Metabolic Myopathy and Rhabdomyolysis Panel

Summary
  • Is a 52 gene panel that includes assessment of non-coding variants
  • Is ideal for patients with a medical condition associated with rhabdomyolysis. The genes on this panel are included in the Comprehensive Metabolism Panel.

Analysis methods
  • PLUS
  • SEQ
  • DEL/DUP
Availability

4 weeks

Number of genes

52

Test code

ME1401

Panel size

Large

CPT codes
SEQ 81479
DEL/DUP 81479

Summary

The Blueprint Genetics Metabolic Myopathy and Rhabdomyolysis Panel (test code ME1401):

ICD codes

Commonly used ICD-10 code(s) when ordering the Metabolic Myopathy and Rhabdomyolysis Panel

ICD-10 Disease
G73.7 Metabolic myopathies
E74.00 Glycogen storage disease
E75.00 Lipid storage disorder
M62.82 Rhabdomyolysis

Sample Requirements

  • Blood (min. 1ml) in an EDTA tube
  • Extracted DNA, min. 2 μg in TE buffer or equivalent
  • Saliva (Oragene DNA OG-500 kit/OGD-500 or OG-575 & OGD-575)

Label the sample tube with your patient's name, date of birth and the date of sample collection.

Note that we do not accept DNA samples isolated from formalin-fixed paraffin-embedded (FFPE) tissue. Read more about our sample requirements here.

Rhabdomyolysis is a medical condition in which damaged striated skeletal muscles break down easily and rapidly. Some end products of this lysis, such as myoglobin, are toxic to kidneys and may cause acute renal failure. Symptoms include muscle pain and vomiting. Common and important causes of rhabdomyolysis include several common situations, such as drugs and toxins, infections, hyperthermia, strong physical exercise and car accidents. However, recurrent rhabdomyolysis is often genetic in nature. The genetic causes for rhabdomyolysis include metabolic myopathy, disorders of intramuscular calcium release, mitochondrial disorders and muscular dystrophies. Metabolic myopathies are a group of genetic muscular diseases resulting from defective metabolism affecting primarily muscles. These myopathies are typically subdivided into three categories: i) glycogen storage diseases, ii) lipid storage diseases and iii) disorders of purine metabolism, all of which are associated with specific enzymatic defects that prevent adequate energy and ATP levels for muscle cells. This panel includes genes associated with all medical conditions that can cause rhabdomyolysis of genetic origin. The prevalence of rhabdomyolysis is not known.

Genes in the Metabolic Myopathy and Rhabdomyolysis Panel and their clinical significance

