The Invitae Autophagic Vacuolar Myopathy Panel analyzes three genes associated with autophagic vacuolar myopathy (AVM), a group of myopathies characterized by unusual autophagic vacuoles with sarcolemmal features and includes Danon disease and X-linked myopathy with excessive autophagy. These genes were curated based on current evidence to provide a comprehensive test for the genetic causes of AVM.
Individuals with clinical signs and symptoms of autophagic vacuolar myopathies may benefit from diagnostic genetic testing to confirm or establish a differential diagnosis, to provide anticipatory guidance, to help determine which relatives are at risk, or to guide enrollment in certain clinical trials.
DES LAMP2 VMA21
DES LAMP2 VMA21
Autophagic vacuolar myopathies (AVMs) are a group of muscle disorders histopathologically categorized by autophagic vacuoles containing both lysosomal and autophagosomal proteins, which are sometimes lined with sarcolemmal proteins such as dystrophin. The AVMs included in this panel are DES-related myopathy, Danon disease, and X-linked myopathy with excessive autophagy (XMEA). DES-related myopathy is characterized by slowly progressive weakness that involves proximal (25% of cases) and distal (80% of cases) skeletal muscles. Age of onset is variable from early childhood to late adulthood. Other features include peripheral neuropathy, present in about 20% of affected individuals, and cardiomyopathy, present in 15%-30% of cases. Danon disease is characterized by cardiomyopathy, arrhythmia, skeletal myopathy, and a varying degree of intellectual disability in males. Additional features may include retinal,liver, or pulmonary disease. Carrier females may also develop features of Danon disease. Age of onset is extremely variable, and child, adolescent, and adult onset cases have been reported in the literature. XMEA is characterized by predominantly childhood onset of progressive muscle weakness and atrophy primarily affecting the proximal muscles.
|Autosomal dominant||Autosomal recessive||X-linked|
|VMA21||✓||X-linked myopathy with excessive autophagy (XMEA)|
Due to the rarity of AVMs, the clinical sensitivity of this panel has not yet been established.
The DES gene is associated with both autosomal dominant and autosomal recessive myopathy. LAMP2-associated Danon disease and VMA21-associated XMEA are X-linked disorders.
Penetrance varies according to the causative gene. DES-related myopathies can present late in adulthood, which makes determination of penetrance difficult. LAMP2 is the only gene known to be associated with Danon disease, although some individuals can present with cardiomyopathy as the initial symptom, making determination of penetrance difficult (PMID:25228319). Incomplete penetrance has been reported for XMEA (PMID:15753448).
AVMs are a rare group of disorders, and the overall prevalence of these conditions is currently unknown.
The clinical spectrum of AVMs is broad. Several muscle disorders can have a similar phenotype and establishing a differential diagnosis may be crucial. Genetic testing may confirm a suspected diagnosis, narrow down the diagnosis to a specific type of AVM, 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|