Increased frequency of FBN1 frameshift and nonsense mutations in Marfan syndrome patients with aortic dissection

Abstract

Background: Marfan syndrome (MFS) is an inherited connective tissue disease that mainly involves Fibrillin-1 (FBN1) mutations and aortic manifestations. In this study, we investigated the correlations between the FBN1 genotype-phenotype and aortic events (aortic dissection and aortic aneurysm) in patients with Marfan syndrome. Methods: Genotype and phenotype information was evaluated in 180 patients with MFS. DNA sequencing was performed on each patient. According to the clinical manifestation, these patients were split into two groups: the aortic dissection group and the aortic aneurysm group. Aortic wall tissue was obtained from Marfan patients who underwent surgery and was used for staining. Results: A total of 180 patients with FBN1 mutations were grouped into four categories: 90 with missense mutations, 32 with splicing mutations, 29 with frameshift mutations, and 29 with nonsense mutations. There was a significantly higher frequency of frameshift and nonsense mutations observed in aortic dissection than in aortic aneurysm (25.58% vs. 4.35%, p = .005; 25.58% vs. 8.70%, p = .033, respectively;), while missense mutations showed a higher frequency in aortic aneurysm than in aortic dissection (69.57% vs. 32.56%, respectively; p < .001) and a higher rate of lens dislocation (34.78% vs. 13.95%, respectively; p = .008). Pathological staining showed that elastic fibers were sparser in patients with a frameshift and nonsense mutations, and the smooth muscle cells were sparser and more disorganized than those observed in patients with missense mutations. Conclusion: This study showed that FBN1 gene frameshift and nonsense mutations are more common in patients with aortic dissection and may have meaningful guidance for the treatment of Marfan syndrome patients. K E Y W O R D Saortic aneurysm, aortic dissection, FBN1, Marfan syndrome

Genotype–Phenotype Correlation in Children: The Impact of FBN1 Variants on Pediatric Marfan Care

“…Other studies confirmed this distribution of variants. Missense variants substituting or creating a cysteine in one of the cbEGF domains (calcium-binding EGF) are the most common [24][25][26][27]. Overall, the distribution of pathogenic variants identified in our cohort is consistent with previous data [28][29][30].…”

“…In addition, in HI patients, treatment with losartan appeared to be more efficient [40]. Moreover, Xu et al and Li et al showed a higher rate of aortic dissection in this patient group [22,26]. The causes of these results could be obscured in childhood, as aortic dissection is rare in the young.…”

Genotype FBN1/phenotype relationship in a cohort of patients with Marfan syndrome

“…Similarly, Franken et al (2016) confirmed the worst prognosis in HI patients with 2.4‐fold greater risk for the combined endpoint of aortic dissection and cardiovascular death than DN patients 8 . In a study by Xu et al (2020), frameshift mutations and nonsense mutations were more common in patients with aortic dissection, whereas missense mutations were more common in patients with aortic aneurysm 35 . Supporting this, the pathological study of aortic wall tissue showed that elastic fibers were sparser and more disorganized in patients with frameshift and nonsense mutations than than in peers with missense variants.…”

A novel intron mutation in FBN-1 gene identified in a pregnant woman with Marfan syndrome

“…The mutation spectrum is composed of nonsense, missense, frameshift, and exon deletion, etc. [ 3 ] Among them, about 90% of MFS patients’ mutation sequence information limited to the coding region and specific splice sites. However, about 10% of patients still cannot identify the genetic cause of the disease [ 1 ].…”