Gene Associated phenotypes Inheritance ClinVar HGMD
ACAD9 Acyl-CoA dehydrogenase family, deficiency AR 26 61
ACADL Long chain acyl-CoA dehydrogenase deficiency AD/AR 1
ACADM Acyl-CoA dehydrogenase, medium chain, deficiency AR 104 169
ACADVL Acyl-CoA dehydrogenase, very long chain, deficiency AR 119 282
ADCK3 Coenzyme Q10 deficiency, Progressive cerebellar ataxia and atrophy, Spinocerebellar ataxia AR 45 43
AGL Glycogen storage disease AR 142 245
AHCY Hypermethioninemia with S-adenosylhomocysteine hydrolase deficiency AR 3 9
ALDOA Glycogen storage disease AR 3 8
AMPD1 Myoadenylate deaminase deficiency AR 5 10
ANO5 Gnathodiaphyseal dysplasia, LGMD2L and distal MMD3 muscular dystrophies AD/AR 64 121
C10ORF2 Perrault syndrome, Mitochondrial DNA depletion syndrome, Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant, 3 AR 37 80
CAV3 Creatine phosphokinase, elevated serum, Hypertrophic cardiomyopathy (HCM), Long QT syndrome, Muscular dystrophy, limb-girdle, type IC, Myopathy, distal, Tateyama type, Rippling muscle disease 2 AD/AR 23 50
COQ2 Coenzyme Q10 deficiency AR 16 31
CPT2 Carnitine palmitoyltransferase II deficiency AR 72 111
DYSF Miyoshi muscular dystrophy, Muscular dystrophy, limb-girdle, Myopathy, distal, with anterior tibial onset AR 244 529
ENO3 Glycogen storage disease AR 3 6
ETFA Glutaric aciduria, Multiple acyl-CoA dehydrogenase deficiency AR 8 29
ETFB Glutaric aciduria, Multiple acyl-CoA dehydrogenase deficiency AR 6 15
ETFDH Glutaric aciduria, Multiple acyl-CoA dehydrogenase deficiency AR 43 190
FKRP Muscular dystrophy-dystroglycanopathy AR 66 140
FKTN Muscular dystrophy-dystroglycanopathy, Dilated cardiomyopathy (DCM), Muscular dystrophy-dystroglycanopathy (limb-girdle) AD/AR 45 58
FLAD1 Lipid storage myopathy due to FLAD1 deficiency (LSMFLAD) AR 9 10
GAA Glycogen storage disease AR 193 573
GBE1 Glycogen storage disease AR 36 70
GYG1 Glycogen storage disease, Polyglucosan body myopathy 2 AR 9 16
GYS1 Glycogen storage disease AR 8 5
HADHA Trifunctional protein deficiency, Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency AR 65 71
HADHB Trifunctional protein deficiency AR 20 65
ISCU Myopathy with lactic acidosis AR 3 3
LDHA Glycogen storage disease AR 1 9
LPIN1 Myoglobinuria, acute, recurrent AR 6 29
MYH3 Arthrogryposis AD 21 45
OPA1 Optic atrophy, Optic atrophy 1, Optic atrophy with or without deafness, Ophthalmoplegia, myopathy, ataxia, and neuropathy, Behr synrome, Mitochondrial DNA depletion syndrome 14 AD/AR 96 390
OPA3 Optic atrophy, 3-methylglutaconic aciduria AD/AR 13 15
PFKM Glycogen storage disease AR 12 26
PGAM2 Glycogen storage disease AR 4 11
PGK1 Phosphoglycerate kinase 1 deficiency XL 16 26
PGM1 Congenital disorder of glycosylation AR 11 35
PHKA1 Glycogen storage disease XL 9 8
POLG POLG-related ataxia neuropathy spectrum disorders, Sensory ataxia, dysarthria, and ophthalmoparesis, Alpers syndrome, Progressive external ophthalmoplegia with mitochondrial DNA deletions, Mitochondrial DNA depletion syndrome AD/AR 89 290
POLG2 Progressive external ophthalmoplegia with mitochondrial DNA deletions AD 5 14
PYGM Glycogen storage disease AR 77 168
RBCK1 Polyglucosan body myopathy AR 11 14
RRM2B Progressive external ophthalmoplegia with mitochondrial DNA deletions, Mitochondrial DNA depletion syndrome AD/AR 41 41
RYR1 Central core disease, Malignant hyperthermia, Minicore myopathy with external ophthalmoplegia, Centronuclear myopathy, Minicore myopathy, Multicore myopathy AD/AR 241 666
SCN4A Hyperkalemic periodic paralysis, Myotonia, potassium-aggravated, Paramyotonia congenita, Myasthenic syndrome, congenital, Normokalemic potassium-sensitive periodic paralysis AD/AR 57 126
SLC22A5 Carnitine deficiency, systemic primary AR 98 151
SLC25A20 Carnitine-acylcarnitine translocase deficiency AR 15 42
SUCLA2 Mitochondrial DNA depletion syndrome AR 9 29
TANGO2 Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration (MECRCN) AR 13 9
TK2 Mitochondrial DNA depletion syndrome AR 38 52
TYMP Mitochondrial DNA depletion syndrome AR 84 94

Gene refers to the HGNC approved gene symbol; Inheritance refers to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR), X-linked (XL), X-linked dominant (XLD) and X-linked recessive (XLR); ClinVar refers to the number of variants in the gene classified as pathogenic or likely pathogenic in this database (ClinVar); HGMD refers to the number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD). The list of associated, gene specific phenotypes are generated from CGD or Orphanet databases.

