Metabolic Myopathy and Rhabdomyolysis Panel

  • bpg-method PLUS
  • bpg-method SEQ
  • bpg-method DEL/DUP

Test code: ME1401

The Blueprint Genetics Metabolic Myopathy and Rhabdomyolysis Panel is a 40 gene test for genetic diagnostics of patients with clinical suspicion of glycogen storage disease, lipid storage disorder, metabolic myopathies or rhabdomyolysis.

Medical conditions associated with rhabdomyolysis are inherited via autosomal recessive, autosomal dominant and X-linked manner. Associated disorders are very different in types and causes. Disorders of glycogen metabolism and fatty acid metabolism are typically inherited in autosomal recessive manner. This Panel in included in the Comprehensive Metabolism Panel.

About Metabolic Myopathy and Rhabdomyolysis

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, earthquakes and bombings. 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 defetcs that prevent adequate energy and ATP levels for muscle cells. This Panel includes comprehensively genes associated with all these medical conditions that can cause rhabdomyolysis of genegic origin. The prevalence of rhabdomyolysis is not known.

Availability

Results in 3-4 weeks. We do not offer a maternal cell contamination (MCC) test at the moment. We offer prenatal testing only for cases where the maternal cell contamination studies (MCC) are done by a local genetic laboratory. Read more: http://blueprintgenetics.com/faqs/#prenatal

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 23 42
ACADL Long chain acyl-CoA dehydrogenase deficiency AD/AR
ACADM Acyl-CoA dehydrogenase, medium chain, deficiency AR 84 166
ACADVL Acyl-CoA dehydrogenase, very long chain, deficiency AR 94 260
AGL Glycogen storage disease AR 82 242
ALDOA Glycogen storage disease AR 2 8
C10ORF2 Perrault syndrome, Mitochondrial DNA depletion syndrome AR 37
CAV3 Creatine phosphokinase, elevated serum, Hypertrophic cardiomyopathy (HCM), Long QT syndrome AD/Digenic 24 48
CPT1B Carnitine palmitoyltransferase deficiency AD
CPT2 Carnitine palmitoyltransferase II deficiency AR 47 104
ENO3 Glycogen storage disease AR 3 4
ETFA Glutaric aciduria, Multiple acyl-CoA dehydrogenase deficiency AR 8 27
ETFB Glutaric aciduria, Multiple acyl-CoA dehydrogenase deficiency AR 6 14
ETFDH Glutaric aciduria, Multiple acyl-CoA dehydrogenase deficiency AR 37 169
GAA Glycogen storage disease AR 136 528
GBE1 Glycogen storage disease AR 30 71
GYG1 Glycogen storage disease AR 8 11
GYS1 Glycogen storage disease AR 5 5
HADHA Trifunctional protein deficiency, Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency AR 42 68
HADHB Trifunctional protein deficiency AR 17 57
ISCU Myopathy with lactic acidosis AR 3 2
LDHA Glycogen storage disease AR 1 8
LPIN1 Myoglobinuria, acute, recurrent AR 6 29
OPA1 Optic atrophy AD/AR 80 372
OPA3 Optic atrophy, 3-methylglutaconic aciduria AD/AR 8 15
PFKM Glycogen storage disease AR 11 26
PGAM2 Glycogen storage disease AR 3 9
PGK1 Phosphoglycerate kinase 1 deficiency XL 15 26
PGM1 Congenital disorder of glycosylation AR 9 30
PHKA1 Glycogen storage disease XL 6 8
PHKG1* Glycogen storage disease due to muscle phosphorylase kinase deficiency AD/AR
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 92 274
PYGM Glycogen storage disease AR 62 153
RBCK1 Polyglucosan body myopathy AR 8 14
RRM2B Progressive external ophthalmoplegia with mitochondrial DNA deletions, Mitochondrial DNA depletion syndrome AD/AR 41 40
RYR1 Central core disease, Malignant hyperthermia, Minicore myopathy with external ophthalmoplegia, Centronuclear myopathy, Minicore myopathy, Multicore myopathy AD/AR 162 607
SLC22A5 Carnitine deficiency, systemic primary AR 76 117
SUCLA2 Mitochondrial DNA depletion syndrome AR 8 27
TK2 Mitochondrial DNA depletion syndrome AR 38 45
TYMP Mitochondrial DNA depletion syndrome AR 85 94

*Some regions of the gene are duplicated in the genome leading to limited sensitivity within the regions. Thus, low-quality variants are filtered out from the duplicated regions and only high-quality variants confirmed by other methods are reported out. Read more.

