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

Summary 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. However, the association of mtDNA mutations with MFS has been unclear. Here, we used targeted mtDNA sequencing to detect whole blood mtDNA mutations from 48 healthy controls and 77 MFS patients, including 7 mother-offspring pedigrees. 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 were more abundant in MFS patients compared to the control group. The mutation rate of the coding region, MT-rRNA and MT-tRNA were higher in the MFS group. These data demonstrate frequent mitochondrial mutation in MFS and suggest that the mtDNA mutation might be a potential modifier of MFS phenotypes.