Metabolic Myopathy and Rhabdomyolysis Panel
In addition, it also includes the maternally inherited mitochondrial genome.
Is ideal for patients with a medical condition associated with rhabdomyolysis. The genes on this panel are included in the Comprehensive Metabolism Panel.
The Blueprint Genetics Metabolic Myopathy and Rhabdomyolysis Panel (test code ME1401):
Read about our accreditations, certifications and CE-marked IVD medical devices here.
Refer to the most current version of ICD-10-CM manual for a complete list of ICD-10 codes.
- Blood (min. 1ml) in an EDTA tube
- Extracted DNA, min. 2 μg in TE buffer or equivalent
- Saliva (Please see Sample Requirements for accepted saliva kits)
Label the sample tube with your patient’s name, date of birth and the date of sample collection.
We do not accept DNA samples isolated from formalin-fixed paraffin-embedded (FFPE) tissue. In addition, if the patient is affected with a hematological malignancy, DNA extracted from a non-hematological source (e.g. skin fibroblasts) is strongly recommended.
Please note that, in rare cases, mitochondrial genome (mtDNA) variants may not be detectable in blood or saliva in which case DNA extracted from post-mitotic tissue such as skeletal muscle may be a better option.
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
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|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|
|B4GAT1||Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 13||AR||3||5|
|C10ORF2||Perrault syndrome, Mitochondrial DNA depletion syndrome, Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant, 3||AD/AR||37||80|
|CAPN3||Muscular dystrophy, limb-girdle, Eosinophilic myositis||AD/AR||184||437|
|CASQ1||Myopathy, vacuolar, with CASQ1 aggregates||AD||2||5|
|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|
|CHKB||Muscular dystrophy, congenital, megaconial||AR||11||27|
|COQ2||Coenzyme Q10 deficiency||AR||16||31|
|CPT2||Carnitine palmitoyltransferase II deficiency||AR||72||111|
|CTDP1||Congenital cataracts, facial dysmorphism, and neuropathy||AR||1||1|
|DGUOK||Mitochondrial DNA depletion syndrome, Portal hypertension, noncirrhotic, Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4||AR||23||62|
|DMD||Becker muscular dystrophy, Duchenne muscular dystrophy, Dilated cardiomyopathy (DCM)||XL||832||3915|
|DNAJB6||Muscular dystrophy, limb-girdle||AD||11||17|
|DPM1||Congenital disorder of glycosylation||AR||9||8|
|DPM2||Congenital disorder of glycosylation||AR||2||2|
|DYSF||Miyoshi muscular dystrophy, Muscular dystrophy, limb-girdle, Myopathy, distal, with anterior tibial onset||AR||244||529|
|EMD||Emery-Dreifuss muscular dystrophy||XL||48||113|
|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|
|FHL1*||Myopathy with postural muscle atrophy, Emery-Dreifuss muscular dystrophy, Reducing bod myopathy||XL||26||62|
|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|
|GMPPB||Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), Limb-girdle muscular dystrophy-dystroglycanopathy||AR||19||41|
|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|
|LAMA2||Muscular dystrophy, congenital merosin-deficient||AR||199||301|
|LDHA||Glycogen storage disease||AR||1||9|
|LPIN1||Myoglobinuria, acute, recurrent||AR||6||29|
|MT-ATP6||Neuropathy, ataxia, and retinitis pigmentosa, Leber hereditary optic neuropathy, Ataxia and polyneuropathy, adult-onset, Cardiomyopathy, infantile hypertrophic, Leigh syndrome, Striatonigral degeneration, infantile, mitochondrial||Mitochondrial||19|
|MT-ATP8||Cardiomyopathy, apical hypertrophic, and neuropathy, Cardiomyopathy, infantile hypertrophic||Mitochondrial||4|
|MT-CO1||Myoglobinuria, recurrent, Leber hereditary optic neuropathy, Sideroblastic anemia, Cytochrome C oxidase deficiency, Deafness, mitochondrial||Mitochondrial||17|
|MT-CO2||Cytochrome c oxidase deficiency||Mitochondrial||8|
|MT-CO3||Cytochrome c oxidase deficiency, Leber hereditary optic neuropathy||Mitochondrial||9|
|MT-ND1||Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, Leber hereditary optic neuropathy, Leber optic atrophy and dystonia||Mitochondrial||21|
|MT-ND2||Leber hereditary optic neuropathy, Mitochondrial complex I deficiency||Mitochondrial||6|
|MT-ND3||Leber optic atrophy and dystonia, Mitochondrial complex I deficiency||Mitochondrial||7|
