Mitochondrial Disorders Panel

Indications for testing:

  • Preferred test to confirm a suspected diagnosis of a mitochondrial disorder caused by a mitochondrial genome (mtDNA) sequence variant or variant(s) in related nuclear genes in individuals with:
    • Complex neurological features or a single neurological symptom and other system involvement
    • Progressive multisystem disorder of unknown etiology

Indications for testing:

  • Assess for sequence variants in the mitochondrial genome (mtDNA) causing mitochondrial disorders, especially for individuals with clinical symptoms characteristic of a specific disorder, such as:
    • Leber hereditary optic neuropathy (LHON)
    • Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS)
    • Myoclonic epilepsy with ragged-red fibers (MERRF)
    • Neurogenic weakness with ataxia and retinitis pigmentosa (NARP)
Familial Mutation, Targeted Sequencing 2001961
Method: Polymerase Chain Reaction/Sequencing

Indication for testing:

  • Recommended test if there is a known familial sequence variant previously identified in a family member.
  • A copy of the family member’s test result documenting the familial variant is required.

The above tests do not assess for large deletions in the mitochondrial genome; thus, ARE NOT RECOMMENDED for the following indications:

  • Chronic progressive external ophthalmoplegia (CPEO)
  • Kearns-Sayre syndrome (KSS)
  • Pearson syndrome

Mitochondrial disorders originate from variants in nuclear DNA or mitochondrial DNA (mtDNA) and result in a spectrum of pathological conditions. Some disorders affect single organs (eg, eye, ear), while others affect multiple systems.

DISEASE OVERVIEW

Incidence – 1/5,000 in U.S.

Symptoms

  • Mitochondrial disorders are clinically and genetically heterogeneous.
  • Tissues most affected by mitochondrial disease are dependent on aerobic metabolism and have a high energy requirement.
  • Some mitochondrial disorders affect single organs, such as the eye or ear, while others affect multiple systems.
  • Symptoms may present at any age, and phenotype may change with age.
    • Poor growth
    • Neurological problems
      • Seizures
      • Encephalopathy
      • Ataxia
      • Spasticity
      • Stroke-like episodes
    • Loss of vision or hearing
    • Liver, kidney, heart disease
    • Myopathy and muscle weakness
  • Severity of disease resulting from variants in mtDNA may be influenced by the presence of heteroplasmy (ratio of mutated to normal mitochondria within a cell, tissue, or individual).

See Common Mitochondrial Syndromes table below.

Inheritance

Variable, dependent on the gene(s) involved

  • Nuclear genes – autosomal recessive, autosomal dominant, or X-linked recessive
  • Mitochondrial genome – maternal

Penetrance

Variable – dependent on the gene(s) involved and the level of heteroplasmy

TEST DESCRIPTION

See Genes Tested tables for mtDNA and nuclear genes included in the panel.

Clinical Sensitivity

Variable, dependent on phenotype/condition

Limitations

  • A negative result does not exclude a mitochondrial disorder.
  • Diagnostic errors can occur due to rare sequence variations.
  • Interpretation of this test result may be impacted if this individual has had an allogeneic stem cell transplantation.
  • The following will not be evaluated:
    • Variants outside the coding regions and intron-exon boundaries of the targeted genes
    • Regulatory region variants and deep intronic variants
    • Breakpoints of large deletions/duplications
    • Deletion/duplication analysis of the mitochondrial genome
    • Deletions/duplications in FBXL4, FOXRED1, LARS2, NDUFA2, NDUFAF2, NUBPL, OPA3, TAZ
    • Variants in the mitochondrial genome D-loop and mosaic variants in nuclear genes
    • Noncoding transcripts
    • The following exons are not sequenced due to technical limitations of the assay:
      • COX10 (NM_001303) 6
      • HSPD1 (NM_002156) 12
      • PDSS1 (NM_014317) 2
      • SDHC (NM_001035511) 5
      • SDHD (NM_001276506) 4
  • The following may not be detected:
    • Deletions/duplications/insertions of any size by massively parallel sequencing
    • Deletions/duplications less than 1kb in the targeted nuclear genes by array
    • Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
    • Low-level somatic variants
    • Variants in the mitochondrial genome present at less than 10 percent heteroplasmy
      • Homoplasmy is defined as greater than or equal to 99 percent of mitochondrial genome sequences identical and heteroplasmy as less than 99 percent of sequences identical
      • The percentage of heteroplasmy will not be reported
    • Single exon deletions/duplications in the following exons:
    • Gene Exon(s)

