Relationship between fibrillin-1 genotype and severity of cardiovascular involvement in Marfan syndrome

Abstract

backgroundThe effect of FBN1 mutation type on the severity of cardiovascular manifestations in patients with Marfan syndrome (MFS) has been reported with disparity results. Objectives This study aims to determine the impact of the FBN1 mutation type on aortic diameters, aortic dilation rates and on cardiovascular events (ie, aortic dissection and cardiovascular mortality). Methods MFS patients with a pathogenic FBN1 mutation followed at two specialised units were included. FBN1 mutations were classified as being dominant negative (DN; incorporation of non-mutated and mutated fibrillin-1 in the extracellular matrix) or having haploinsufficiency (HI; only incorporation of nonmutated fibrillin-1, thus a decreased amount of fibrillin-1 protein). Aortic diameters and the aortic dilation rate at the level of the aortic root, ascending aorta, arch, descending thoracic aorta and abdominal aorta by echocardiography and clinical endpoints comprising dissection and death were compared between HI and DN patients. results Two hundred and ninety patients with MFS were included: 113 (39%) with an HI-FBN1 mutation and 177 (61%) with a DN-FBN1. At baseline, patients with HI-FBN1 had a larger aortic root diameter than patients with DN-FBN1 (HI: 39.3±7.2 mm vs DN: 37.3±6.8 mm, p=0.022), with no differences in age or body surface area. After a mean follow-up of 4.9±2.0 years, aortic root and ascending dilation rates were increased in patients with HI-FBN1 (HI: 0.57±0.8 vs DN: 0.28±0.5 mm/year, p=0.004 and HI: 0.59±0.9 vs DN: 0.30±0.7 mm/year, p=0.032, respectively). Furthermore, patients with HI-FBN1 tended to be at increased risk for the combined endpoint of dissection and death compared with patients with DN-FBN1 (HR: 3.3, 95% CI 1.0 to 11.4, p=0.060). conclusions Patients with an HI mutation had a more severely affected aortic phenotype, with larger aortic root diameters and a more rapid dilation rate, and tended to have an increased risk of death and dissections compared with patients with a DN mutation.

Marfan Syndrome, A Review

“…Grouping patients based on effect of the FBN1 mutations on the protein resulted in improved genotype-phenotype correlation 38,39,40,41 , with a striking effect on the response to medication 42 , as discussed below. One group was defined as "haploinsufficiency" (HN), with reduced production of normal fibrillin 1 due to deletion of the gene or null allele caused by nonsense mediated decay.…”

“…However, I noticed in discussions with patients that they often consider the ocular symptoms, severe myopia and lens luxation, the worst for themselves, because the latter may lead to blindness. Journal of Biomedicine and Translational Research 02 (2018) [33][34][35][36][37][38][39][40] It is important to realize that the obvious skeletal features are not always present. Within families we often see carriers of the same pathogenic mutation, that have very different phenotypes 3,4,5 .…”

Communicating with our patients for shared decision making

“…3 In addition, we still have large knowledge gaps in individual risk assessment, despite recent insights into genotype–phenotype correlations 4. They also remind us that undertaking earlier surgery, even in a patient who want to ‘get it over with’ entails risks that might not be appreciated by the patient.…”

Genotype–phenotype correlations in Marfan syndrome

“…These gaps in knowledge pose important limitations in clinical decision making with respect to timing of elective surgery, frequency of imaging follow-up, physical activity restriction and drug management. In their  Heart  paper, Franken et al have undertaken the important task of investigating whether the specific subtype of FBN1 mutation could be used to predict the risk of TAA severity 1. The current study examined 290 patients with MFS and known FBN1 mutations followed at two specialist units, including Universitat Autonoma de Barcelona in Spain, and the Academic Medical Centre of Amsterdam, The Netherlands.…”