Non-coding variants covered by Metabolic Myopathy and Rhabdomyolysis Panel

Gene Genomic location HG19 HGVS RefSeq RS-number
ACADM Chr1:76200457 c.388-19T>A NM_000016.4
ACADM Chr1:76211473 c.600-18G>A NM_000016.4 rs370523609
ACADVL Chr17:7125469 c.822-27C>T NM_001270447.1 rs374911841
ACADVL Chr17:7125485 c.822-11T>G NM_001270447.1
ACADVL Chr17:7126948 c.1252-15A>G NM_001270447.1 rs765390290
AGL Chr1:100381954 c.4260-12A>G NM_000028.2 rs369973784
DYSF Chr2:71840553 c.4410+13T>G NM_003494.3
ETFDH Chr4:159593534 c.-75A>G NM_004453.2
FKTN Chr9:108368857 c.648-1243G>T NM_006731.2
GAA Chr17:78078341 c.-32-13T>G NM_000152.3 rs386834236
GAA Chr17:78078341 c.-32-13T>A NM_000152.3
GAA Chr17:78078351 c.-32-3C>A NM_000152.3
GAA Chr17:78078351 c.-32-3C>A/G NM_000152.3
GAA Chr17:78078352 c.-32-2A>G NM_000152.3
GAA Chr17:78078369 c.-17C>T NM_000152.3
GAA Chr17:78082266 c.1076-22T>G NM_000152.3 rs762260678
GAA Chr17:78092432 c.2647-20T>G NM_000152.3
GBE1 Chr3:81542963 c.2053-3358_2053-3350delGTGTGGTGGinsTGTTTTTTACATGACAGGT NM_000158.3
GYG1 Chr3:148717967 c.481+3276C>G NM_004130.3
HADHB Chr2:26500642 c.442+614A>G NM_000183.2
ISCU Chr12:108961426 c.418+382G>C NM_213595.2 rs767000507
OPA1 Chr3:193335986 c.610+360G>A NM_130837.2
OPA1 Chr3:193335990 c.610+364G>A NM_130837.2
OPA1 Chr3:193374829 c.2179-40G>C NM_130837.2
PFKM Chr12:48535459 c.1626-64A>G NM_001166686.1
PGM1 Chr1:64113966 c.1199-222G>T NM_001172818.1
PGM1 Chr1:64124734 c.1654-523G>A NM_001172818.1
PYGM Chr11:64523631 c.661-601G>A NM_005609.2
PYGM Chr11:64525847 c.425-26A>G NM_005609.2 rs764313717
RYR1 Chr19:38997317 c.8692+131G>A NM_000540.2
RYR1 Chr19:39073707 c.14647-1876C>T NM_000540.2 rs193922885
RYR1 Chr19:39074134 c.14647-1449A>G NM_000540.2 rs193922886
SLC22A5 Chr5:131714054 c.394-16T>A NM_003060.3 rs775097754
SLC22A5 Chr5:131722665 c.825-52G>A NM_003060.3

Test Strengths

The strengths of this test include:
  • CAP and ISO-15189 accreditations covering all operations at Blueprint Genetics including all Whole Exome Sequencing, NGS panels and confirmatory testing
  • CLIA-certified personnel performing clinical testing in a CLIA-certified laboratory
  • Powerful sequencing technologies, advanced target enrichment methods and precision bioinformatics pipelines ensure superior analytical performance
  • Careful construction of clinically effective and scientifically justified gene panels
  • Our Nucleus online portal providing transparent and easy access to quality and performance data at the patient level
  • Our publically available analytic validation demonstrating complete details of test performance
  • ~1,500 non-coding disease causing variants in Blueprint WES assay (please see below ‘Non-coding disease causing variants covered by this panel’)
  • Our rigorous variant classification based on modified ACMG variant classification scheme
  • Our systematic clinical interpretation workflow using proprietary software enabling accurate and traceable processing of NGS data
  • Our comprehensive clinical statements

Test Limitations

This test does not detect the following:
  • Complex inversions
  • Gene conversions
  • Balanced translocations
  • Mitochondrial DNA variants
  • Repeat expansion disorders unless specifically mentioned
  • Non-coding variants deeper than ±20 base pairs from exon-intron boundary unless otherwise indicated (please see above Panel Content / non-coding variants covered by the panel).
This test may not reliably detect the following:
  • Low level mosaicism (variant with a minor allele fraction of 14.6% is detected with 90% probability)
  • Stretches of mononucleotide repeats
  • Indels larger than 50bp
  • Single exon deletions or duplications
  • Variants within pseudogene regions/duplicated segments

The sensitivity of this test may be reduced if DNA is extracted by a laboratory other than Blueprint Genetics.

For additional information, please refer to the Test performance section and see our Analytic Validation.

The Blueprint Genetics metabolic myopathy and rhabdomyolysis panel covers classical genes associated with metabolic myopathies, glycogen storage disease, lipid storage disorder and rhabdomyolysis. The genes on the panel have been carefully selected based on scientific literature, mutation databases and our experience.

Our panels are sliced from our high-quality whole exome sequencing data. Please see our sequencing and detection performance table for different types of alterations at the whole exome level (Table).

Assays have been validated for different starting materials including EDTA-blood, isolated DNA (no FFPE), saliva and dry blood spots (filter card) and all provide high-quality results. The diagnostic yield varies substantially depending on the assay used, referring healthcare professional, hospital and country. Blueprint Genetics’ Plus Analysis (Seq+Del/Dup) maximizes the chance to find a molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be a cost-effective first line test if your patient’s phenotype is suggestive of a specific mutation type.

Performance of Blueprint Genetics Whole Exome Sequencing (WES) assay. All individual panels are sliced from WES data.

