Invitae Nemaline Myopathy Panel

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  • Test code: 03369
  • 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
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Test description

The Invitae Nemaline Myopathy Panel analyzes 11 genes associated with nemaline myopathy—a variable spectrum of skeletal muscle disorders that is typically characterized by muscle weakness and visualization of nemaline bodies observed on muscle biopsy specimens. These genes were curated based on current available evidence to provide a comprehensive test for the genetic causes of nemaline myopathy.

Given that nemaline myopathy is a heterogeneous group of disorders, identification of the underlying genetic cause can help predict patient outcome and inform recurrence risk.

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Primary panel (11 genes)

ACTA1 CFL2 KBTBD13 KLHL40 KLHL41 LMOD3 MYPN NEB TNNT1 TPM2 TPM3

Alternative tests to consider

For a broader analysis of genes associated with congenital myopathies, clinicians may consider the Invitae Congenital Myopathy Panel, or the Invitae Comprehensive Myopathy Panel. These broader panels can be ordered at no additional charge.

Nemaline myopathies (NMs) are a heterogeneous group of disorders characterized by muscle weakness, hypotonia, depressed or absent deep tendon reflexes, and the presence of rod-like structures called nemaline bodies in the skeletal muscle (identified upon histologic examination). Muscle weakness most commonly affects the face, neck flexors, and proximal muscles. Weakness of the respiratory muscles is also common.

The clinical presentation of NM, including age of onset and severity of symptoms, is highly variable, and six clinical categories have been defined. The most common form of NM is the typical congenital form, which presents in infancy or early childhood with hypotonia, static or slowly progressive muscle weakness, and feeding difficulties. Most affected individuals with the typical congenital form of NM have delayed motor development but achieve independent ambulation. The intermediate congenital form of NM is associated with spontaneous movement at birth; however, affected children are unable to achieve independent respiration or ambulation in childhood. The severe congenital form of the disorder is typically characterized by lack of spontaneous movements and respiration at birth, congenital fractures, and contractures. Milder forms of NM with either childhood or adult onset have also been reported. Other forms of NM are characterized by atypical features that are not commonly observed in NM cases, such as cardiomyopathy and ophthalmoplegia.

Gene Subtype Proportion of NM cases Inheritance Clinical phenotypes observed
Autosomal dominant Autosomal recessive
ACTA1 NM3 15%–25% Typical congenital; severe congenital; intermediate congenital; childhood-onset; other/atypical form
CFL2 NM7 Unknown Typical congenital
KBTBD13 NM6 Unknown Childhood onset
KLHL40 NM8 Unknown Severe congenital
KLHL41 NM9 Unknown Severe congenital; intermediate congenital; typical congenital
LMOD3 NM10 Unknown Severe congenital; typical congenital
MYPN Unknown Childhood and adult-onset (PMID:28017374)
NEB NM2 ~50% Typical congenital (majority of cases); severe congenital; intermediate congenital; childhood-onset; adult-onset; other/atypical form
TNNT1 NM5 ~100% in cases of Amish NM Severe congenital (Amish form)
TPM2 NM4 <1% Typical congenital
TPM3 NM1 2%–3% Severe congenital; intermediate congenital; childhood-onset

The genes NEB and ACTA1 are the most common known causes of NM; together, they account for up to 75% of affected individuals. TPM3 is associated with 2%–3% of NM and TPM2 is associated with <1% of NM. Other rare genes are also included on this panel, which may increase the clinical sensitivity, though the exact contribution of these additional genes to NM is not known. In the Old Order Amish population, the TNNT1 gene accounts for up to 100% of cases of NM.

NM can be inherited in an autosomal dominant or autosomal recessive pattern.

Penetrance may be <100% in autosomal dominant forms of NM.

NM has an estimated incidence of 1 in 50,000 births and accounts for approximately 17% of all cases of congenital myopathy. In the Old Order Amish population, the incidence of NM is estimated to be as high as 1 in 500.

The clinical presentation of nemaline myopathies can be variable. 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.

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
CFL2 NM_021914.7
KBTBD13 NM_001101362.2
KLHL40 NM_152393.3
KLHL41 NM_006063.2
LMOD3 NM_198271.4
MYPN NM_032578.3
NEB* NM_001271208.1
TNNT1 NM_003283.5
TPM2 NM_003289.3
TPM3 NM_152263.3

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.