Study on the FBN1 gene mutation spectrum and association between genotype and clinical phenotype in 300 Marfan syndrome patients and their relatives

Objective To investigate the correlations between the FBN1 gene mutation types and the clinical phenotype. Methods 87 probands with Marfan or Marfan-like syndromes and their family members were enrolled in this study(total 300 cases). The clinical manifestations of each patients involving the ocular, cardiovascular system, skeletal system and other implicated systems were collected and evaluated. According to the clinical manifestations, these patients were divided into two groups, namely aortic dissection group and aortic root aneurysm group. Blood samples were taken from patients and DNA sequencing was performed on each patient by the genetic aortic disease gene Panel. The detected single nucleotide variants(SNVs)/indel were interpreted according to the ACMG guidelines, and the pathogenic variation was confirmed through Sanger sequencing. The aortic wall tissue was obtained from MFS patients who underwent surgery. The correlations between genotypes and clinical phenotypes were further explored by comparing the aortic wall tissue histological specimens of each genotype patient. Results A total of 92 FBN1 mutations(31%) were detected in 300 people with Marfan syndromes or Marfan-like syndromes, 18 of which were undiscovered mutations. There were 49 missense mutations(53.26%), 13 splicing mutations(14.13%), 17 frameshift mutations(18.48%), and 13 nonsense mutations(14.13%). In this cohort, 24 cases had aortic dissection and 25 cases were aortic root aneurysm. Statistical analysis revealed that patients with aortic dissection mostly appeared in frameshift mutations(29.17% vs. 4.00%, P=0.017). However, patients with aortic root aneurysm mostly appeared in missense mutations(72.00% vs. 37.50%, P=0.015), and accompanied with ectopia lentis(41.67% vs. 8.33%, P=0.008). Pathological specimens staining found that elastic fibers in the aortic wall of patients with frameshift mutations are sparser, and the smooth muscle cells are more deficient and more disorganized than patients with missense mutations. Conclusion FBN1 gene frameshift mutations result a lack of elastic fibers and disorganized smooth muscle cells in aortic wall and are presented more in patients with aortic dissection than aortic root aneurysm. Key words: Aortic dissection; Aortic root aneurysm; Fibrillin-1; Marfan syndrome