Next-generation sequencing for mitochondrial diseases: a wide diagnostic spectrum

Area of Science:

• Genetics
• Molecular Biology
• Medical Diagnostics

Background:

• Mitochondrial disorders are challenging to diagnose, often requiring invasive procedures with inconclusive results.
• Current genetic testing is limited to a small subset of known genes.
• Massively parallel sequencing presents a promising tool for investigating genetically diverse mitochondrial disorders.

Purpose of the Study:

• To evaluate the utility of targeted next-generation sequencing for diagnosing mitochondrial disorders.
• To identify genetic variants in nuclear genes associated with respiratory chain complex activities.
• To assess the diagnostic yield of sequencing nuclear genes in patients with suspected mitochondrial disorders.

Main Methods:

• Targeted next-generation sequencing was applied to 26 patients with suspected mitochondrial disorders.
• In-solution capture was used for exons of 908 nuclear genes (known and candidate).
• Illumina genome analyzer was employed for sequencing.

Main Results:

• No molecular defects in respiratory chain complex (RCC) subunits or assembly factors were found in 18 patients with abnormal RCC activities (excluding one control).
• Pathogenic variants were identified in known genes like CPT2, POLG, PDSS1, UBE3A, and SDHD.
• Potentially pathogenic variants were found in candidate genes, including MTO1 and SCL7A13.

Conclusions:

• Sequencing only nuclear genes for RCC may not be sufficient for diagnosing all suspected mitochondrial disorders.
• The genetic basis of mitochondrial disorders is more diverse than anticipated, highlighting risks of misdiagnosis.
• Targeted next-generation sequencing demonstrates significant clinical benefits and serves as a model for evaluating this heterogeneous patient group.