      ACAD9

      (NM_014049) 10

      ACADM

      (NM_000016) 1, 12

      ACADM

      (NM_001286042) 1

      ACADS

      (NM_000017) 1, 9

      ACADVL

      (NM_000018) 1, 2, 17

      APTX

      (NM_175073) 9

      ASS1

      (NM_000050) 9, 15

      COQ8A

      (NM_020247) 5, 10

      COQ9

      (NM_020312) 1, 9

      COX10

      (NM_001303) 6

      COX15

      (NM_001320974) 9

      DNAJC19

      (NM_145261) 1

      ETFA

      (NM_000126) 1

      ETFB

      (NM_001985) 3

      ETFDH

      (NM_004453) 13

      ETHE1

      (NM_001320868) 2

      ETHE1

      (NM_014297) 1, 2

      FH

      (NM_000143) 1

      GFM1

      (NM_001308164) 6

      HADH

      (NM_001331027) 1

      HMGCL

      (NM_000191) 1, 6

      LRPPRC

      (NM_133259) 1

      MCCC2

      (NM_022132) 1

      MRPS16

      (NM_016065) 1

      NDUFAF3

      (NM_199069) 1

      NDUFAF5

      (NM_024120) 4

      NDUFS7

      (NM_024407) 4, 6, 7

      NDUFS8

      (NM_002496) 5

      NDUFV1

      (NM_001166102) 1

      NDUFV1

      (NM_007103) 1, 10

      PCK2

      (NM_004563) 1

      PDHA1

      (NM_000284) 1, 9

      PDHA1

      (NM_001173454) 2

      PDHB

      (NM_000925) 2

      PDSS1

      (NM_014317) 1, 2

      PUS1

      (NM_025215) 1

      RARS2

      (NM_020320) 4, 19

      SDHD

      (NM_001276506) 4

      SLC25A13

      (NM_014251) 1

      SLC25A22

      (NM_024698) 5

      SPG7

      (NM_003119) 1, 3

      SUCLA2

      (NM_003850) 6, 11

      SURF1

      (NM_003172) 1, 2

      TK2

      (NM_001271934) 3

      TK2

      (NM_004614) 1

      TRMU

      (NM_018006) 1

      TSFM

      (NM_001172696) 5

      TUFM

      (NM_003321) 1

      TYMP

      (NM_001953) 2, 8, 9, 10

Analytical Sensitivity

For nuclear genes by massively parallel sequencing:

Variant Class Analytical Sensitivity (PPA Estimatea (%) Analytical Sensitivity (PPA) 95% Credibility Regiona (%)

SNVs

99.2

96.9-99.4

Deletions 1-10 bp

93.8

84.3-98.2

Deletions 11-44 bp

100

87.8-100

Insertions 1-10 bp

94.8

86.8-98.5

Insertions 11-23 bp

100

62.1-100

aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived.

bp, base pairs; PPA, positive percent agreement; SNVs, single nucleotide variants

Common Mitochondrial Disorders 

Common Mitochondrial Syndromes
Disorder Major Clinical Features Inheritance Commonly Associated Genes/Variants

Chronic progressive external ophthalmoplegia (CPEO)

External ophthalmoplegia

Bilateral ptosis

Mild proximal myopathy

Sporadic

mtDNA large deletions confined to skeletal muscle in ~50% of cases

Maternal

Various mtDNA point variants

Autosomal dominant/recessive

eg, OPA1, POLG, POLG2, RRMB2, SLC25A4, SPG7, TYMP

Kearns-Sayre syndrome (KSS)

PEO onset <20 years of age

Pigmentary retinopathy

CSF protein >1g/L

Cerebellar ataxia

Heart block

Sporadic (infrequently maternally transmitted)

Large mtDNA large deletions in ~90% of cases

m.8470_1344del4977 is most frequent

Leber hereditary optic neuropathy (LHON)

Subacute painless bilateral visual failure

Median age of onset 24 years

Males:females, 4:1

Maternal

90% of cases due to one of three common mtDNA variants

MT-ND4 m.11778G>A

MT-ND6 m.14484T>C

MT-ND1 m.3460G>A

Variants in other mtDNA genes cause ~10% of LHON

Leigh syndrome (LS)

Progressive neurological disease with motor and intellectual developmental delay

Cerebellar and brain stem signs

Infantile onset

Maternal

mtDNA large deletions causative for <5% of LS

MT-ATP6 (10% of cases)

Other mtDNA genes (10-20% of cases)

Autosomal recessive or X-linked recessive

Majority of cases due to nuclear gene variants (numerous genes implicated)

Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS)

