Application of Whole Genome Sequencing to screen Mitochondrial Disorders

Application of Whole Genome Sequencing to Screen Mitochondrial Disorders

Mitochondrial disorders are a clinically and genetically heterogeneous group of conditions caused by dysfunction of the mitochondria — the energy-producing organelles found in virtually every cell of the body. Because mitochondria are essential for energy production, mitochondrial disorders can affect almost any organ system, with the brain, muscles, heart, liver, and kidneys being most commonly affected.

What Are Mitochondrial Disorders?

Mitochondrial disorders can be caused by mutations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) genes that encode mitochondrial proteins. Key features include:

• Multi-system involvement — affecting organs with high energy demands (brain, heart, skeletal muscle)

• Variable clinical presentation — ranging from mild exercise intolerance to severe, life-threatening disease

• Complex inheritance patterns — mtDNA mutations are maternally inherited; nDNA mutations follow Mendelian inheritance patterns

• Heteroplasmy — a mix of normal and mutated mtDNA within cells, which influences disease severity

Common Mitochondrial Disorders

• MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes)

• MERRF (Myoclonic Epilepsy with Ragged Red Fibres)

• Leigh syndrome (subacute necrotising encephalomyelopathy)

• LHON (Leber’s Hereditary Optic Neuropathy)

• Kearns-Sayre syndrome

The Role of Whole Genome Sequencing (WGS)

Whole Genome Sequencing (WGS) simultaneously sequences both the nuclear genome and the mitochondrial genome, making it a powerful tool for diagnosing mitochondrial disorders. WGS can detect point mutations, deletions, duplications, and heteroplasmy in mtDNA, as well as mutations in the hundreds of nuclear genes that encode mitochondrial proteins. WGS has a significantly higher diagnostic yield than traditional targeted testing approaches for mitochondrial disorders.