The Invitae Multiminicore Disease Panel analyzes the two genes associated with multiminicore disease (MmD), a congenital myopathy that is typically characterized by axial and proximal muscle weakness and by findings of multiple minicores on muscle biopsy. These genes were curated based on current available evidence to provide a comprehensive test for the known genetic causes of MmD.
Given that MmD is a genetically heterogeneous disorder, identification of the underlying genetic cause can help predict patient outcome and inform recurrence risk.
For a broader analysis of genes associated with congenital myopathies, clinicians may consider the Invitae Congenital Fiber Type Disproportion Panel, the Invitae Congenital Myopathy Panel, or the Invitae Comprehensive Myopathy Panel. These broader panels can be ordered at no additional charge.
MmD is a congenital myopathy that is characterized by muscle biopsy findings of minicores, which are small, focal muscle fiber lesions with sarcomeric disorganization and lack of oxidative activity. The classic form of MmD is associated with infantile or early-childhood onset hypotonia, delayed motor development, and slowly progressive axial and proximal muscle weakness. Spinal rigidity, progressive scoliosis, and respiratory involvement are common in classic MmD, and cardiac disease may develop secondary to respiratory issues. Affected individuals may remain ambulatory into adulthood despite significant scoliosis and respiratory issues. Atypical presentations of MmD also exist, including a form with distal weakness, joint hyperlaxity, and amyotrophy of the hands, a form with external ophthalmoplegia, and a severe neonatal form associated with congenital contractures.
The RYR1 gene is also associated with malignant hyperthermia susceptibility (MHS), a pharmacogenetic disorder characterized by susceptibility to uncontrolled skeletal muscle hypermetabolism after exposure to certain volatile anesthetics. Some individuals with RYR1-related MmD may have increased risk of MHS. SELENON-related MmD is not known to be associated with MHS.
RYR1 and SELENON are the only genes known to be associated with MmD. Pathogenic variants in SELENON account for an estimated 30%–54% of cases. The proportion of cases of MmD caused by pathogenic variants in RYR1 is unknown.
MmD is typically inherited in an autosomal recessive pattern.
The prevalence of MmD is unknown, but it is thought to be a rare disorder. MmD has been identified in a diverse range of ethnicities.
The clinical presentation of MmD is variable. Genetic testing may confirm a suspected diagnosis or rule out disorders with similar symptoms. A genetic diagnosis may also help to 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|
SEPN1: SELENON: Analysis includes the NM_20451.2:c.*1107T>C variant in the 3' UTR.