Stroke-like episodes <40 years of age

Encephalopathy with seizures and/or dementia

Mitochondrial myopathy, evidenced by lactic acidosis and/or ragged-red fibers

Maternal

MT-TL1 (accounts for majority of cases)

m.3243A>G

m.3271T>C

m.3252A>G

MT-ND5

m.13513G>A

Variants in other mtDNA genes are rare

Myoclonic epilepsy with ragged-red fibers (MERRF)

Myoclonus

Seizures

Cerebellar ataxia

Myopathy

Maternal

MT-TK (accounts for ~90% of cases)

m.8344A>G

m.8356T>C

m.8363G>A

m.8361G>A

Causative variants in other mtDNA genes, including MT-TF, MT-TL1, MT-TI, and MT-TP account for <5% of cases

Neurogenic weakness with ataxia and retinitis pigmentosa (NARP)

Late-childhood or adult-onset peripheral neuropathy

Ataxia

Pigmentary retinopathy

Maternal

MT-ATP6 (estimated to account for >50% of cases)

m.8993T>G

m.8993T>C

Pearson syndrome

Sideroblastic anemia of childhood

Pancytopenia

Exocrine pancreatic failure

Sporadic (infrequently maternally transmitted)

mtDNA large deletions

Genes Tested

Mitochondrial DNA (mtDNA) Genes
Gene Symbol MIM #

MT-ATP6

516060

MT-ATP8

516070

MT-CO1

516030

MT-CO2

516040

MT-CO3

516050

MT-CYB

516020

MT-ND1

516000

MT-ND2

516001

MT-ND3

516002

MT-ND4

516003

MT-ND4L

516004

MT-ND5

516005

MT-ND6

516006

MT-RNR1

561000

MT-RNR2

561010

MT-TA

590000

MT-TC

590020

MT-TD

590015

MT-TE

590025

MT-TF

590070

MT-TG

590035

MT-TH

590040

MT-TI

590045

MT-TK

590060

MT-TL1

590050

MT-TL2

590055

MT-TM

590065

MT-TN

590010

MT-TP

590075

MT-TQ

590030

MT-TR

590005

MT-TS1

590080

MT-TS2

590085

MT-TT

590090

MT-TV

590105

MT-TW

590095

MT-TY

590100

Nuclear Genes Tested
Gene MIM Number Disorder Inheritance

ABCB7

300135

Sideroblastic anemia and ataxia

XL

ACAD9

611103

Mitochondrial complex I deficiency due to ACAD9 deficiency

AR

ACADM

607008

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency

AR

ACADS

606885

Short-chain acyl-CoA dehydrogenase (SCAD) deficiency

AR

ACADVL

609575

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency

AR

ACAT1

607809

Alpha-methylacetoacetic aciduria

AR

APTX

606350

Early-onset ataxia with oculomotor apraxia and hypoalbuminemia

AR

ASS1

603470

Citrullinemia type I

AR

ATPAF2

608918

Mitochondrial complex V (ATP synthase) deficiency, nuclear type 1

AR

BCKDHA

608348

Maple syrup urine disease type 1a

AR

BCKDHB

248611

Maple syrup urine disease type 1b

AR

BCS1L

603647

Mitochondrial complex III deficiency, nuclear type 1

Leigh syndrome

AR

COQ2

609825

Primary coenzyme q10 deficiency, 1

AR

COQ8A

606980

Primary coenzyme q10 deficiency, 4

AR

COQ9

612837

Primary coenzyme q10 deficiency, 5

AR

COX10

602125

Mitochondrial complex IV deficiency

Leigh syndrome

AR

COX15

603646

Leigh syndrome

Cardioencephalomyopathy, fatal infantile, due to cytochrome C oxidase deficiency

AR

COX4I2

607976

Exocrine pancreatic insufficiency, dyserythropoietic anemia, and calvarial hyperostosis

AR

COX6B1

124089

Mitochondrial complex IV deficiency

AR

CPT1A

600528

Carnitine palmitoyltransferase deficiency, hepatic, type 1a

AR

CPT2

600650

Carnitine palmitoyltransferase deficiency, type II

AR

CYCS

123970

Thrombocytopenia 4

AD

DARS2

610956

Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation

AR

DBT

248610

Maple syrup urine disease type 2

AR

DGUOK

601465

Mitochondrial DNA depletion syndrome 3 (hepatocerebral type)

