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, +/- 10 base pairs of adjacent intronic sequence, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.
Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|
RYR1: Deletion/duplication analysis is not offered for exons 48 or 49.