|MT-ND4||Leber hereditary optic neuropathy, Leber optic atrophy and dystonia, Mitochondrial complex I deficiency||Mitochondrial||11|
|MT-ND4L||Leber hereditary optic neuropathy||Mitochondrial||2|
|MT-ND5||Myoclonic epilepsy with ragged red fibers, Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, Leber hereditary optic neuropathy, Mitochondrial complex I deficiency||Mitochondrial||19|
|MT-ND6||Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, Oncocytoma, Leber hereditary optic neuropathy, Leber optic atrophy and dystonia, Mitochondrial complex I deficiency||Mitochondrial||16|
|MT-TC||Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes||Mitochondrial||3|
|MT-TE||Diabetes-deafness syndrome, Mitochondrial myopathy, infantile, transient, Mitochondrial myopathy with diabetes||Mitochondrial||5|
|MT-TF||Myoclonic epilepsy with ragged red fibers, Nephropathy, tubulointerstitial, Encephalopathy, mitochondrial, Epilepsy, mitochondrial, Myopathy, mitochondrial, Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes||Mitochondrial||7|
|MT-TK||Myoclonic epilepsy with ragged red fibers, Leigh syndrome||Mitochondrial||5|
|MT-TL1||Cytochrome c oxidase deficiency, Myoclonic epilepsy with ragged red fibers, Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, Diabetes-deafness syndrome, Cyclic vomiting syndrome, SIDS, susceptibility to||Mitochondrial||14|
|MT-TL2||Mitochondrial multisystemic disorder, Progressive external ophthalmoplegia, Mitochondrial Myopathy, Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes||Mitochondrial||5|
|MT-TM||Leigh syndrome, Mitochondrial multisystemic disorder||Mitochondrial||1|
|MT-TN||Progressive external ophthalmoplegia, Mitochondrial multisystemic disorder||Mitochondrial||3|
|MT-TQ||Mitochondrial multisystemic disorder||Mitochondrial||2|
|MT-TS1||Myoclonic epilepsy with ragged red fibers, Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes||Mitochondrial||10|
|MT-TS2||Mitochondrial multisystemic disorder||Mitochondrial||2|
|MT-TV||Hypertrophic cardiomyopathy (HCM), Leigh syndrome, Mitochondrial multisystemic disorder, Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes||Mitochondrial||3|
|MT-TW||Leigh syndrome, Myopathy, mitochondrial||Mitochondrial||8|
|MT-TY||Mitochondrial multisystemic disorder||Mitochondrial||4|
|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|
|PDSS2||Coenzyme Q10 deficiency||AR||8||4|
|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|
|PHKB||Glycogen storage disease||AR||9||26|
|PNPLA2||Neutral lipid storage disease with myopathy||AR||13||35|
|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|
|POMGNT2||Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 8||AR||6||9|
|POMK||Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies, type A, 12, Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies, type C, 12, Muscle-eye brain disease, Walker-Warburg syndrome||AR||6||8|
|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|
|SGCA||Muscular dystrophy, limb-girdle||AR||60||100|
|SGCB||Muscular dystrophy, limb-girdle||AR||37||64|
|SGCD||Muscular dystrophy, limb-girdle, Dilated cardiomyopathy (DCM)||AR||21||27|
|SGCG||Muscular dystrophy, limb-girdle||AR||33||63|
|SLC22A5||Carnitine deficiency, systemic primary||AR||98||151|
|SLC25A20||Carnitine-acylcarnitine translocase deficiency||AR||15||42|
|STAC3||Native American myopathy||3||4|
|SUCLA2||Mitochondrial DNA depletion syndrome||AR||9||29|
|SUCLG1||Mitochondrial DNA depletion syndrome||AR||12||28|
|TANGO2||Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration (MECRCN)||AR||13||9|
|TCAP||Muscular dystrophy, limb-girdle, Hypertrophic cardiomyopathy (HCM), Dilated cardiomyopathy (DCM)||AD/AR||12||28|
|TK2#||Mitochondrial DNA depletion syndrome||AR||38||52|
|TNPO3||Muscular dystrophy, limb-girdle||AD||3||5|
|TRIM32||Bardet-Biedl syndrome, Muscular dystrophy, limb-girdle||AR||13||16|
|TYMP||Mitochondrial DNA depletion syndrome||AR||84||94|
The gene has suboptimal coverage (means <90% of the gene’s target nucleotides are covered at >20x with mapping quality score (MQ>20) reads), and/or the gene has exons listed under Test limitations section that are not included in the panel as they are not sufficiently covered with high quality sequence reads.
Some, or all, of the gene is duplicated in the genome. Read more.
