Comprehensive Neuromuscular Panel

Neuromuscular disorders (NMDs) are a clinically, pathologically, and genetically heterogeneous group of diseases that impair muscle function or the peripheral nervous system and result in muscle weakness. The clinical diagnosis of these patients is based on clinical presentation, electromyography (EMG), muscle biopsy histopathology, biochemical and genetic testing. Although some NMDs are acquired or pharmaceutical-induced, many have a genetic cause. The age-of-onset of clinical symptoms depends on the specific diagnosis and can range from the neonatal period to adulthood.

The muscular dystrophies are typically diseases of the muscle membrane or supporting proteins and are characterized by ongoing muscle degeneration and regeneration. Patients with a muscular dystrophy can present with elevated creatine kinase (CK) levels, cardiomyopathy, joint contractures, respiratory issues, developmental delay, and in severe cases, brain and eye abnormalities. Myopathies are typically caused by defects in the contractile apparatus of the muscle and are typically considered less progressive than the dystrophies. In general, these patients have muscle weakness and loss in tone and can also exhibit joint contractures, respiratory complications, and spinal deformities. Congenital myasthenic syndromes (CMS) are disorders of the neuromuscular junction resulting from abnormalities of presynaptic, synaptic, or post synaptic proteins. CMS are characterized by fatigable weakness affecting limb, ocular, facial, and bulbar muscles. Neonates present with feeding problems, choking, feeble cry, and muscle weakness.

This panel includes genes for limb girdle muscular dystrophies, congenital muscular dystrophies, congenital myopathies, distal myopathies, myotonias, congenital myasthenic syndrome, and distal arthrogryposis. This panel is intended for patients in whom a muscle disease is suspected. We also offer a comprehensive neuropathy panel.

Neuromuscular disorders are genetically heterogenous and can be inherited in an autosomal dominant (AD), autosomal recessive (AR), and X-linked (XL) manner.

See individual gene test descriptions for information on clinical features, molecular biology of gene products, and spectra of pathogenic variants.

The sensitivity of this panel will vary based on the clinical phenotype of the patient and EMG or muscle biopsy results. In an Italian cohort of 504 patients in which 112 similar neuromuscular genes were tested, a definitive molecular diagnosis was made in 43% of patients (Savarese et al. 2016. PubMed ID: 27281536). In another study in which 44 known muscular dystrophy and myopathy genes were analyzed in 55 unrelated Chinese patients with muscle biopsy confirmed MD or congenital myopathy, 36 (65%) were found to have causative pathogenic variants (Dai et al. 2015. PubMed ID: 25987458). In another recent study in which 180 known or candidate myopathy genes were analyzed, a molecular diagnosis was made in 34% of patients (Evilä et al. 2016. PubMed ID: 26627873).

Many of the genes in this panel have no or very few large deletions/duplications reported. However, the CRPPA/ISPD, DMD, DYSF, GAA, LARGE1, and LAMA2 genes have a higher proportion of gross deletions/duplications reported (Human Gene Mutation Database). Approximately two-thirds of the pathogenic variants in Duchenne muscular dystrophy (DMD) patients are deletions of one or more exons in the DMD gene. The occurrence of deletions is slightly higher in Becker muscular dystrophy (BMD) patients. Duplications are found in approximately 10% of DMD patients and 20% of BMD patients (Monaco et al. 1988. PubMed ID: 3384440; Aartsma-Rus et al. 2006. PubMed ID: 16770791).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 98.3% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Exons 82-105 of the NEB gene are organized in three nearly identical repetitive blocks of 8 exons each making this region difficult to analyze. Since there are six highly homologous alleles, there is some limitation in variant and zygosity calling in this region. If an undocumented or pathogenic variant is detected in this region via NextGen Sequencing, a unique PCR and Sanger sequencing method will be used for confirmation.

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).