Progressive external ophthalmoplegia with mitochondrial DNA deletions, 4

AR

DLAT

608770

Pyruvate dehydrogenase E2 deficiency

AR

DLD

238331

Dihydrolipoamide dehydrogenase deficiency

AR

DNAJC19

608977

3-methylglutaconic aciduria, type V

AR

DNM1L

603850

Optic atrophy 5

Encephalopathy due to defective mitochondrial and peroxisomal fission

AD

Encephalopathy due to defective mitochondrial and peroxisomal fission

AR

ETFA

608053

Glutaric acidemia IIA

AR

ETFB

130410

Glutaric acidemia IIB

AR

ETFDH

231675

Glutaric acidemia IIC

AR

ETHE1

608451

Encephalopathy, ethylmalonic

AR

FASTKD2

612322

Mitochondrial complex IV deficiency

AR

FBXL4

605654

Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type)

AR

FH

136850

Fumarase deficiency

AR

FOXRED1

613622

Mitochondrial complex I deficiency

Leigh syndrome

AR

GFER

600924

Progressive mitochondrial myopathy with congenital cataract, hearing loss, and developmental delay

AR

GFM1

606639

Combined oxidative phosphorylation deficiency 1

AR

HADH

601609

3-hydroxyacyl-CoA dehydrogenase deficiency

Hyperinsulinemic hypoglycemia, familial, 4

AR

HADHA

600890

Mitochondrial trifunctional protein deficiency

Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency

AR

HADHB

143450

Mitochondrial trifunctional protein deficiency

AR

HMGCL

613898

HMG-CoA lyase deficiency

AR

HMGCS2

600234

HMG-CoA synthase-2 deficiency

AR

HSPD1

118190

Spastic paraplegia 13

AD

Hypomyelinating leukodystrophy, 4

AR

ISCU

611911

Hereditary myopathy with lactic acidosis

AR

LARS2

604544

Perrault syndrome 4

AR

LRPPRC

607544

Leigh syndrome, French Canadian type

AR

MCCC2

609014

3-methylcrotonyl-CoA carboxylase 2 deficiency

AR

MFN2

608507

Hereditary motor and sensory neuropathy, type Via

Charcot-Marie-Tooth disease, axonal, type 2A2A

AD

Charcot-Marie-Tooth disease, axonal, type 2A2B

AR

MPV17

137960

Mitochondrial DNA depletion syndrome 6 (hepatocerebral type)

AR

MRPS16

609204

Combined oxidative phosphorylation deficiency 2

AR

MRPS22

605810

Combined oxidative phosphorylation deficiency 5

AR

NDUFA1

300078

Mitochondrial complex I deficiency

AR

NDUFA11

612638

Mitochondrial complex I deficiency

AR

NDUFA2

602137

Leigh syndrome due to mitochondrial complex I deficiency

AR

NDUFAF1

606934

Mitochondrial complex I deficiency

AR

NDUFAF2

609653

Mitochondrial complex I deficiency

AR

NDUFAF3

612911

Mitochondrial complex I deficiency

AR

NDUFAF4

611776

Mitochondrial complex I deficiency

AR

NDUFAF5

612360

Mitochondrial complex I deficiency

AR

NDUFS1

157655

Mitochondrial complex I deficiency

AR

NDUFS2

602985

Mitochondrial complex I deficiency

AR

NDUFS3

603846

Mitochondrial complex I deficiency

Leigh syndrome

AR

NDUFS4

602694

Mitochondrial complex I deficiency

Leigh syndrome

AR

NDUFS6

603848

Mitochondrial complex I deficiency

AR

NDUFS7

601825

Leigh syndrome

AR

NDUFS8

602141

Leigh syndrome

AR

NDUFV1

161015

Mitochondrial complex I deficiency

AR

NDUFV2

600532

Mitochondrial complex I deficiency

AR

NUBPL

613621

Mitochondrial complex I deficiency

AR

OPA1

605290

Optic atrophy 1

Optic atrophy plus syndrome

AD

Behr syndrome

AR

OPA3

606580

Optic atrophy 3 with cataract

AD

3-methylglutaconic aciduria, Type III

AR

OXCT1

601424

Succinyl-CoA:3-oxoacid-CoA transferase deficiency

AR

PC

608786

Pyruvate carboxylase deficiency

AR

PCK2

614095

Phosphoenolpyruvate carboxykinase deficiency, mitochondrial

AR

PDHA1

300502

Pyruvate dehydrogenase E1-alpha deficiency

XL

PDHB

179060

Pyruvate dehydrogenase E1-beta deficiency

XL

PDHX

608769

Pyruvate dehydrogenase E3-binding protein deficiency

AR

PDP1

605993

Pyruvate dehydrogenase phosphatase deficiency

AR

PDSS1

607429

Coenzyme q10 deficiency, primary, 2

AR

PDSS2

610564

Coenzyme q10 deficiency, primary, 3

AR

POLG

174763

Progressive external ophthalmoplegia 

Mitochondrial DNA depletion syndrome 4a (Alpers type) or 4b (MNGIE type)