The sensitivity to detect variants may be limited in genes marked with an asterisk (*) or number sign (#). Due to possible limitations these genes may not be available as single gene tests.
Gene refers to the HGNC approved gene symbol; Inheritance refers to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR), mitochondrial (mi), 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 Mitomap databases.
Non-coding variants covered by Metabolic Myopathy and Rhabdomyolysis Panel
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|Gene||Genomic location HG19||HGVS||RefSeq||RS-number|
The strengths of this test include:
- CAP accredited laboratory
- 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
- Some of the panels include the whole mitochondrial genome (please see the Panel Content section)
- Our Nucleus online portal providing transparent and easy access to quality and performance data at the patient level
- ~2,000 non-coding disease causing variants in our clinical grade NGS assay for panels (please see ‘Non-coding disease causing variants covered by this panel’ in the Panel Content section)
- Our rigorous variant classification scheme
- Our systematic clinical interpretation workflow using proprietary software enabling accurate and traceable processing of NGS data
- Our comprehensive clinical statements
The following exons are not included in the panel as they are not sufficiently covered with high quality sequence reads: *B3GALNT2* (NM_001277155:2), *TK2* (NM_001271934:3). Genes with suboptimal coverage in our assay are marked with number sign (#) and genes with partial, or whole gene, segmental duplications in the human genome are marked with an asterisk (*) if they overlap with the UCSC pseudogene regions. Gene is considered to have suboptimal coverage when >90% of the gene’s target nucleotides are not covered at >20x with mapping quality score (MQ>20) reads. The technology may have limited sensitivity to detect variants in genes marked with these symbols (please see the Panel content table above).
This test does not detect the following:
- Complex inversions
- Gene conversions
- Balanced translocations
- Some of the panels include the whole mitochondrial genome but not all (please see the Panel Content section)
- 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 in nuclear genes (variant with a minor allele fraction of 14.6% is detected with 90% probability)
- Stretches of mononucleotide repeats
- Low level heteroplasmy in mtDNA (>90% are detected at 5% level)
- Indels larger than 50bp
- Single exon deletions or duplications
- Variants within pseudogene regions/duplicated segments
- Some disease causing variants present in mtDNA are not detectable from blood, thus post-mitotic tissue such as skeletal muscle may be required for establishing molecular diagnosis.
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.
The genes on the panel have been carefully selected based on scientific literature, mutation databases and our experience.
Our panels are sectioned from our high-quality, clinical grade NGS assay. Please see our sequencing and detection performance table for details regarding our ability to detect different types of alterations (Table).
Assays have been validated for various sample types including EDTA-blood, isolated DNA (excluding from formalin fixed paraffin embedded tissue), saliva and dry blood spots (filter cards). These sample types were selected in order to maximize the likelihood for high-quality DNA yield. The diagnostic yield varies depending on the assay used, referring healthcare professional, hospital and country. Plus analysis increases the likelihood of finding a genetic diagnosis for your patient, as large deletions and duplications cannot be detected using sequence analysis alone. Blueprint Genetics’ Plus Analysis is a combination of both sequencing and deletion/duplication (copy number variant (CNV)) analysis.
The performance metrics listed below are from an initial validation performed at our main laboratory in Finland. The performance metrics of our laboratory in Marlborough, MA, are equivalent.
Performance of Blueprint Genetics high-quality, clinical grade NGS sequencing assay for panels.
|Sensitivity % (TP/(TP+FN)||Specificity %|
|Single nucleotide variants||99.89% (99,153/99,266)||>99.9999%|
|Insertions, deletions and indels by sequence analysis|
|1-10 bps||99.2% (7,745/7,806)||>99.9999%|
|11-50 bps||99.13% (2,524/2,546)||>99.9999%|
|Copy number variants (exon level dels/dups)|
|1 exon level deletion (heterozygous)||100% (20/20)||NA|
|1 exon level deletion (homozygous)||100% (5/5)||NA|
|1 exon level deletion (het or homo)||100% (25/25)||NA|
|2-7 exon level deletion (het or homo)||100% (44/44)||NA|
|1-9 exon level duplication (het or homo)||75% (6/8)||NA|
|Simulated CNV detection|
|5 exons level deletion/duplication||98.7%||100.00%|
|Microdeletion/-duplication sdrs (large CNVs, n=37))|
|Size range (0.1-47 Mb)||100% (25/25)|
|The performance presented above reached by Blueprint Genetics high-quality, clinical grade NGS sequencing assay with the following coverage metrics|
|Mean sequencing depth||143X|
|Nucleotides with >20x sequencing coverage (%)||99.86%|
Performance of Blueprint Genetics Mitochondrial Sequencing Assay.
