Genetic basis of mitochondrial diseases

Area of Science:

• Genetics
• Molecular Biology
• Biochemistry

Background:

• Mitochondrial disorders are monogenic diseases affecting oxidative phosphorylation, caused by variants in over 340 genes.
• Whole-exome sequencing has advanced diagnosis and identified more disease genes, yet a significant portion of cases remain genetically unresolved.

Purpose of the Study:

• To review the current understanding of the genetic basis of mitochondrial diseases.
• To discuss existing challenges and future directions in diagnosing these disorders.
• To explore genetic factors beyond protein-coding regions and Mendelian inheritance.

Main Methods:

• Literature review of genetic studies in mitochondrial disorders.
• Analysis of diagnostic yield from whole-exome sequencing.
• Discussion of emerging OMICS technologies and variant interpretation strategies.

Main Results:

• Whole-exome sequencing has significantly improved diagnostic rates but limitations persist.
• A substantial fraction of mitochondrial disorders lack a known genetic cause, suggesting novel genetic mechanisms.
• Pathogenic variants may exist outside protein-coding regions, and non-Mendelian inheritance patterns are relevant.

Conclusions:

• Despite advances, the genetic diagnosis of mitochondrial disorders requires improved computational and sequencing methods.
• Expanding the scope to non-coding regions and complex inheritance patterns is essential for a comprehensive understanding.
• Future research should integrate diverse OMICS data to unravel the full genetic landscape of mitochondrial diseases.