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Test Code MITOP Mitochondrial Full Genome Analysis, Next-Generation Sequencing (NGS), Varies

Useful For

Diagnosis of the subset of mitochondrial diseases that results from variants in the mitochondrial genome

 

A second-tier test for patients in whom previous targeted gene variant analyses for specific mitochondrial disease-related genes were negative

 

Identifying variants within genes of the mitochondrial genome that are known to be associated with mitochondrial disease, allowing for predictive testing of at-risk family members

Reflex Tests

Test ID Reporting Name Available Separately Always Performed
CULFB Fibroblast Culture for Genetic Test Yes No

Testing Algorithm

For skin biopsy or cultured fibroblast specimens, fibroblast culture testing will be performed at an additional charge. If viable cells are not obtained, the client will be notified.

 

The following algorithms are available:

-Epilepsy: Unexplained Refractory and/or Familial Testing Algorithm

-Neuromuscular Myopathy Testing Algorithm

Method Name

Long-Range Polymerase Chain Reaction (LR-PCR) followed by Next-Generation Sequencing (NGS)

Reporting Name

Mitochondrial Full Genome Analysis

Specimen Type

Varies


Ordering Guidance


If testing for variants in the mitochondrial genes encoded by the nuclear genome is requested, order MITON / Mitochondrial Nuclear Gene Panel, Next-Generation Sequencing (NGS), Varies



Shipping Instructions


Ambient blood is preferred to arrive within 96 hours of collection.



Necessary Information


Molecular Genetics: Biochemical Disorders Patient Information (T527) is available to provide information useful for accurate test interpretation. At minimum, provide a reason for testing with each specimen. Although testing may proceed without this information, ordering providers are strongly encouraged to complete the form and send it with the specimen.



Specimen Required


Patient Preparation: A previous bone marrow transplant from an allogenic donor will interfere with testing. Call 800-533-1710 for instructions for testing patients who have received a bone marrow transplant.

 

Submit only 1 of the following specimens:

 

Specimen Type: Whole blood

Container/Tube:

Preferred: Lavender top (EDTA) or yellow top (ACD)

Acceptable: Any anticoagulant

Specimen Volume: 3 mL

Collection Instructions:

1. Invert several times to mix blood.

2. Send whole blood specimen in original tube. Do not aliquot.

Specimen Stability Information: Ambient (preferred)/Refrigerated

 

Specimen Type: Cultured fibroblasts

Container/Tube: T-75 or T-25 flask

Specimen Volume: 1 Full T-75 or 2 full T-25 flasks

Specimen Stability Information: Ambient (preferred)/Refrigerated <24 hours

Additional Information: A separate culture charge will be assessed under CULFB / Fibroblast Culture for Biochemical or Molecular Testing. An additional 3 to 4 weeks is required to culture fibroblasts before genetic testing can occur.

 

Specimen Type: Skin biopsy

Supplies: Fibroblast Biopsy Transport Media (T115)

Container/Tube: Sterile container with any standard cell culture media (eg, minimal essential media, RPMI 1640). The solution should be supplemented with 1% penicillin and streptomycin.

Specimen Volume: 4-mm punch

Specimen Stability Information: Refrigerated (preferred)/Ambient

Additional Information: A separate culture charge will be assessed under CULFB / Fibroblast Culture for Biochemical or Molecular Testing. An additional 3 to 4 weeks is required to culture fibroblasts before genetic testing can occur.

 

Specimen Type: Muscle tissue biopsy

Supplies: Muscle Biopsy Kit (T541)

Collection Instructions: Prepare and transport specimen per instructions in Muscle Biopsy Specimen Preparation Instructions.

Specimen Volume: 10-80 mg

Specimen Stability Information: Frozen (preferred)/Ambient/Refrigerated

 

Specimen Type: Snap frozen nerve tissue biopsy

Collection Instructions: Prepare snap frozen tissue biopsy per surgical procedure

Specimen Volume: 0.25-0.5 cm

Specimen Stability Information: Frozen

 

Specimen Type: Blood spot

Supplies: Card-Blood Spot Collection (Filter Paper) (T493)

Preferred: Collection card (Whatman Protein Saver 903 Paper)

Acceptable: PerkinElmer 226 (formerly Ahlstrom 226) filter paper or blood spot collection card

 

Specimen Volume: 2 to 5 Blood spots

Collection Instructions:

1. An alternative blood collection option for a patient older than 1 year is a fingerstick. For detailed instructions, see How to Collect Dried Blood Spot Samples.

2. Let blood dry on the filter paper at ambient temperature in a horizontal position for a minimum of 3 hours.

3. Do not expose specimen to heat or direct sunlight.

4. Do not stack wet specimens.

5. Keep specimen dry

Specimen Stability Information: Ambient (preferred)/Refrigerated

Additional Information:

1. Due to lower concentration of DNA yielded from blood spot, it is possible that additional specimen may be required to complete testing.

2. For collection instructions, see Blood Spot Collection Instructions

3. For collection instructions in Spanish, see Blood Spot Collection Card-Spanish Instructions (T777)

4. For collection instructions in Chinese, see Blood Spot Collection Card-Chinese Instructions (T800)


Specimen Minimum Volume

Blood: 1 mL
Muscle tissue biopsy: 20 mg
Nerve tissue biopsy: See Specimen Required.
Blood Spots: 5 punches-3 mm diameter

Specimen Stability Information

Specimen Type Temperature Time Special Container
Varies Varies

Reject Due To

All specimens will be evaluated by at Mayo Clinic Laboratories for test suitability.

