This test is for central core disease (CCD), a form of congenital myopathy that is caused by pathogenic variants in the RYR1 gene. CCD is a congenital myopathy with muscle weakness that is defined by the presence of central cores on muscle biopsy.
Age of onset is variable with CCD, and clinical presentation overlaps with other forms of myopathy. Identification of the underlying genetic cause may direct medical treatment, predict outcome for the patient, and inform recurrence risk.
For a broader analysis of genes associated with congenital myopathies, clinicians may consider the following panels: Invitae Congenital Fiber Type Disproportion Panel, Invitae Multiminicore Disease Panel, Invitae Centronuclear Myopathy Panel, Invitae Congenital Myopathy Panel, Invitae Comprehensive Myopathy Panel. These broader panels can be ordered at no additional charge.
Central core disease (CCD) is a form of congenital myopathy with a broad clinical spectrum that is defined by the presence of central cores on muscle biopsy. Symptom severity of RYR1-related myopathies ranges from fetal akinesia to mild muscle weakness in adults. The most severely affected individuals may present with congenital contractures, severe hypotonia, and respiratory failure. The majority of affected individuals have a mild form of CCD associated with hypotonia in infancy, delayed motor development, and static or slowly progressive mild proximal muscle weakness. Other possible features include congenital hip dislocation, scoliosis, and foot deformities. Cardiomyopathy and ophthalmoplegia are not typical features of CCD.
The RYR1 gene is also associated with malignant hyperthermia susceptibility (MHS), a pharmacogenetic disorder that is characterized by susceptibility to uncontrolled skeletal muscle hypermetabolism after exposure to certain volatile anesthetics. Some individuals with RYR1-related CCD may be at increased risk of MHS.
RYR1 is the only gene known to be associated with CCD and accounts for an estimated 90% of cases.
CCD is typically inherited in an autosomal dominant pattern. In some cases, an autosomal recessive inheritance pattern may be observed.
CCD is thought to be close to 100% penetrant. In some cases, functional improvement can occur over time in affected individuals, and individuals who were symptomatic in childhood and adolescence may appear asymptomatic in adulthood.
The prevalence of CCD in England is estimated at 1 in 250,000. The prevalence of CCD in other populations is unknown.
The clinical presentation of CCD 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 recommendations, 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|