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Test Catalog

Test ID: MITON    
Mitochondrial Nuclear Gene Panel by Next-Generation Sequencing (NGS), Varies

Useful For Suggests clinical disorders or settings where the test may be helpful

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

Genetics Test Information Provides information that may help with selection of the correct genetic test or proper submission of the test request

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.

Testing Algorithm Delineates situations when tests are added to the initial order. This includes reflex and additional tests.

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.

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

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.

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Interpretation Provides information to assist in interpretation of the test results

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.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

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.

Clinical Reference Recommendations for in-depth reading of a clinical nature

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&sectionid=225086827

3. Wong LJ: Molecular genetics of mitochondrial disorders. Dev Disabil Res. Rev 2010 Jun;16(2):154-162

Special Instructions Library of PDFs including pertinent information and forms related to the test