Rare Disease Report

Can Next Generation Sequencing Quickly Identify Rare Muscle Disorders?

JANUARY 27, 2016
James Radke, PhD
Late-onset Pompe disease is a rare lysosomal disease characterized by progressive lysosomal glycogen accumulation and muscle weakness. And while there is treatment available for the condition, a proper diagnosis can take years. Similar delays can be observed with other rare muscle disorders. The reason for the delayed diagnosis are multifactorial. Conditions such as late-onset Pompe disease are often a slow, progressive diseases with symptoms that can mimic other neuromuscular conditions, including limb-girdle muscular dystrophies. Also, the rarity of the condition means many neurologists are unfamiliar the subtle symptomology so testing for conditions like late-onset Pompe disease may be overlooked as they pursue more common muscle disorders.
In a new study published in the Orphanet Journal of Rare Disorders, Lévesque et al examined the feasibility of using next-generation sequencing to diagnose late-onset Pompe disease among various patients with other related muscle disorders. Late-onset Pompe disease is due to a mutation in the GAA gene. Having a panel that can identify the GAA mutation could significantly reduce the time to diagnosing late-onset Pompe disease to weeks instead of years.
The researchers designed a gene panel to analyze the coding sequences and splice site junctions of GAA causing late-onset Pompe disease, along with 77 other genes causing muscle disorders with overlapping phenotypes. These included genetic disorders that are part of the differential diagnosis of late-onset Pompe disease [muscular dystrophies with limb-girdle weakness pattern, rigid spine syndromes, scapuloperoneal syndromes, congenital myasthenic syndromes, congenital myopathies (nemaline, myofibrillar), congenital muscular dystrophies, metabolic myopathies (fatty acid oxidation disorders, glycogen storage disorders), and peroxisomal disorders].
The researcher then recruited patients (n=34) with undetermined muscle disorders.


The panel they developed showed 100% sensitivity and 98% specificity across all selected genes, using known variations in Pompe patients and controls.
Applying the panel to the 34 patients, they panel was able to determine a diagnosis in 11 patients, including 1 patient with late-onset Pompe disease.

Table: Diagnosis of patients with undetermined neuromuscular diseases
Patient Age
Age of
Onset (yrs)
Gene Disease
11 10 6 Proximal and distal limb muscle weakness COL6A1 Bethlem myopathy
13 11 0.3 Motor delay DNAJB6 LGMD1E
17 21 11 Proximal and distal limb muscle weakness FKTN LGMD2M
20 35 25 Limb-girdle muscle weakness ANO5 LGMD2L
21 56 N/A Limb-girdle muscle weakness COL6A3 Bethlem myopathy
22 46 <26 Limb-girdle muscle weakness DYSF LGMD2B
25 48 N/A Proximal and distal limb muscle weakness NEB Nemaline myopathy
27 60 57 Limb-girdle muscle weakness VCP inclsuion body myopathy
28 43 <10 Limb-girdle muscle weakness DMD Duchenne muscular dystrophy
29 48 <36 Limb-girdle muscle weakness GAA Pompe disease
30 1 0 motor delay and generalized hypotonia POMT2 Muscular dystrophy-dystroglycanopathy


The authors proposed that “gene panels should be used as a first-tier test in patients with suspected muscle disorders of undetermined etiology. With decreasing sequencing costs and increasing availability of NGS-based tests, there are several advantages of performing gene panels early in the investigation of patients with muscle weakness.”


Lévesque S, Auray-Blais C, Gravel E, et al. Diagnosis of late-onset Pompe disease and other muscle disorders by next-generation sequencing. Orphanet J Rare Dis. 2016;11:8. DOI: 10.1186/s13023-016-0390-6



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