Diagnosis of the subset of mitochondrial disease that results from variants in the nuclear-encoded genes
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 nuclear genome that are known to be associated with mitochondrial disease, allowing for predictive testing of at-risk family members
This test includes next-generation sequencing (NGS) and supplemental Sanger sequencing to evaluate for variants in the following genes: AARS2, AASS, ABAT, ABCB7, ACACA, ACAD9, ACO2, AFG3L2, AGK, AIFM1, ALDH3A2, AMPD1, APOPT1, APTX, ATP5A1, ATP5E, ATP5G3, ATPAF2, AUH, BCS1L, BOLA3, C12orf65, CA5A, CHAT, CLPP, COA5, COA6, COQ2, COQ4, COQ6, COQ8A (ADCK3), COQ8B (ADCK4), COQ9, COX10, COX14, COX15, COX20, COX4I2, COX6B1, COX7B, CYC1, D2HGDH, DARS2, DGUOK, DLAT, DLD, DNA2, DNAJC19, DNM1L, EARS2, ELAC2, ETFA, ETFB, ETFDH, ETHE1, FARS2, FASTKD2, FBXL4, FH, FOXRED1, FXN, GAMT, GARS, GCDH, GFER, GFM1, HARS2, HIBCH, IARS2, IBA57, IDH2, ISCU, L2HGDH, LARS2, LIAS, LRPPRC, LYRM4, LYRM7, MARS2, MGME1, MICU1, MPC1, MPV17, MRPL3, MRPL44, MRPS16, MRPS22, MTFMT, MTO1, MTPAP, NDUFA1, NDUFA2, NDUFA9, NDUFA10, NDUFA11, NDUFA12, NDUFAF1, NDUFAF2, NDUFAF3, NDUFAF4, NDUFAF5, NDUFAF6, NDUFB3, NDUFB9, NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS6, NDUFS7, NDUFS8, NDUFV1, NDUFV2, NFU1, NUBPL, OGDH, OPA1, OPA3, OXCT1, PANK2, PC, PCK2, PDHA1, PDHB, PDHX, PDP1, PDSS1, PDSS2, PNKD, PNPT1, POLG, POLG2, PUS1, RARS2, RMND1, RRM2B, SACS, SARS2, SCO1, SCO2, SDHAF1, SERAC1, SFXN4, SLC19A3, SLC25A1, SLC25A3, SLC25A4, SLC25A12, SLC25A19, SLC52A2, SUCLA2, SUCLG1, SUGCT, SURF1, TACO1, TARS2, TAZ, TIMM8A, TIMM44, TK2, TMEM126A, TMEM70, TPK1, TRAP1, TRMU, TSFM, TTC19, TUFM, TWNK (C10orf2), TYMP, UQCRB, UQCRC2, UQCRQ, VARS2, XPNPEP3, and YARS2.
See Targeted Genes Interrogated by Mitochondrial Nuclear Gene Panel in Special Instructions for details regarding the targeted gene regions identified by this test.
Test Id | Reporting Name | Available Separately | Always Performed |
---|---|---|---|
FIBR | Fibroblast Culture | Yes | No |
CRYOB | Cryopreserve for Biochem Studies | No | No |
If skin biopsy is received, fibroblast culture and cryopreservation for biochemical studies will be added at an additional charge.
See Neuromuscular Myopathy Testing Algorithm in Special Instructions.
Custom Sequence Capture and Targeted Next-Generation Sequencing (NGS) followed by Polymerase Chain Reaction (PCR) and Sanger Sequencing when appropriate
Next Gen Sequencing Test
Mitochondrial disease
Mitochondrial nuclear genes
Leigh syndrome
Coenzyme Q10 deficiency
Barth syndrome
Complex I deficiency
Complex II deficiency
Complex III deficiency
Complex IV deficiency
Complex V deficiency
Pyruvate Dehydrogenase deficiency
MNGIE
Mitochondrial neurogastrointestinal encephalomyopathy
Cytochrome c Oxidase deficiency
If skin biopsy is received, fibroblast culture and cryopreservation for biochemical studies will be added at an additional charge.
See Neuromuscular Myopathy Testing Algorithm in Special Instructions.
Varies
Specimen preferred to arrive within 96 hours of collection.
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 specimen in original tube.
3. To ensure minimum volume and concentration of DNA is met, the preferred volume of blood must be submitted. Testing may be canceled if DNA requirements are inadequate.
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
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
Specimen Type: Tissue biopsy
Supplies: Muscle Biopsy Kit (T541)
Collection Instructions: Prepare and transport specimen per instructions in Muscle Biopsy Specimen Preparation in Special Instructions.
Specimen Volume: 10-80 mg
Specimen Stability Information: Frozen (preferred)/Ambient/Refrigerated
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 in Special Instructions:
-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 a Neurology Specialty Testing Client Test Request (T732) with the specimen.
