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Published on: August 15, 2019
Genotype impacts survival in Marfan syndrome
Romy Franken1,2, Maarten Groenink1,2,3, Vivian de Waard4
1Department of Cardiology, Academic Medical Center Amsterdam, B2-240, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands.
Aims:
The aorta in Marfan syndrome (MFS) patients is variably affected. We investigated the assumed genotype-effect on protein production as a risk factor for a severe aortic phenotype in adult MFS patients.
Methods And Results:
We collected clinical and genetic data from all 570 adults with MFS who had been included in the Dutch CONgenital CORvitia registry since the start in 2001. Mean age was 36.5 ± 13.5 years (51.2% male, 28.9% prior aortic surgery, 8.2% prior aortic dissection). Patients were prospectively followed for a mean duration of 8.2 ± 3.1 years. Men had more frequently aortic surgery at baseline (38.0 vs. 19.4%, P < 0.001) and during follow-up (24.0 vs. 15.1%, P = 0.008) compared with women. After 10-year follow-up cumulative survival was 93.8% and dissection-free survival was 84.2%. We found a pathogenic FBN1 mutation in 357 patients, of whom 146 patients (40.9%) were positive for a mutation causing haploinsufficiency (reduced fibrillin-1 protein) and 211 (59.1%) for a mutation leading to a DN effect (abnormal fibrillin-1 protein). Corrected for age, sex, and previous aortic complications, patients with a haploinsufficient (HI) mutation had a 2.5-fold increased risk for cardiovascular death (hazard ratio, HR: 2.5, 95% CI: 1.0-6.1, P = 0.049), a 2.4-fold increased risk for the combined endpoint comprising death and dissection (HR: 2.4, 95% CI: 1.4-4.2, P < 0.001) and a 1.6-fold increased risk for any aortic complication compared with patients with a DN mutation (HR: 1.6, 95% CI 1.1-2.3, P = 0.014).
Conclusion:
Marfan syndrome patients with an HI mutation are at increased risk for cardiovascular death and aortic dissection compared with patients with a DN mutation.
Insights
Marfan syndrome patients with haploinsufficiency (HI) mutations face a higher risk of cardiovascular death and aortic dissection. This contrasts with patients carrying dominant-negative (DN) mutations, highlighting genotype-specific aortic risks.
Area of Science:
- Cardiovascular Genetics
- Marfan Syndrome Research
- Aortic Disease
Background:
- Marfan syndrome (MFS) is a genetic disorder affecting the aorta.
- The relationship between specific FBN1 mutations and aortic disease severity in MFS is not fully understood.
- Genotype-effect on fibrillin-1 protein production may influence aortic phenotype.
Purpose of the Study:
- To investigate the genotype-effect on protein production as a risk factor for severe aortic phenotype in adult MFS patients.
- To compare cardiovascular outcomes between MFS patients with haploinsufficiency (HI) mutations and dominant-negative (DN) mutations.
- To analyze clinical and genetic data from a large MFS cohort.
Main Methods:
- Clinical and genetic data from 570 adult MFS patients were collected from the Dutch CONgenital CORvitia registry.
- Patients were followed prospectively for a mean of 8.2 years.
- FBN1 mutations were classified as causing haploinsufficiency (HI) or dominant-negative (DN) effects; outcomes were compared using hazard ratios, corrected for age, sex, and prior aortic complications.
Main Results:
- Men had higher rates of aortic surgery than women.
- After 10-year follow-up, cumulative survival was 93.8% and dissection-free survival was 84.2%.
- MFS patients with HI mutations showed a 2.5-fold increased risk of cardiovascular death and a 2.4-fold increased risk for death/dissection compared to those with DN mutations.
Conclusions:
- Marfan syndrome patients with HI mutations have a significantly increased risk for cardiovascular death and aortic dissection.
- The type of FBN1 mutation (HI vs. DN) is a critical determinant of aortic complication risk in MFS.
- Genotype-specific risk stratification is crucial for managing MFS patients.
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