Mitochondrial Disorders Panel (Nuclear Genes Only)

Disorders of mitochondrial energy metabolism, or oxidative phosphorylation (OXPHOS) disorders, are characterized by reduced activity of one (isolated) or more (combined) mitochondrial respiratory chain enzyme complexes. Mitochondrial disorders are clinically heterogeneous, and phenotypes, which range in severity and progression, can involve single or multiple organ systems. As OXPHOS defects cripple the body’s ability to produce adequate energy, organ systems with high metabolic demands (the heart, brain, and muscle) are often most severely affected (Ghezzi and Zeviani. 2018. PubMed ID: 30030362). Lactic acidosis of the blood and/or cerebrospinal fluid is often a prevailing symptom (Chinnery. 2014. PubMed ID: 20301403).

Clinical presentations of OXPHOS disorders may include but are not limited to: fatal infantile lactic acidosis (FILA), isolated myopathy, encephalomyopathy, encephalocardiomyopathy, neurogastrointestinal encephalomyopathy, hepatopathy, nephropathy, hypertrophic cardiomyopathy, hypotonia, seizures, ataxia, progressive external ophthalmoplegia (PEO), exercise intolerance, ptosis, optic atrophy, sensorineural deafness, and/or Leigh or Leigh-like syndrome (Chinnery. 2014. PubMed ID: 20301403; Ghezzi and Zeviani. 2018. PubMed ID: 30030362). Leigh syndrome is a hallmark clinical presentation characterized by a combination of lactic acidosis, psychomotor delay or regression, neurologic manifestations such as hypotonia or ataxia, and bilateral symmetric necrotic lesions in the basal ganglia, brain stem, thalamus, and/or spinal cord (Wedatilake et al. 2013. PubMed ID: 23829769; Leigh. 1951. PubMed ID: 14874135).

Prevalence of OXPHOS deficiency in the general population has been reported to be ~1:8,500 live births (Chinnery. 2014. PubMed ID: 20301403). Age at onset varies widely, but neonatal or early childhood presentations are the most common (Ghezzi and Zeviani. 2018. PubMed ID: 30030362). However, adult-onset has also been described, and symptoms in older cohorts can include ataxia, spasticity, muscle weakness, neuropathy, dementia, cerebellar atrophy, leukoencephalopathy, and/or retinitis pigmentosa, among others (Boczonadi et al. 2018. PubMed ID: 29980628).

At the present time, there are limited treatment options available to individuals with mitochondrial disorders, and management of these diseases is primarily supportive. Molecular diagnosis may help access recurrence risks, as well as allow for appropriate screening for potential future symptoms. Oral administration of certain supplements (e.g., riboflavin for complex I and/or complex II deficiencies) has been shown to have some benefit in certain cases (Udhayabanu et al. 2017. PubMed ID: 28475111).  

Pathogenic variants in over 250 genes, both nuclear and mitochondrial, have been described; however, more than 1000 genes encoding mitochondrial proteins have been documented, and more of these are likely involved in disease than have been reported to date (Chinnery. 2014. PubMed ID: 20301403; Craven et al. 2017. PubMed ID: 28415858). While the majority of reported genes encode for structural or assembly components of the mitochondrial respiratory complexes, causative variants in a number of genes involved in mitochondrial replication, transcription, or translation may also result in primary OXPHOS disorders, in addition to genes that function in cofactor biosynthesis or ubiquinone (coenzyme Q10) synthesis (Ghezzi and Zeviani. 2018. PubMed ID: 30030362). In addition, secondary OXPHOS dysfunction may result from defects in genes involved in fatty acid oxidation such as HADHA/HADHB or ECHS1, among others (Nsiah-Sefaa and McKenzie. 2016. PubMed ID: 26839416).

This panel covers genes encoded by nuclear DNA (>240) that have been previously associated with oxidative phosphorylation deficiency. Genes located in the mitochondrial genome are currently not included in this panel.

Disorders of oxidative phosphorylation may be inherited in an autosomal recessive, autosomal dominant, X-linked, or maternally-inherited manner, although the majority of genes located in the nuclear genome exhibit autosomal recessive inheritance. Known or suspected modes of inheritance for the genes in this panel are listed below.