Mitochondrial recessive ataxia syndrome (SANDO and scale)

AR

Progressive external ophthalmoplegia

AD

POLG2

604983

Progressive external ophthalmoplegia with mitochondrial DNA deletions, 4

AD

PREPL

609557

Congential myasthenic syndrome, 22

AR

PUS1

608109

Myopathy, lactic acidosis, and sideroblastic anemia 1

AR

RARS2

611524

Pontocerebellar hypoplasia, type 6

AR

RRM2B

604712

Mitochondrial DNA depletion syndrome 8a or 8b

AR

Progressive external ophthalmoplegia with mitochondrial DNA deletions, 5

AD

SCO1

603644

Mitochondrial complex IV deficiency

AR

SCO2

604272

Cardioencephalomyopathy, fatal infantile, due to cytochrome C oxidase deficiency 1

AR

SDHAF1

612848

Mitochondrial complex II deficiency

AR

SDHB

185470

Mitochondrial complex II deficiency

AR

SDHC

602413

Mitochondrial complex II deficiency

AR

SDHD

602690

Mitochondrial complex II deficiency

AR

SLC22A5

603377

Carnitine deficiency, systemic primary

AR

SLC25A13

603859

Citrullinemia, type II, adult-onset

Citrullinemia, type II, neonatal-onset

AR

SLC25A15

603861

Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome

AR

SLC25A19

606521

Microcephaly, Amish type

Thiamine metabolism dysfunction syndrome 4

AR

SLC25A20

613698

Carnitine-acylcarnitine translocase deficiency

AR

SLC25A22

609302

Epileptic encephalopathy, early infantile, 3

AR

SLC25A3

600370

Mitochondrial phosphate carrier deficiency

AR

SLC25A4

103220

Mitochondrial DNA depletion syndrome 12a

Progressive external ophthalmoplegia with mitochondrial DNA deletions 2

AD

Mitochondrial DNA depletion syndrome 12b

AR

SLC3A1

104614

Cystinuria

AR

SPG7

602783

Spastic paraplegia 7

AR

SUCLA2

603921

Mitochondrial DNA depletion syndrome 5

AR

SUCLG1

611224

Mitochondrial DNA depletion syndrome 9

AR

SUOX

606887

Sulfite oxidase deficiency

AR

SURF1

185620

Leigh syndrome due to COX IV deficiency

Charcot-Marie-Tooth disease, type 4k

AR

TAZ

300394

Barth syndrome

XL

TIMM8A

300356

Mohr-Tranebjaerg syndrome

XL

TK2

188250

Mitochondrial DNA depletion syndrome 2 (myopathic type)

AR

TMEM70

612418

Mitochondrial complex v (ATP synthase) deficiency, nuclear type 2

AR

TRMU

610230

Liver failure, transient infantile

AR

TSFM

604723

Combined oxidative phosphorylation deficiency 3

AR

TUFM

602389

Combined oxidative phosphorylation deficiency 4

AR

TWNK

606075

Mitochondrial DNA depletion syndrome 7 (hepatocerebral type)

Perrault syndrome 5

AR

Progressive external ophthalmoplegia with mitochondrial DNA deletions, 3

AD

TYMP

131222

Mitochondrial DNA depletion syndrome 1 (MNGIE type)

AR

UQCRB

191330

Mitochondrial complex III deficiency, nuclear type 3

AR

UQCRQ

612080

Mitochondrial complex III deficiency, nuclear type 4

AR

WFS1

606201

Wolfram-like syndrome 1

AD

Wolfram syndrome 1

AR

AD, autosomal dominant; AR, autosomal recessive; XL, X-linked
References 
  1. DiMauro S, Hirano M. MELAS. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews, University of Washington, 1993-2018. Seattle, WA [Last Update: Nov 2013; Accessed: Nov 2018]
  2. DiMauro S, Hirano M. MERRF. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews, University of Washington, 1993-2018. Seattle, WA [Last Update: Jan 2015; Accessed: Nov 2018]
  3. Thorburn D, Rahman J, Rahman S. Mitochondrial DNA-Associated Leigh Syndrome and NARP. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews, University of Washington, 1993-2018. Seattle, WA [Last Update: Sep 2017; Accessed: Nov 2018]
  4. Yu-Wai-Man P, Chinnery P. Leber Hereditary Optic Neuropathy. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews, University of Washington, 1993-2018. Seattle, WA [Last Update: Jun 2016; Accessed: Nov 2018]

Last Update: February 2019