Blood: 1 mL
Tissue Biopsy: 200 mg
Specimen Type | Temperature | Time | Special Container |
---|---|---|---|
Varies | Varies (preferred) |
Diagnosis of the subset of mitochondrial disease that results from variants in the nuclear-encoded genes
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 nuclear genome that are known to be associated with mitochondrial disease, allowing for predictive testing of at-risk family members
This test includes next-generation sequencing (NGS) and supplemental Sanger sequencing to evaluate for variants in the following genes: AARS2, AASS, ABAT, ABCB7, ACACA, ACAD9, ACO2, AFG3L2, AGK, AIFM1, ALDH3A2, AMPD1, APOPT1, APTX, ATP5A1, ATP5E, ATP5G3, ATPAF2, AUH, BCS1L, BOLA3, C12orf65, CA5A, CHAT, CLPP, COA5, COA6, COQ2, COQ4, COQ6, COQ8A (ADCK3), COQ8B (ADCK4), COQ9, COX10, COX14, COX15, COX20, COX4I2, COX6B1, COX7B, CYC1, D2HGDH, DARS2, DGUOK, DLAT, DLD, DNA2, DNAJC19, DNM1L, EARS2, ELAC2, ETFA, ETFB, ETFDH, ETHE1, FARS2, FASTKD2, FBXL4, FH, FOXRED1, FXN, GAMT, GARS, GCDH, GFER, GFM1, HARS2, HIBCH, IARS2, IBA57, IDH2, ISCU, L2HGDH, LARS2, LIAS, LRPPRC, LYRM4, LYRM7, MARS2, MGME1, MICU1, MPC1, MPV17, MRPL3, MRPL44, MRPS16, MRPS22, MTFMT, MTO1, MTPAP, NDUFA1, NDUFA2, NDUFA9, NDUFA10, NDUFA11, NDUFA12, NDUFAF1, NDUFAF2, NDUFAF3, NDUFAF4, NDUFAF5, NDUFAF6, NDUFB3, NDUFB9, NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS6, NDUFS7, NDUFS8, NDUFV1, NDUFV2, NFU1, NUBPL, OGDH, OPA1, OPA3, OXCT1, PANK2, PC, PCK2, PDHA1, PDHB, PDHX, PDP1, PDSS1, PDSS2, PNKD, PNPT1, POLG, POLG2, PUS1, RARS2, RMND1, RRM2B, SACS, SARS2, SCO1, SCO2, SDHAF1, SERAC1, SFXN4, SLC19A3, SLC25A1, SLC25A3, SLC25A4, SLC25A12, SLC25A19, SLC52A2, SUCLA2, SUCLG1, SUGCT, SURF1, TACO1, TARS2, TAZ, TIMM8A, TIMM44, TK2, TMEM126A, TMEM70, TPK1, TRAP1, TRMU, TSFM, TTC19, TUFM, TWNK (C10orf2), TYMP, UQCRB, UQCRC2, UQCRQ, VARS2, XPNPEP3, and YARS2.
See Targeted Genes Interrogated by Mitochondrial Nuclear Gene Panel in Special Instructions for details regarding the targeted gene regions identified by this test.
If skin biopsy is received, fibroblast culture and cryopreservation for biochemical studies will be added at an additional charge.
See Neuromuscular Myopathy Testing Algorithm in Special Instructions.
The mitochondrion occupies a unique position in eukaryotic biology. It is the site of energy metabolism, and 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 has been well characterized.
The diagnosis of mitochondrial disease can be particularly challenging as the presentation can occur at any age, involve virtually any organ system, and be associated with widely varying severities. Due to the considerable overlap in the clinical phenotypes of various mitochondrial disorders, it is often difficult to distinguish these specific inherited disorders without genetic testing. This test utilizes massively parallel sequencing, also termed next-generation sequencing (NGS), to analyze 176 nuclear-encoded genes implicated in mitochondrial disease. The utility of this test is to assist in the diagnosis of the subset of mitochondrial diseases that result from variants in the nuclear encoded genes. This includes disorders of mitochondrial protein synthesis, disorders of coenzyme Q10 biosynthesis, disorders of the respiratory chain complexes and disorders of mtDNA maintenance (ie, mitochondrial DNA depletion disorders).
See Targeted Genes Interrogated by Mitochondrial Nuclear Gene Panel in Special Instructions for details regarding the targeted genes identified by this test.
An interpretive report will be provided.
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.