Autosomal recessive: AARS2, ACAD9, ACAT1, ACO2, AFG3L2, AGK, APTX, ATP5F1A, ATP5F1D, ATP5F1E, ATP7B, ATPAF2, BCS1L, BOLA3, C12orf65, C1QBP, CA5A, CARS2, CHKB, CLPB, COA3, COA5, COA6, COA7, COA8/APOPT1, COQ2, COQ4, COQ5, COQ6, COQ7, COQ8A, COQ8B, COQ9, COX4I1, COX10, COX14, COX15, COX20, COX5A, COX6A1, COX6B1, COX8A, CYC1, DARS2, DGUOK, DLAT, DLD, DNA2, DNAJC19, DNM1L, EARS2, ECHS1, ELAC2, ETFA, ETFB, ETFDH, ETHE1, FARS2, FASTKD2, FBXL4, FDX2, FDXR, FH, FLAD1, FOXRED1, GATB, GATC, GFER, GFM1, GFM2, GLRX5, GTPBP3, HADHA, HADHB, HARS2, HIBCH, HLCS, HMGCL, HMGCS2, HSPD1, HTRA2, IARS1/IARS, IARS2, IBA57, ISCA1, ISCA2, ISCU, KARS1, LARS2, LIAS, LIPT1, LONP1, LRPPRC, LYRM4, LYRM7, MARS2, MDH2. MECR, MFF, MGME1, MICOS13, MIPEP, MPC1, MPV17, MRM2, MRPL12, MRPL3, MRPL44, MRPS14, MRPS16, MRPS2, MRPS22, MRPS23, MRPS34, MRPS7, MTFMT, MTO1, MTPAP, NADK2, NARS2, NAXE, NDUFA10, NDUFA11, NDUFA12, NDUFA13, NDUFA2, NDUFA4, NDUFA9, NDUFAF1, NDUFAF2, NDUFAF3, NDUFAF4, NDUFAF5, NDUFAF6, NDUFAF8, NDUFB10, NDUFB3, NDUFB8, NDUFB9, NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS6, NDUFS7, NDUFS8, NDUFV1, NDUFV2, NFS1, NFU1, NSUN3, NUBPL, OPA1, OPA3, OXA1L, PARS2, PC, PCCA, PCCB, PDHB, PDHX, PDP1, PDSS1, PDSS2, PET100, PET117, PMPCB, PNPLA8, PNPT1, POLG, POLG2, PPA2, PTCD3, PUS1, QRSL1, RARS1, RARS2, RMND1, RNASEH1, RRM2B, RTN4IP1, SARS2, SCO1, SCO2, SDHA, SDHAF1, SDHD, SERAC1, SFXN4, SLC19A2, SLC19A3, SLC22A5, SLC25A1, SLC25A13, SLC25A19, SLC25A20, SLC25A26, SLC25A3, SLC25A38, SLC25A42, SLC25A46, SPG7, SUCLA2, SUCLG1, SURF1, TACO1, TARS2, TFAM, TIMM22, TIMM50, TIMMDC1, TK2, TMEM126B, TMEM65, TMEM70, TPK1, TRIT1, TRMT10C, TRMT5, TRNT1, TSFM, TTC19, TUFM, TWNK, TYMP, UQCC2, UQCC3, UQCRB, UQCRC2, UQCRQ, VARS2, WARS2, XPNPEP3, YARS2

Autosomal dominant: COQ2, DNM1L, GARS1/GARS, HSPD1, MFN2, POLG, POLG2, SDHA, SDHB, SDHD, SLC25A4, SPG7, TWNK

X-linked: ABCB7, AIFM1, ALAS2, COX7B, HSD17B10, NDUFA1, NDUFB11, PDHA1, PNPLA4, TAFAZZIN, TIMM8A

For the majority of genes on this panel, large copy number variants (gross deletions or duplications/insertions) are a rare cause of disease. Exceptions to this may include OPA1, ATP7B, PCCA, PDHA1, SPG7, and TAFAZZIN.

See individual gene summaries for more information about molecular biology of gene products and spectra of pathogenic variants. 

As no large cohort has been described to date that has been tested for this subset of genes, clinical sensitivity is difficult to estimate.

In terms of isolated complex deficiencies, a few studies have been reported. Approximately 25% of complex I (CI)-deficient patients were found to harbor defects in nuclear-encoded genes, while another ~25% carry a pathogenic variant in a mitochondrial-encoded gene (Fassone and Rahman. 2012. PubMed ID: 22972949). In patients with a molecular diagnosis of complex I deficiency, ~60% have defects in genes that encode core subunits of CI, while the remaining ~40% have defects in genes that encode accessory subunits.

Isolated complex II deficiency is considered a rare form of mitochondrial disease, accounting for approximately 2-23% of all respiratory chain deficiencies (biochemical diagnosis only; Parfait et al. 2000. PubMed ID: 10746566; Vladutiu and Heffner. 2000. PubMed ID: 11100052).

Isolated complex III deficiency accounted for approximately 5% of all oxidative phosphorylation (OXPHOS) disorders in one cohort (biochemical diagnosis only; Skladal et al. 2003. PubMed ID: 14601919).

Clinical sensitivity is expected to be higher in individuals of certain ancestries due to founder effects. For example, in a group of patients with French-Canadian Leigh syndrome (LS) and complex IV deficiency, 56/56 (100%) harbored pathogenic variants in LRPPRC; with one exception, all patients were homozygous for the p.Ala354Val change (Debray et al. 2011. PubMed ID: 21266382). In a different cohort of complex IV-deficient patients, 47 (~26%) carried causative variants in SURF1, primarily due to the Slavic founder variant (p.Ser282Cysfs*9; Bohm et al. 2006. PubMed ID: 16326995).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.2% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Of note, Next Generation Sequencing analysis of the SDHA gene is technically challenging due to the presence of segmental duplications and paralogy. Therefore, analysis of CNVs in this region is not included in this test.

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).