Clinical Information

The mitochondrion occupies a unique position in eukaryotic biology. First, it is the site of energy metabolism, without which aerobic metabolism and life as we know it would not be possible. Second, it is the sole subcellular organelle that is composed of proteins derived from 2 genomes, mitochondrial and nuclear. A group of hereditary disorders due to variants in either the mitochondrial genome or nuclear mitochondrial genes have been well characterized.

 

The diagnosis of mitochondrial disease can be particularly challenging as the presentation can occur at any age, involving virtually any organ system, and with widely varying severities. This test utilizes massively parallel sequencing, also termed next-generation sequencing (NGS), to determine the exact sequence of the entire 16,569 base-pair mitochondrial genome. The utility of this test is to assist in the diagnosis of the subset of mitochondrial diseases that result from variants in the mitochondrial genome .This includes certain types of myopathies and neuro-ophthalmologic diseases, such as MELAS (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes), MERRF (myoclonic epilepsy with ragged red fibers), mitochondrial myopathy, neurogenic muscle weakness, ataxia, retinitis pigmentosa, Leigh syndrome, Leber hereditary optic neuropathy, and chronic progressive external ophthalmoplegia . In addition to the detection of single base changes with these disorders, large deletions, such as those associated with Kearns-Sayre or Pearson syndromes, are also detected. Variants in mitochondrial proteins that are encoded by genes in the nucleus, such as the enzymes of fatty acid oxidation, are not detected using this test.

 

In contrast to variants in nuclear genes, which are present in either 0, 1, or 2 copies, mitochondrial variants can be present in any fraction of the total organelles, a phenomenon known as heteroplasmy. Typically, the severity of disease presentation is a function of the degree of heteroplasmy. Individuals with a higher fraction of altered mitochondria present with more severe disease than those with lower percentages of altered alleles. The sensitivity for the detection of altered alleles in a background of wild-type (or normal) mitochondrial sequences by NGS is approximately 10%.

Reference Values

An interpretive report will be provided.

Interpretation

All detected alterations are evaluated according to American College of Medical Genetics and Genomics recommendations.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance. The degree of heteroplasmy of each single nucleotide or delin (deletion/insertion) variant, defined as the ratio (percentage) of variant sequence reads to the total number of reads, will also be reported. Large deletions will be reported as either homoplasmic or heteroplasmic, but the degree of heteroplasmy will not be estimated, due to possible preferential amplification of the smaller deletion product by long-range polymerase chain reaction.

Cautions

Clinical Correlations:

A small percentage of individuals who have mitochondrial genome involvement may have a variant that is not identified by the methods performed. The absence of a variant, therefore, does not eliminate the possibility of a mitochondrial disease due to variant in the mitochondrial genome. Variants in mitochondrial genes encoded by the nuclear genome will not be detected with this assay. For predictive testing of asymptomatic individuals, it is important to first document the presence of a gene variant in an affected family member.

 

Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Misinterpretation of results may occur if the information provided is inaccurate or incomplete.

 

Technical Limitations:

In some cases, DNA variants of undetermined significance may be identified.

 

Rare variants (ie, polymorphisms) exist that could lead to false-negative or false-positive results. If results obtained do not match the clinical findings, additional testing should be considered.

 

Evaluation Tools:

Multiple in-silico evaluation tools were used to assist in the interpretation of these results. These tools are updated regularly; therefore, changes to these algorithms may result in different predictions for a given alteration. Additionally, the predictability of these tools for the determination of pathogenicity is currently unvalidated.

 

Unless reported or predicted to cause disease, alterations in protein coding genes that do not result in an amino acid substitution are not reported. The mitochondrial haplogroup classification of the patient will be reported, but the individual nucleotide changes that define the haplogroup will not be reported. These and common alterations identified for this patient are available upon request.

 

Reclassification of Variants-Policy:

At this time, it is not standard practice for the laboratory to systematically review likely deleterious alterations or variants of uncertain significance that are detected and reported. The laboratory encourages healthcare providers to contact the laboratory at any time to learn how the status of a particular variant may have changed over time.

Day(s) Performed

Monday

Report Available

28 to 42 days

Performing Laboratory

Mayo Clinic Laboratories in Rochester

Test Classification

This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. It has not been cleared or approved by the US Food and Drug Administration.

CPT Code Information

81460-Whole Mitochondrial Genome

81465-Whole Mitochondrial Genome Large Deletion Analysis

88233-Tissue culture, skin, solid tissue biopsy (if appropriate)

88240-Cryopreservation (if appropriate)

LOINC Code Information

Test ID Test Order Name Order LOINC Value
MITOP Mitochondrial Full Genome Analysis In Process

 

Result ID Test Result Name Result LOINC Value
55281 Result Summary 50397-9
55282 Result 82939-0
55283 Interpretation 69047-9
55284 Additional Information 48767-8
55285 Specimen 31208-2
55286 Source 31208-2
55287 Released By 18771-6

Forms

1. New York Clients-Informed consent is required. Document on the request form or electronic order that a copy is on file. The following documents are available:

-Informed Consent for Genetic Testing (T576)

-Informed Consent for Genetic Testing-Spanish (T826)

2. Molecular Genetics: Biochemical Disorders Patient Information (T527)

3. If not ordering electronically, complete, print, and send 1 of the following forms with the specimen:

-Neurology Specialty Testing Client Test Request (T732)

-Biochemical Genetics Test Request (T798)