Gene, refers to HGNC approved gene symbol; Inheritance to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL); ClinVar, refers to a number of variants in the gene classified as pathogenic or likely pathogenic in ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/); HGMD, refers to a number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD, http://www.hgmd.cf.ac.uk/ac/). The list of associated (gene specific) phenotypes are generated from CDG (http://research.nhgri.nih.gov/CGD/) or Orphanet (http://www.orpha.net/) databases.

Gene Genomic location HG19 HGVS RefSeq RS-number
ACADM Chr1:76211473 c.600-18G>A NM_000016.4 rs370523609
GAA Chr17:78078341 c.-32-13T>G NM_000152.3 rs386834236
GAA Chr17:78078351 c.-32-3C>A NM_000152.3
GAA Chr17:78082266 c.1076-22T>G NM_000152.3 rs762260678
GBE1 Chr3:81542963 c.2053-3358_2053-3350delGTGTGGTGGinsTGTTTTTTACATGACAGGT NM_000158.3
ISCU Chr12:108961426 c.418+382G>C NM_213595.2 rs767000507
PYGM Chr11:64525847 c.425-26A>G NM_005609.2 rs764313717
RYR1 Chr19:39074134 c.14647-1449A>G NM_000540.2 rs193922886

The strengths of this test include:

  • Blueprint Genetics is one of the few laboratories worldwide with CAP and ISO-15189 accreditation for NGS panels and CLIA certification
  • Superior sequencing quality
  • Careful selection of genes based on current literature, our experience and the most current mutation databases
  • Transparent and easy access to quality and performance data at the patient level that are accessible via our Nucleus portal
  • Transparent and reproducible analytical validation for each panel (see Test performance section; for complete details, see our Analytic Validation)
  • Sequencing and high resolution del/dup analysis available in one test
  • Inclusion of non-coding disease causing variants where clinically indicated (please see individual Panel descriptions)
  • Interpretation of variants following ACMG variant classification guidelines
  • Comprehensive clinical statement co-written by a PhD geneticist and a clinician specialist

 

This test does not detect the following:

  • Complex inversions
  • Gene conversions
  • Balanced translocations
  • Mitochondrial DNA variants
  • Variants in regulatory or non-coding regions of the gene unless otherwise indicated (please see Non-coding disease causing variants covered by the panel). This mean for instance intronic variants locating deeper than 15 nucleotides from the exon-intron boundary.

 

This test may not reliably detect the following:

  • Low level mosaicism
  • Stretches of mononucleotide repeats
  • Indels larger than 50bp
  • Single exon deletions or duplications
  • Variants within pseudogene regions/duplicated segments
  • Disorders caused by long repetitive sequences (e.g. trinucleotide repeat expansions)

 

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.

Blueprint Genetics offers a comprehensive Metabolic Myopathy and Rhabdomyolysis Panel that covers classical genes associated with glycogen storage disease, lipid storage disorder, metabolic myopathies and rhabdomyolysis. The genes are carefully selected based on the existing scientific evidence, our experience and most current mutation databases. Candidate genes are excluded from this first-line diagnostic test. The test does not recognise balanced translocations or complex inversions, and it may not detect low-level mosaicism. The test should not be used for analysis of sequence repeats or for diagnosis of disorders caused by mutations in the mitochondrial DNA.

