Congenital Myopathy Panel

Overview

Congenital Myopathy Panel

Establish or confirm diagnosis

NM is inherited in an autosomal dominant or autosomal recessive manner. In one series, approximately 20% of cases were autosomal recessive, approximately 30% autosomal dominant, and approximately 50% simplex (i.e., single occurrences in a family) representing heterozygosity for de novo dominant mutations or homozygosity for autosomal recessive mutations. Accurate recurrence risk information requires determination of the mode of inheritance, if possible, through pedigree analysis and a combination of clinical evaluation, molecular genetic testing, and muscle biopsy of the parents. Carrier testing for at-risk relatives in families with autosomal recessive NM is possible if the disease-causing mutations in the family are known. Prenatal molecular genetic testing is possible for pregnancies at increased risk for NM if the disease-causing mutation(s) in the family are known. BIN1 mutations appear to be relatively rare, accounting for approximately 25% of cases of CNM with apparent recessive inheritance but only a small percentage of all CNM cases combined. To date, only a small number of mutations have been described in the BIN1 gene, including several missense changes and nonsense mutations. The BIN1 gene codes for Bridging Integrator 1, also known as amphiphysin II, and has a muscle specific isoform. Amphiphysin II is regulated by phosphoinositides and is believed to be involved in membrane remodeling and T tubule organization. Majczenko et al, 2012, identified a heterozygous mutation in CCDC78 in a family with AD CNM. The CCDC78 gene encodes a protein that is important in skeletal muscle function. Compton et al, 2008 identified a homozygous frameshift mutation in the CNTN1 gene in affected individuals of a large consanguineous Egyptian family. The CNTN1 gene encodes for contactin-1, a neural adhesion molecular of the immunoglobulin superfamily. The majority of patients with autosomal dominant or later onset CNM, including DNM2-associated CNM, are ambulatory into adulthood. Intelligence is usually normal but at least one family with a DNM2 mutation has been reported to have mild cognitive impairment, as well as mild axonal peripheral nerve involvement. DNM2 mutations account for most, but not all, cases of CNM with autosomal dominant inheritance or later onset. NADH staining of patients with DNM2 mutations often reveals radial arrangement of sarcoplasmic strands, which is highly characteristic, but not diagnostic, of DNM2-associated CNM. Patients with X-linked myotubular myopathy (XLMTM) generally present with hypotonia, feeding difficulties, respiratory distress, and delayed motor milestones. Death in infancy is common in males with the classic form of this condition. Milder forms of XLMTM have been identified and are characterized by fewer respiratory complications and longer life expectancy than observed in the severe cases. Truncating and splice site MTM1 mutations are more likely to be associated with the severe neonatal form, whereas the milder phenotypes are often caused by missense mutations outside of the functional domains. Missense mutations may result in a mild or severe phenotype based on their position in the MTM1 gene. Approximately 80% of males with a diagnosis of myotubular myopathy by muscle biopsy will have a mutation in MTM1 identifiable by sequence analysis. About 7% of mutations in MTM1 are deletions. Kerst et al, 2000 identified a heterozygous missense mutation in the MYF6 gene in a boy with myopathy and an increase of muscle fibers with central nuclei. The MYF6 gene is a novel member of the human gene family of muscle determination factors. Heterozygous mutations in MYH7 have been associated with isolated hypertrophic/dilated cardiomyopathy, Laing distal myopathy and myosin storage myopathy. Inheritance is generally dominant, but recessive inheritance has been reported in at least one family with a more severe presentation that included cardiomyopathy. RYR1 is typically associated with autosomal recessive CNM, although a de novo autosomal dominant mutation in this gene has also been reported. CNM-associated mutations identified in RYR1 have included missense, frameshift, and intronic. Mutations in RYR1 have also been associated with malignant hyperthermia [OMIM#145600], central core disease [OMIM#117000] and multi-minicore disease [OMIM#255320]. The RYR1 gene, located at 19q13.2, encodes the skeletal muscle ryanodine receptor, which is the principal sarcoplasmic reticulum calcium release channel with a crucial role in excitation-contraction coupling. Clarke et al, 2006 identified a homozygous mutation in the SEPN1 gene in two sisters with congenital fiber type disproportion. Homozygous or compound heterozygous mutations in SEPN1 have also been seen in multi-minicore disease, rigid spine muscular dystrophy and desmin-related myopathy with Mallory body-like inclusions. Mutations in TTN have been described in patients with hereditary myopathy with early respiratory failure, tibial muscular dystrophy, and dilated cardiomyopathy type 1G. Titin is a muscle protein expressed in the cardiac and skeletal muscles and plays a key role in muscle assembly.

• Clinical Testing/Confirmation of Mutations Identified Previously
• Confirmation of research findings
• Custom Prenatal Testing
• Custom mutation-specific/Carrier testing