The Invitae Myofibrillar Myopathy Panel analyzes eight genes that are associated with myofibrillar myopathy, a disorder whose diverse spectrum of clinical features includes slowly progressive muscle weakness that can involve both proximal and distal muscles. These genes were curated based on current available evidence to provide a comprehensive test for the genetic causes of myofibrillar myopathy.
Given that myofibrillar myopathy is a heterogeneous disorder, identification of the underlying genetic cause can help predict patient outcome and inform recurrence risk.
BAG3 CRYAB DES DNAJB6 FHL1 FLNC LDB3 MYOT
BAG3 CRYAB DES DNAJB6 FHL1 FLNC LDB3 MYOT
For a broader analysis of genes associated with myopathies, clinicians may consider the Invitae Distal Myopathy Panel, or the Invitae Comprehensive Myopathy Panel. These broader panels can be ordered at no additional charge.
Myofibrillar myopathy (MFM) is characterized by slowly progressive weakness that can involve both proximal and distal muscles. In approximately 25% of affected individuals, distal muscle weakness is more pronounced than proximal weakness. An estimated 25% of affected individuals have peripheral neuropathy, and 15%–30% have cardiomyopathy, which may precede muscle weakness. The age of onset varies widely, from age 2 to age 77 years, and may depend in part on the causative gene. Histopathologic muscle biopsy findings in MFM include myofibrillar disorganization beginning at the Z-disk, accumulation of myofibrillar degradation products, and ectopic expression of multiple proteins including desmin.
|Gene||Proportion of MFM cases||Inheritance||Typical age of onset||Cardiomyopathy|
|Autosomal dominant||Autosomal recessive||X-linked|
|BAG3||5%||✓||Childhood||✓ ~90% of cases have cardiomyopathy|
|CRYAB||3%||✓||✓||Variable||✓ Frequency unknown, limited cases reported to date|
|DES||7%||✓||✓||Variable||✓ ~90% of cases have cardiomyopathy|
|DNAJB6||2%||✓||Adulthood||Not reported to date (limited cases available)|
|FHL1||3%||✓||Variable||Not reported to date (limited cases available)|
|FLNC||3%||✓||Adulthood||✓ ~30% of cases have cardiomyopathy|
|LDB3||11%||✓||Adulthood||✓ ~30% of cases have cardiomyopathy|
|MYOT||9%||✓||Adulthood||✓ ~30% of cases have cardiomyopathy|
There are a total of eight genes known to be associated with MFM. The most common is LDB3, which accounts for 11% of affected individuals. The others (BAG3, CRYAB, DES, DNAJB6, FHL1, FLNC and MYOT) each account for less than 10% of affected individuals with MFM.
MFM associated with the BAG3, DNAJB6, FLNC, LDB3, and MYOT genes is inherited in an autosomal dominant pattern. CRYAB- and DES-associated MFM can be inherited in either an autosomal dominant or a recessive pattern. FHL1-associated MFM is an X-linked disorder.
Incomplete penetrance has been observed in some families with DES-associated MFM. MFM can have a very late onset, which makes determination of penetrance difficult.
MFM is a rare condition whose prevalence is unknown.
The clinical presentation of myofibrillar 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.
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 in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
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|
|LDB3||NM_001080116.1; NM_001171610.1; NM_007078.2|