Clinical Correlations:
A small percentage of individuals who have involvement of 1 of more of the genes on the panel may have a variant that is not identified by the methods performed (eg, large deletions/duplications, promoter alterations, deep intronic alterations). The absence of a variant, therefore, does not eliminate the possibility of a mitochondrial disease. Variants responsible for mitochondrial disorders encoded by the mitochondrial 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 alterations 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. These and common polymorphisms 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 have been previously detected and reported. The laboratory encourages health care providers to contact the laboratory at any time to learn how the status of a particular variant may have changed over time.
1. Richards CS, Nazneen A, Bale S, et al: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-424
2. Munnich A, Rotig A, Cormier-Daire V, Rustin P: Clinical presentation of respiratory chain deficiency. In: Valle D, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA, eds. The Metabolic and Molecular Basis of Inherited Disease. McGraw-Hill Education; 2019. Accessed September 28, 2020. https://ommbid.mhmedical.com/content.aspx?bookid=2709§ionid=225086827
3. Wong LJ: Molecular genetics of mitochondrial disorders. Dev Disabil Res. Rev 2010 Jun;16(2):154-162
Next-generation sequencing (NGS) and/or Sanger sequencing is performed to test for the presence of a mutation in the following genes: AARS2, AASS, ABAT, ABCB7, ACACA, ACAD9, ACO2, AFG3L2, AGK, AIFM1, ALDH3A2, AMPD1, APOPT1, APTX, ATP5A1, ATP5E, ATP5G3, ATPAF2, AUH, BCS1L, BOLA3, C12orf65, CA5A, CHAT, CLPP, COA5, COA6, COQ2, COQ4, COQ6, COQ8A (ADCK3), COQ8B (ADCK4), COQ9, COX10, COX14, COX15, COX20, COX4I2, COX6B1, COX7B, CYC1, D2HGDH, DARS2, DGUOK, DLAT, DLD, DNA2, DNAJC19, DNM1L, EARS2, ELAC2, ETFA, ETFB, ETFDH, ETHE1, FARS2, FASTKD2, FBXL4, FH, FOXRED1, FXN, GAMT, GARS, GCDH, GFER, GFM1, HARS2, HIBCH, IARS2, IBA57, IDH2, ISCU, L2HGDH, LARS2, LIAS, LRPPRC, LYRM4, LYRM7, MARS2, MGME1, MICU1, MPC1, MPV17, MRPL3, MRPL44, MRPS16, MRPS22, MTFMT, MTO1, MTPAP, NDUFA1, NDUFA2, NDUFA9, NDUFA10, NDUFA11, NDUFA12, NDUFAF1, NDUFAF2, NDUFAF3, NDUFAF4, NDUFAF5, NDUFAF6, NDUFB3, NDUFB9, NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS6, NDUFS7, NDUFS8, NDUFV1, NDUFV2, NFU1, NUBPL, OGDH, OPA1, OPA3, OXCT1, PANK2, PC, PCK2, PDHA1, PDHB, PDHX, PDP1, PDSS1, PDSS2, PNKD, PNPT1, POLG, POLG2, PUS1, RARS2, RMND1, RRM2B, SACS, SARS2, SCO1, SCO2, SDHAF1, SERAC1, SFXN4, SLC19A3, SLC25A1, SLC25A3, SLC25A4, SLC25A12, SLC25A19, SLC52A2, SUCLA2, SUCLG1, SUGCT, SURF1, TACO1, TARS2, TAZ, TIMM8A, TIMM44, TK2, TMEM126A, TMEM70, TPK1, TRAP1, TRMU, TSFM, TTC19, TUFM, TWNK (C10orf2), TYMP, UQCRB, UQCRC2, UQCRQ, VARS2, XPNPEP3, and YARS2.
There are regions of the genes COX10, COX20, NDUFV2, and TSFM that cannot be effectively sequenced as a result of technical limitations of the assay. Regions of homology, high GC-rich content, and repetitive sequences may not provide accurate sequence. Therefore, all reported alterations detected by NGS are confirmed by an independent reference method. However, this does not rule out the possibility of a false-negative result in these regions. Sanger sequencing is used to confirm alterations detected by NGS when appropriate.(Unpublished Mayo method)
Varies
This test was developed, and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the US Food and Drug Administration.
81440
88233-Tissue culture, skin or solid tissue biopsy (if appropriate)
88240-Cryopreservation (if appropriate)
Test Id | Test Order Name | Order LOINC Value |
---|---|---|
MITON | Mitochondrial Nuclear Gene Panel | In Process |
Result Id | Test Result Name |
Result LOINC Value
Applies only to results expressed in units of measure originally reported by the performing laboratory. These values do not apply to results that are converted to other units of measure.
|
---|---|---|
40220 | Result Summary | 50397-9 |
40221 | Result | 82939-0 |
40222 | Interpretation | 69047-9 |
40223 | Additional Information | 48767-8 |
40224 | Specimen | 31208-2 |
40225 | Source | 31208-2 |
40226 | Released By | 18771-6 |