Sensitivity % (TP/(TP+FN) Specificity %
Single nucleotide variants 99.65% (412,456/413,893) >99.99%
Insertions, deletions and indels by sequence analysis
1-10 bps 96.94% (17,070/17,608) >99.99%
11-50 bps 99.07% (957/966) >99.99%
Copy number variants (exon level dels/dups)
Clinical samples (small CNVs, n=52)
1 exon level deletion 92.3% (24/26) NA
2 exons level deletion/duplication 100.0% (11/11) NA
3-7 exons level deletion/duplication 93.3% (14/15) NA
Microdeletion/-duplication sdrs (large CNVs, n=37))
Size range (0.1-47 Mb) 100% (37/37)
Simulated CNV detection
2 exons level deletion/duplication 90.98% (7,357/8,086) 99.96%
5 exons level deletion/duplication 98.63% (7,975/8,086) 99.98%
     
The performance presented above reached by WES with the following coverage metrics
     
Mean sequencing depth at exome level 174x
Nucleotides with >20x sequencing coverage (%) 99.4%

Bioinformatics

The target region for each gene includes coding exons and ±20 base pairs from the exon-intron boundary. In addition, the panel includes non-coding variants if listed above (Non-coding variants covered by the panel). Some regions of the gene(s) may be removed from the panel if specifically mentioned in the ‘Test limitations” section above. The sequencing data generated in our laboratory is analyzed with our proprietary data analysis and annotation pipeline, integrating state-of-the art algorithms and industry-standard software solutions. Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results. Our pipeline is streamlined to maximize sensitivity without sacrificing specificity. We have incorporated a number of reference population databases and mutation databases such as, but not limited, to 1000 Genomes Project, gnomAD, ClinVar and HGMD into our clinical interpretation software to make the process effective and efficient. For missense variants, in silico variant prediction tools such as SIFT, PolyPhen, MutationTaster are used to assist with variant classification. Through our online ordering and statement reporting system, Nucleus, the customer has an access to details of the analysis, including patient specific sequencing metrics, a gene level coverage plot and a list of regions with inadequate coverage if present. This reflects our mission to build fully transparent diagnostics where customers have easy access to crucial details of the analysis process.

Clinical interpretation

We provide customers with the most comprehensive clinical report available on the market. Clinical interpretation requires a fundamental understanding of clinical genetics and genetic principles. At Blueprint Genetics, our PhD molecular geneticists, medical geneticists and clinical consultants prepare the clinical statement together by evaluating the identified variants in the context of the phenotypic information provided in the requisition form. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals regardless of whether they have formal training in genetics.

Variant classification is the corner stone of clinical interpretation and resulting patient management decisions. Our classifications follow the Blueprint Genetics Variant Classification Schemes based on the ACMG guideline 2015. Minor modifications were made to increase reproducibility of the variant classification and improve the clinical validity of the report. Our experience with tens of thousands of clinical cases analyzed at our laboratory allowed us to further develop the industry standard.

The final step in the analysis is orthogonal confirmation. Sequence variants classified as pathogenic, likely pathogenic and variants of uncertain significance (VUS) are confirmed using bi-directional Sanger sequencing when they do not meet our stringent NGS quality metrics for a true positive call.
Reported copy number variations with a size <10 exons are confirmed by orthogonal methods such as qPCR if the specific CNV has been seen less than three times at Blueprint Genetics (Plus analysis only).

Our clinical statement includes tables for sequencing and copy number variants that include basic variant information (genomic coordinates, HGVS nomenclature, zygosity, allele frequencies, in silico predictions, OMIM phenotypes and classification of the variant). In addition, the statement includes detailed descriptions of the variant, gene and phenotype(s) including the role of the specific gene in human disease, the mutation profile, information about the gene’s variation in population cohorts and detailed information about related phenotypes. We also provide links to the references used, congress abstracts and mutation databases to help our customers further evaluate the reported findings if desired. The conclusion summarizes all of the existing information and provides our rationale for the classification of the variant.

Identification of pathogenic or likely pathogenic variants in dominant disorders or their combinations in different alleles in recessive disorders are considered molecular confirmation of the clinical diagnosis. In these cases, family member testing can be used for risk stratification within the family. In the case of variants of uncertain significance (VUS), we do not recommend family member risk stratification based on the VUS result. Furthermore, in the case of VUS, we do not recommend the use of genetic information in patient management or genetic counseling.

Our interpretation team analyzes millions of variants from thousands of individuals with rare diseases. Thus, our database, and our understanding of variants and related phenotypes, is growing by leaps and bounds. Our laboratory is therefore well positioned to re-classify previously reported variants as new information becomes available. If a variant previously reported by Blueprint Genetics is re-classified, our laboratory will issue a follow-up statement to the original ordering health care provider at no additional cost.

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