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Diagnostic utility of exome sequencing in patients with suspected mitochondrial disease: A Single-center Experience 

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical Genetics
  • Secondary Categories:
    • Clinical Genetics
Introduction:
Mitochondrial diseases (MD) are a heterogeneous group of rare disorders, characterized by an impairment of mitochondrial structure or function, particularly involving the respiratory chain (RC) enzyme complexes. Diseases caused by mutations in the 13 mtDNA genes are maternally inherited. However, pathogenic mutations in more than 400 protein-encoding nuclear DNA (nDNA) genes have been associated with MD and display a range of inheritance patterns, including autosomal dominant, autosomal recessive, and X-linked inheritance. This study aims to evaluate the utility of whole-exome sequencing (WES) in diagnosing suspected MD. Given the high phenotypic and genetic heterogeneity of MD, traditional diagnostic approaches often remain inconclusive.

 

Methods:
A cohort of 246 patients, selected based on the Mitochondrial Disease Criteria Scale, was assessed at a single center in South Korea. Diagnostic analysis included screening for mtDNA variants and a targeted next-generation sequencing (NGS) panel for nDNA, covering mitochondrial single-nucleotide variants, indels, and structural variants. WES was conducted, employing trio exome sequencing to analyze the DNA of both patient and parents.

 

Results:
Pathogenic mtDNA variants were identified in 96 patients, achieving a diagnostic yield of 39%. After nuclear DNA analysis using a mitochondrial DNA panel in the remaining 150 suspected mitochondrial disorder patients the diagnosis rate of the cases was increased to 44.5% (110/246). Fourteen cases were diagnosed in twelve genes previously shown to cause OXPHPS disease: ADCK3, COX20, FASTKD2, FBXL4, HSD17B10, IARS2, MPV17, NDUFAF6, NDUFS2, PDHA1, SLC19A3 and, SURF1 in non-consanguineous families. Additionally, copy-number variants classified as likely pathogenic were detected in 10 patients. Applying WES to the 39 remaining undiagnosed cases further increased the diagnostic yield to 64.6%, including novel disease-associated variants not previously identified as primary MD causes.

 

Conclusion:
WES has demonstrated substantial diagnostic utility in cases of suspected MD that were not resolved with traditional mtDNA and nDNA testing. By increasing the diagnostic yield to 64.6%, WES provides critical insights for phenotypically and genetically diverse MD cases, underscoring its value as a complementary diagnostic tool for more comprehensive patient care. This study highlights the importance of WES in advancing diagnostic precision and clinical outcomes for patients with suspected MD.

 

Agenda

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