Mitochondrial DNA mutations as a potential modifier for the clinical variability of Marfan syndrome.

BACKGROUND

Marfan syndrome (MFS) is an autosomal genetic disease caused by FBN1 mutation. Patients with the same FBN1 mutation type exhibit different phenotypes, which indicates additional risk factors. Mitochondrial dysfunction was observed in the aorta of both MFS patients and Marfan murine models. Single-nucleotide variants in mitochondrial DNA (mtDNA) may have harmful consequences on a cell.

AIM: This study investigates the association between mtDNA mutations and MFS.

DESIGN

We analyzed mtDNA mutations in 48 healthy controls and 77 MFS patients, including seven mother-offspring pedigrees.

METHODS

Targeted sequencing of mitochondrial DNA was performed on whole blood samples from both healthy controls and MFS patients. Detected variants were validated using Sanger sequencing. Subsequently, variants were annotated, and conservation analysis and protein structural predictions were conducted.

RESULTS

Three rare mtDNA mutations, m.279T > C, m.2361G > A and m.3316G > A, were identified in a family whose predominant phenotype was eye lesions. The MFS patients with these mutations had more severe symptoms than family members without the mutation. m.9738G > A was identified in a family whose dominant phenotype was aortic manifestation. A sporadic case with this rare mutation site has an aortic aneurysm. We also described the mutation frequency and mutation rate in MFS. The frequency of all solid variants, nonsynonymous variants, pathogenic or likely pathogenic variants and variants of uncertain significance was more abundant in MFS patients compared to the control group. The mutation rate of the coding region, MT-rRNA and MT-tRNA was higher in the MFS group.

CONCLUSION

These data demonstrate frequent mitochondrial mutation in MFS and suggest that the mtDNA mutation might be a potential modifier of MFS phenotypes.