Effect of mutation type and location on clinical outcome in 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study

Abstract

Mutations in the fibrillin-1 (FBN1) gene cause Marfan syndrome (MFS) and have been associated with a wide range of overlapping phenotypes. Clinical care is complicated by variable age at onset and the wide range of severity of aortic features. The factors that modulate phenotypical severity, both among and within families, remain to be determined. The availability of international FBN1 mutation Universal Mutation Database (UMD-FBN1) has allowed us to perform the largest collaborative study ever reported, to investigate the correlation between the FBN1 genotype and the nature and severity of the clinical phenotype. A range of qualitative and quantitative clinical parameters (skeletal, cardiovascular, ophthalmologic, skin, pulmonary, and dural) was compared for different classes of mutation (types and locations) in 1,013 probands with a pathogenic FBN1 mutation. A higher probability of ectopia lentis was found for patients with a missense mutation substituting or producing a cysteine, when compared with other missense mutations. Patients with an FBN1 premature termination codon had a more severe skeletal and skin phenotype than did patients with an inframe mutation. Mutations in exons 24-32 were associated with a more severe and complete phenotype, including younger age at diagnosis of type I fibrillinopathy and higher probability of developing ectopia lentis, ascending aortic dilatation, aortic surgery, mitral valve abnormalities, scoliosis, and shorter survival; the majority of these results were replicated even when cases of neonatal MFS were excluded. These correlations, found between different mutation types and clinical manifestations, might be explained by different underlying genetic mechanisms (dominant negative versus haploinsufficiency) and by consideration of the two main physiological functions of fibrillin-1 (structural versus mediator of TGF beta signalling). Exon 24-32 mutations define a high-risk group for cardiac manifestations associated with severe prognosis at all ages.

Figure 1.

Types of FBN1 mutations included in the study. Of 1,013, 573 (56%) could be classified as missense mutations, 170 (17%) as frameshift mutations, 137 (14%) as nonsense mutations, 110 (11%) as splicing mutations, and 23 (2%) as inframe deletions or insertions.

Figure 2.

Kaplan-Meier analyses for the probability of ectopia lentis diagnoses for patients with different types of mutations. A, Probability of ectopia lentis in PTC versus inframe mutations. The cumulative probability of diagnosis of ectopia lentis before or at age 25 years was 23% (99.9% CI 15%–32%) for patients with PTC mutations (thin line) compared with 50% (99.9% CI 43%–57%) for patients with inframe mutations (thick line) (log-rank test P<.0001). B, Probability of ectopia lentis for patients with missense mutation involving a cysteine versus other missense mutations. The cumulative probability of diagnosis of ectopia lentis before or at age 25 years was 59% (99.9% CI 50%–68%) for patients with missense mutations involving a cysteine (thin line) compared with 32% (99.9% CI 22%–44%) for patients with other missense mutations (thick line) (log-rank test P<.0001).

Figure 3.

Frequency of skeletal, skin, pulmonary, and dural phenotypes in study participants with PTC mutations (gray bars), compared with those with inframe mutations (black bars). An asterisk (*) indicates that differences between groups were statistically significant (MH test P<.001).

Figure 4.

Kaplan-Meier analyses for the probability of MFS clinical-features diagnosis for patients with different locations of mutations. A, Age at diagnosis of type I fibrillinopathy with a mutation in exons 24–32 versus in other exons. Fifty percent of patients with a mutation in exons 24–32 (thin line) received a diagnosis at age 9 years (IQR 1–24 years) versus age 24 years (IQR 12–35 years) of patients with a mutation in other exons (thick line) (log-rank test P<.0001). B, Survival of patients with mutations in exons 24–32 versus in other exons. Seventy-six percent of patients with mutations within exons 24–32 (thin line) were alive at age 40 years (99.9%CI 61%–87% years) compared with 98% (99.9% CI 93%–99%) of patients with mutations located in other exons (thick line) (log-rank test P<.0001). C, Probability of diagnosing a dilatation of the ascending aorta for patients with mutations in exons 24–32 versus in other exons. The cumulative probability of diagnosis of ascending aortic dilatation before or at age 40 years was 87% (99.9% CI 77%–95%) for patients with mutations in exons 24–32 (thin line) compared with 72% (99.9% CI 67%–78%) for patients with mutations in other exons (thick line) (log-rank test P<.0001). D, Probability of aortic surgery for patients with mutations in exons 24–32 versus in other exons. The cumulative probability of aortic surgery before or at age 40 years was 55% (99.9% CI 35%–77%) for patients with mutations in exons 24–32 (thin line) compared with 38% (99.9% CI 30%–48%) for patients with mutations in other exons (thick line) (log-rank test P<.0001). E, Probability of ectopia lentis for patients with mutations in exons 24–32 versus in other exons. The cumulative probability of ectopia lentis diagnosis before or at age 25 years was 53% (99.9% CI 39%–67%) for patients with mutations in exons 24–32 (thin line) compared with 38% (99.9% CI 33%–44%) for patients with mutations in other exons (thick line) (log-rank test P=.0003). F, Probability of scoliosis for patients with mutations in exons 24–32 versus in other exons. The cumulative probability of scoliosis diagnosis before or at age 25 years was 61% (99.9% CI 47%–75%) for patients with mutations in exons 24–32 (thin line) compared with 44% (99.9% CI 38%–51%) for patients with mutations in other exons (thick line) (log-rank test P<.0001).