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.
ACTA1 CFL2 KBTBD13 KLHL40 KLHL41 LMOD3 MYPN NEB TNNT1 TPM2 TPM3
ACTA1 CFL2 KBTBD13 KLHL40 KLHL41 LMOD3 MYPN NEB TNNT1 TPM2 TPM3
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|
|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)|
|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.
For management guidelines please refer to:
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|
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.