|Sensitivity %||Specificity %|
|ANALYTIC VALIDATION (NA samples; n=4)|
|Single nucleotide variants|
|Heteroplasmic (45-100%)||100.0% (50/50)||100.0%|
|Heteroplasmic (35-45%)||100.0% (87/87)||100.0%|
|Heteroplasmic (25-35%)||100.0% (73/73)||100.0%|
|Heteroplasmic (15-25%)||100.0% (77/77)||100.0%|
|Heteroplasmic (10-15%)||100.0% (74/74)||100.0%|
|Heteroplasmic (5-10%)||100.0% (3/3)||100.0%|
|Heteroplasmic (<5%)||50.0% (2/4)||100.0%|
|CLINICAL VALIDATION (n=76 samples)|
|Single nucleotide variants n=2026 SNVs|
|Heteroplasmic (45-100%)||100.0% (1940/1940)||100.0%|
|Heteroplasmic (35-45%)||100.0% (4/4)||100.0%|
|Heteroplasmic (25-35%)||100.0% (3/3)||100.0%|
|Heteroplasmic (15-25%)||100.0% (3/3)||100.0%|
|Heteroplasmic (10-15%)||100.0% (9/9)||100.0%|
|Heteroplasmic (5-10%)||92.3% (12/13)||99.98%|
|Heteroplasmic (<5%)||88.9% (48/54)||99.93%|
|Insertions and deletions by sequence analysis n=40 indels|
|Heteroplasmic (45-100%) 1-10bp||100.0% (32/32)||100.0%|
|Heteroplasmic (5-45%) 1-10bp||100.0% (3/3)||100.0%|
|Heteroplasmic (<5%) 1-10bp||100.0% (5/5)||99,997%|
|SIMULATION DATA /(mitomap mutations)|
|Insertions, and deletions 1-24 bps by sequence analysis; n=17|
|Homoplasmic (100%) 1-24bp||100.0% (17/17)||99.98%|
|Heteroplasmic (50%)||100.0% (17/17)||99.99%|
|Heteroplasmic (25%)||100.0% (17/17)||100.0%|
|Heteroplasmic (20%)||100.0% (17/17)||100.0%|
|Heteroplasmic (15%)||100.0% (17/17)||100.0%|
|Heteroplasmic (10%)||94.1% (16/17)||100.0%|
|Heteroplasmic (5%)||94.1% (16/17)||100.0%|
|Copy number variants (separate artifical mutations; n=1500)|
|Homoplasmic (100%) 500 bp, 1kb, 5 kb||100.0%||100.0%|
|Heteroplasmic (50%) 500 bp, 1kb, 5 kb||100.0%||100.0%|
|Heteroplasmic (30%) 500 bp, 1kb, 5 kb||100.0%||100.0%|
|Heteroplasmic (20%) 500 bp, 1kb, 5 kb||99.7%||100.0%|
|Heteroplasmic (10%) 500 bp, 1kb, 5 kb||99.0%||100.0%|
|The performance presented above reached by following coverage metrics at assay level (n=66)|
|Mean of medians||Median of medians|
|Mean sequencing depth MQ0 (clinical)||18224X||17366X|
|Nucleotides with >1000x MQ0 sequencing coverage (%) (clinical)||100%|
|rho zero cell line (=no mtDNA), mean sequencing depth||12X|
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 and regulatory 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. If the test includes the mitochondrial genome the target region gene list contains the mitochondrial genes. 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 including, 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, ordering providers have access to the details of the analysis, including patient specific sequencing metrics, a gene level coverage plot and a list of regions with suboptimal coverage (<20X for nuclear genes and <1000X for mtDNA) if applicable. This reflects our mission to build fully transparent diagnostics where ordering providers can easily visualize the crucial details of the analysis process.
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 cornerstone of clinical interpretation and resulting patient management decisions. Our classifications follow the ACMG guideline 2015.
The final step in the analysis is orthogonal confirmation. Sequence and copy number variants classified as pathogenic, likely pathogenic, and variants of uncertain significance (VUS) are confirmed using bi-directional Sanger sequencing or by orthogonal methods such as qPCR/ddPCR when they do not meet our stringent NGS quality metrics for a true positive call.
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, abstracts, and variant databases used to help ordering providers 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. We do not recommend using variants of uncertain significance (VUS) for family member risk stratification or patient management. Genetic counseling is recommended.
Our interpretation team analyzes millions of variants from thousands of individuals with rare diseases. Our internal database and our understanding of variants and related phenotypes increases with every case analyzed. 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 healthcare provider at no additional cost, according to our latest follow-up reporting policy.