Mitochondrial DNA mutations in Marfan Syndrome with aortic complications

Background and aims: Marfan syndrome (MFS) is an autosomal genetic disease caused by FBN1 mutation. Patients with the same FBN1 mutation type exhibit different phenotypes, which indicates extra risk factors. The primary risk factor for death in MFS patients is cardiovascular complications, including aortic root enlargement, aortic aneurysm and aortic dissection. Mitochondrial dysfunction was observed in the aortas of both MFS patients and marfan murine models. Single nucleotide variants (SNVs) in mitochondrial DNA (mtDNA) may cause mitochondrial dysfunction. However, the association of mtDNA mutations with MFS and its cardiovascular complications has been unclear.

Methods: Blood samples (48 healthy controls and 77 MFS patients, including 7 mother-offspring pedigrees) were obtained from the Beijing Anzhen Hospital, with informed consent. The identification of SNVs in the mitochondrial genome was through alignment to the GRCh38.p14 reference genome. Mutants were identified by VarScan2. Targeted mtDNA sequencing was used to detect single nucleotide variants in mtDNA.

Results: We found that, in the MFS group, 64.93% of patients enrolled have aortic manifestations, including width, dissection, and aneurysm. m.9738G>A was identified in a family whose dominant phenotype was aortic manifestations. The proband of pedigree Ⅱ is a 5-year-old boy with a maternally inherited FBN1 mutation (Exon2; p.R5C) and dilatation of the aorta (z-score = +5.63), whose mother has type A dissection. A mtDNA mutation m.9738G > A (VAF = 0.9993, AF in Mitomap = 0.0012) in the MT-CO3 gene was inherited from the Ⅰ-2 mother to the proband. The same variant was detected in a sporadic case, a 47-year-old woman with an FBN1 mutation who had an aneurysm (z-score = +9.19).

Conclusions: These data demonstrate frequent and specific mitochondrial mutational pattern in MFS patients with cardiovascular complications. The mtDNA mutation might be a potential modifier and diagnostics of MFS phenotypes, especially MFS patients with cardiovascular complications.