CSM1; CSM2; LGMD2R
The DES gene is associated with autosomal dominant and recessive myofibrillar myopathy 1 (MFM1) (MedGen UID: 330449). It is also associated with autosomal recessive limb-girdle muscular dystrophy type 2R (LGMD2R)(MedGen UID: 815467) and autosomal dominant dilated cardiomyopathy (DCM) (MedGen UID: 387998).
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Invitae tests that include this gene:
DES mutations account for approximately 7% of known familial cases of myofibrillar myopathy, and the genetic cause is understood for only approximately half of all such cases. DES mutations are a rare cause of limb girdle muscular dystrophy and DCM.
DES encodes desmin, a cardiac and skeletal muscle protein that forms an intermediate filament connecting the contractile apparatus (by encircling the Z-band) to the sarcolemma and cytoplasmic organelles. Desmin functions to transmit force.
The phenotypes caused by pathogenic variants in DES are a clinically heterogeneous spectrum of conditions, sometimes called desminopathies. They are generally characterized by skeletal and cardiac muscle myopathy, including myofibrillar myopathy (MFM1; MedGen UID: 330449), limb-girdle muscular dystrophy (LGMD; MedGen UID: 151940), and dilated cardiomyopathy (DCM; MedGen UID: 387998; PMID: 20718792).
MFM1 is typically characterized by slowly progressive distal muscle weakness, cardiomyopathy, and cardiac conduction disease, although the disease is highly variable within and among families with regard to onset (childhood to adulthood), features, and severity (PMID: 20718792, 14991347). Skeletal myopathy usually begins in the lower extremities, followed by the upper extremities, and slowly spreads proximally to other muscle groups (PMID: 20718792). A muscle biopsy can show desmin-positive aggregates and degenerative changes of the myofibrillar apparatus; however, these are not specific to DES-related myopathy (PMID: 19561540, 9697706). Cardiomyopathy can be hypertrophic, dilated, or restrictive, and is often accompanied or preceded by conduction defects and arrhythmia (PMID: 20718792).
DES-related LGMD is characterized by progressive proximal weakness and non-specific atrophy, affecting both the shoulder and pelvic girdles with cardiac conduction block without cardiomyopathy. The age of onset is typically in the teens or twenties (PMID: 23687351, 24843229).
DCM is defined by dilation and impaired contraction of the left or both ventricles (PMID: 10099905). DES-related DCM can be associated with conduction defects, and symptoms may include edema, shortness of breath, fatigue, palpitations, dizziness, syncope, and sudden cardiac arrest or death (PMID: 17325244, 25584016).
DES encodes the protein desmin, which is the main intermediate filament protein in skeletal, cardiac, and smooth muscle, and interacts with other proteins to form a continuous cytoskeletal network maintaining the spatial relationship between muscle contractile apparatus and other structural cellular elements (PMID: 7188712, 20718792). Within this cytoskeletal network, desmin provides maintenance of cellular integrity, force transmission, and mechanochemical signaling, enabling the heart to contract in a coordinated fashion (PMID: 20718792, 23143191).
Pathogenic variants in DES can cause disease in an autosomal dominant or recessive manner, and may be inherited or occur de novo (PMID: 9697706, 24843229, 20718792). In autosomal dominant disease, an affected individual with a pathogenic variant has a 50% chance of passing that variant onto their offspring. In autosomal recessive disease, affected individuals have two pathogenic variants, one in each copy of their DES genes. Affected individuals will pass one pathogenic DES variant to all of their children. DES pathogenic variants exhibit reduced penetrance and variable expression, meaning that it is possible that an individual with a disease-causing variant will not develop symptoms of the disease within their lifetime.
While no comprehensive surveillance and management guideline currently exists across all DES-related conditions, the recommendations below may be appropriate for conditions within the desminopathy spectrum.
Upon discovery of a DES pathogenic variant, referral to a multidisciplinary clinic with expert specialists is recommended, so that the patient can be screened for appropriate symptoms of DES-related conditions and managed accordingly (PMID: 25313375, 19254666).
Initial evaluations after a DES pathogenic variant is identified include:
Ongoing evaluations and management of symptoms include:
Review date: December 2017
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|