MITOCHONDRIAL DISEASE

Mitochondrial Disease — affecting 1 in 5,000 people, caused by variants in either the mitochondrial or nuclear genome, where whole genome sequencing is the only test that evaluates both genomes simultaneously.

Whole genome sequencing reads the complete mitochondrial genome (37 genes) and all 300+ nuclear genes encoding mitochondrial proteins — resolving the dual-genome diagnostic challenge that makes mitochondrial disease one of the most difficult molecular diagnoses in medicine.

MT-TL1
MT-TK
POLG
SURF1

About this condition

Mitochondrial Disease

Mitochondrial diseases are a heterogeneous group of disorders caused by impaired oxidative phosphorylation (OXPHOS) — the mitochondrial energy-producing pathway that generates approximately 90% of cellular ATP. These disorders are genetically unique because mitochondrial function depends on two genomes: the mitochondrial genome (mtDNA, 37 genes encoding 13 OXPHOS subunits, 22 tRNAs, and 2 rRNAs) and the nuclear genome (encoding ~1,500 mitochondrial-targeted proteins including OXPHOS assembly factors, mtDNA maintenance enzymes, and metabolic enzymes). Combined prevalence is approximately 1 in 5,000 — making mitochondrial disease among the most common inherited metabolic conditions.

Clinical presentation reflects tissue energy demands: organs with high metabolic rates are preferentially affected. Common features include progressive external ophthalmoplegia (CPEO), ptosis, myopathy, cardiomyopathy, sensorineural hearing loss, diabetes mellitus, seizures, stroke-like episodes, ataxia, peripheral neuropathy, retinal degeneration, and lactic acidosis. Well-defined mitochondrial syndromes include MELAS (mitochondrial encephalopathy, lactic acidosis, stroke-like episodes — typically m.3243A>G in MT-TL1), MERRF (myoclonic epilepsy with ragged-red fibers — m.8344A>G in MT-TK), Kearns-Sayre syndrome (CPEO, pigmentary retinopathy, cardiac conduction defects — large mtDNA deletions), and Leigh syndrome (progressive brainstem and basal ganglia neurodegeneration — multiple genetic causes).

The genetic complexity of mitochondrial disease creates unique diagnostic challenges. mtDNA variants follow maternal inheritance with variable heteroplasmy (the proportion of mutant vs. wild-type mtDNA in each tissue, which determines clinical severity). Nuclear gene variants follow standard Mendelian inheritance. The same clinical syndrome can be caused by either mtDNA or nuclear variants (e.g., Leigh syndrome has >90 genetic causes). Sequential testing of mtDNA alone, then nuclear panels, delays diagnosis by months to years. WGS evaluates both genomes simultaneously — the only clinically available test that does so.

mtDNA heteroplasmy — the proportion of mutant vs. wild-type mitochondrial genomes — determines clinical severity. WGS quantifies heteroplasmy levels, providing the prognostic information that targeted mtDNA testing may miss at low heteroplasmy levels.

Gene locus: MT-TL1 (m.3243A>G for MELAS), MT-TK (m.8344A>G for MERRF), POLG (15q26.1), SURF1 (9q34.2), plus 300+ additional genes

Mitochondrial disease is caused by variants in two separate genomes. Testing one genome at a time delays diagnosis by months. WGS evaluates both mtDNA and nuclear DNA simultaneously — the only test that does.

Dual-genome evaluation in a single test — WGS reads both mtDNA and all 300+ nuclear mitochondrial genes simultaneously

Traditional mitochondrial disease workup involves sequential testing: mtDNA sequencing first, then (when negative) nuclear gene panels, then (when still negative) whole exome sequencing of nuclear DNA. Each step takes weeks to months, and many patients endure years of diagnostic odyssey. WGS evaluates the complete mitochondrial genome (including heteroplasmy quantification) and all nuclear-encoded mitochondrial genes in a single test from a single blood sample. This parallel evaluation identifies both mtDNA and nuclear variants simultaneously, eliminating the sequential testing delays.

Large mtDNA deletions cause Kearns-Sayre syndrome and CPEO — these are missed by mtDNA point mutation panels

Single large-scale mtDNA deletions (typically 4,977 bp 'common deletion' or other unique deletions ranging from 1-10 kb) cause Kearns-Sayre syndrome, chronic progressive external ophthalmoplegia, and Pearson syndrome. Standard mtDNA point mutation panels (which test specific nucleotide positions) do not detect these deletions — they require Southern blot, long-range PCR, or whole mitochondrial genome sequencing. WGS reads across the entire mitochondrial genome, detecting both point variants and structural rearrangements including deletions, duplications, and rearrangements.

Mitochondrial Disease — affecting 1 in 5,000 people, caused by variants in either the mitochondrial or nuclear genome, where whole genome sequencing is the only test that evaluates both genomes simultaneously.

Mitochondrial Disease

Mitochondrial disease is caused by variants in two separate genomes. Testing one genome at a time delays diagnosis by months. WGS evaluates both mtDNA and nuclear DNA simultaneously — the only test that does.

Dual-genome evaluation in a single test — WGS reads both mtDNA and all 300+ nuclear mitochondrial genes simultaneously

Large mtDNA deletions cause Kearns-Sayre syndrome and CPEO — these are missed by mtDNA point mutation panels

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