Analytical validation is a continuous process at Blueprint Genetics. Our mission is to improve the quality of the sequencing process and each modification is followed by our standardized validation process. Average sensitivity and specificity in Blueprint NGS Panels is 99.3% and 99.9% for detecting SNPs. Sensitivity to for indels vary depending on the size of the alteration: 1-10bps (96.0%), 11-20 bps (88.4%) and 21-30 bps (66.7%). The longest detected indel was 46 bps by sequence analysis. Detection limit for Del/Dup (CNV) analysis varies through the genome depending on exon size, sequencing coverage and sequence content. The sensitivity is 71.5% for single exon deletions and duplications and 99% for three exons’ deletions and duplications. We have validated the assays for different starting materials including EDTA-blood, isolated DNA (no FFPE) and saliva that all provide high-quality results. The diagnostic yield varies substantially depending on the used assay, referring healthcare professional, hospital and country. Blueprint Genetics’ Plus Analysis (Seq+Del/Dup) maximizes the chance to find molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be cost-effective first line test if your patient’s phenotype is suggestive for a specific mutation profile.

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. The highest relevance in the reported variants is achieved through elimination of false positive findings based on variability data for thousands of publicly available human reference sequences and validation against our in-house curated mutation database as well as the most current and relevant human mutation databases. Reference databases currently used are the 1000 Genomes Project (http://www.1000genomes.org), the NHLBI GO Exome Sequencing Project (ESP; http://evs.gs.washington.edu/EVS), the Exome Aggregation Consortium (ExAC; http://exac.broadinstitute.org), ClinVar database of genotype-phenotype associations (http://www.ncbi.nlm.nih.gov/clinvar) and the Human Gene Mutation Database (http://www.hgmd.cf.ac.uk). The consequence of variants in coding and splice regions are estimated using the following in silico variant prediction tools: SIFT (http://sift.jcvi.org), Polyphen (http://genetics.bwh.harvard.edu/pph2/), and Mutation Taster (http://www.mutationtaster.org).

Through our online ordering and statement reporting system, Nucleus, the customer can access specific details of the analysis of the patient. This includes coverage and quality specifications and other relevant information on the analysis. This represents our mission to build fully transparent diagnostics where the customer gains easy access to crucial details of the analysis process.

In addition to our cutting-edge patented sequencing technology and proprietary bioinformatics pipeline, we also provide the customers with the best-informed clinical report on the market. Clinical interpretation requires fundamental clinical and genetic understanding. At Blueprint Genetics our geneticists and clinicians, who together evaluate the results from the sequence analysis pipeline in the context of phenotype information provided in the requisition form, prepare the clinical statement. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals, even without training in genetics.

Variants reported in the statement are always classified using the Blueprint Genetics Variant Classification Scheme modified from the ACMG guidelines (Richards et al. 2015), which has been developed by evaluating existing literature, databases and with thousands of clinical cases analyzed in our laboratory. Variant classification forms the corner stone of clinical interpretation and following patient management decisions. Our statement also includes allele frequencies in reference populations and in silico predictions. We also provide PubMed IDs to the articles or submission numbers to public databases that have been used in the interpretation of the detected variants. In our conclusion, we summarize all the existing information and provide our rationale for the classification of the variant.

A final component of the analysis is the Sanger confirmation of the variants classified as likely pathogenic or pathogenic. This does not only bring confidence to the results obtained by our NGS solution but establishes the mutation specific test for family members. Sanger sequencing is also used occasionally with other variants reported in the statement. In the case of variant of uncertain significance (VUS) we do not recommend risk stratification based on the genetic finding. Furthermore, in the case VUS we do not recommend use of genetic information in patient management or genetic counseling. For some cases Blueprint Genetics offers a special free of charge service to investigate the role of identified VUS.

We constantly follow genetic literature adapting new relevant information and findings to our diagnostics. Relevant novel discoveries can be rapidly translated and adopted into our diagnostics without delay. These processes ensure that our diagnostic panels and clinical statements remain the most up-to-date on the market.

Find more info in Support

Choose an analysis method

$ $ 1700
$ $ 1000
$ $ 1900
Total $
Order now

ICD & CPT codes

CPT codes

SEQ 81479
DEL/DUP 81479


ICD codes

Commonly used ICD-10 codes 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

Accepted sample types

  • EDTA blood, min. 1 ml
  • Purified DNA, min. 5μg
  • Saliva (Oragene DNA OG-500 kit)

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.

Subscribe to our newsletter