
STAC3 Native American myopathy
TNNT1 nemaline myopathy-5
TPM2 congenital fiber-type disproportion, nemaline myopathy-4
TPM3 congenital fiber-type disproportion, nemaline myopathy-1
TTN centronuclear myopathy

*Preliminary-evidence gene

In a study of 66 individuals with congenital myopathy, 40% had pathogenic variants in RYR1, 10% had pathogenic variants in SEPN1, and 10% had pathogenic variants in ACTA1. Pathogenic variants in MTM1, TPM3 and NEB were each identified in 3% of individuals or less. This panel also includes other genes that have been identified as causes of congenital myopathy, although the exact contribution of these genes to the overall detection rate is not known and is dependent on the clinical presentation of the patient.

Congenital myopathies caused by variants in the CCDC78, DNM2, KBTBD13, MYF6, and TPM2 genes are associated with autosomal dominant inheritance, while the CFL2, CNTN1, FKBP14, KLHL40, KLHL41, LMOD3, MEGF10, NEB, STAC3, TNNT1 and TTN genes are associated with autosomal recessive forms of congenital myopathy. A number of congenital myopathy genes have been associated with both autosomal dominant and recessive inheritance, including ACTA1, BIN1, COL12A1, COL6A1, COL6A2, COL6A3, MYH7, RYR1, SEPN1, and TPM3. MTM1-associated congenital myopathy is an X-linked condition.

Incomplete penetrance has been observed for some autosomal dominant forms of congenital myopathy, including congenital fiber-type disproportion and nemaline myopathy. Central core disease is thought to have penetrance approaching 100%, although some affected individuals may have functional improvement over time, and/or may appear asymptomatic in adulthood. Bethlem myopathy and Ullrich congenital muscular dystrophy are thought to have complete penetrance, but some individuals are mildly affected and can appear asymptomatic if careful clinical evaluation has not been performed. MTM1-associated CNM is considered to be 100% penetrant in males; carrier females are typically asymptomatic. Most other forms of congenital myopathy are rare, and penetrance estimates are not known.

Congenital myopathies are rare disorders. The prevalence in the United States is estimated to be 1 in 26,000.

The clinical spectrum of congenital myopathies is broad. Genetic testing may confirm a suspected diagnosis or rule out disorders with similar symptoms. A genetic diagnosis may also help predict disease progression and inform recurrence risk.

  1. Colombo, I, et al. Congenital myopathies: Natural history of a large pediatric cohort. Neurology. 2015; 84(1):28-35. PMID: 25428687
  2. Das, S, et al. X-Linked Centronuclear Myopathy. 2002 Feb 25. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301605
  3. DeChene, ET, et al. Congenital Fiber-Type Disproportion. 2007 Jan 12. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301436
  4. Jungbluth, H, et al. Centronuclear (myotubular) myopathy. Orphanet J Rare Dis. 2008; 3:26. PMID: 18817572
  5. Lampe, AK, et al. Collagen Type VI-Related Disorders. 2004 Jun 25. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301676
  6. Maggi, L, et al. Congenital myopathies--clinical features and frequency of individual subtypes diagnosed over a 5-year period in the United Kingdom. Neuromuscul. Disord. 2013; 23(3):195-205. PMID: 23394784
  7. Malicdan, MCV, Nishino, I. Central Core Disease. 2007 May 16. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301565
  8. North, KN, Ryan, MM. Nemaline Myopathy. 2002 Jun 19. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301465
  9. Stamm, DS, et al. Native American myopathy: congenital myopathy with cleft palate, skeletal anomalies, and susceptibility to malignant hyperthermia. Am. J. Med. Genet. A. 2008; 146A(14):1832-41. PMID: 18553514
  10. Wang, CH, et al. Consensus statement on standard of care for congenital myopathies. J. Child Neurol. 2012; 27(3):363-82. PMID: 22431881

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, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
ACTA1 NM_001100.3
BIN1 NM_139343.2
CCDC78 NM_001031737.2
CFL2 NM_021914.7
CNTN1 NM_001843.3
COL12A1 NM_004370.5
COL6A1 NM_001848.2
COL6A2 NM_001849.3
COL6A3 NM_004369.3
DNM2 NM_001005360.2
FKBP14 NM_017946.3
KBTBD13 NM_001101362.2
KLHL40 NM_152393.3
KLHL41 NM_006063.2
LMOD3 NM_198271.4
MEGF10 NM_032446.2
MTM1 NM_000252.2
MYF6 NM_002469.2
MYH7 NM_000257.3
NEB* NM_001271208.1
RYR1* NM_000540.2
SEPN1* NM_020451.2
STAC3 NM_145064.2
TNNT1 NM_003283.5
TPM2 NM_003289.3
TPM3 NM_152263.3
TTN* NM_001267550.2

NEB: This assay detects the exon 55 deletion found in Ashkenazi Jewish individuals in association with nemaline myopathy. Exons 82-105 contain a large triplicated region. Deletion/duplication analysis excludes this region. Sequence changes in this region can be detected, but this assay cannot determine which of the three repeat units is affected (and zygosity is often ambiguous). All variants in this region are reported relative to the exon 82-89 repeat.
RYR1: Deletion/duplication analysis is not offered for exons 48 or 49.
SEPN1: Analysis includes the NM_20451.2:c.*1107T>C variant in the 3' UTR.
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).