Abstract 1790: Relation Between Genotype and Left-Ventricular Dilatation in Patients With Marfan Syndrome
BACKGROUND: Cardiovascular manifestations in Marfan syndrome (MFS) are related to aortic and valvular abnormalities. However, left ventricular (LV) dysfunction can occur, even in the absence of aortic surgery or valvular abnormalities. We evaluated genetic characteristics of patients fulfilling the MFS clinical criteria with LV dilatation without previous aortic surgery or valvular abnormalities.
METHODS: 182 MFS patients without valvular abnormalities or previous aortic surgery, with a complete fibrillin 1 (FBN1) gene analysis, were studied. The mutations were subdivided by type, localization and predicted effect on protein. In patients without a FBN1 mutation, the genes encoding transforming growth factor-beta receptor I and II (TGFBR1, TGFBR2) were studied.
RESULTS: FBN1 mutations were identified in 83% of patients. Twenty-nine patients (16%) demonstrated LV dilatation (left ventricular end diastolic diameter corrected for age and body surface area >112%). FBN1-positive patients carrying a mutation most likely leading to haploinsufficiency, more often had LV dilatation than missense-mutation carriers (14/75 versus 5/75; p<0.05). It was mainly patients carrying large deletions/null-alleles or frameshift mutations who contributed to this effect. Finally, FBN1-negative MFS patients significantly more often demonstrated LV dilatation than FBN1-positive patients (10/31 versus 19/151; p<0.05). Because only one TGFBR2 variant was identified in FBN1-negative MFS patients, we could exclude this as an important causative factor for LV dilatation in this subgroup.
Conclusion: LV dilatation in MFS patients is more often seen in those patients with a mutation most likely leading to haploinsufficiency (in particular large deletions/null-alleles or frameshift mutations) compared to missense-mutation carriers and to those without an FBN1 mutation. Therefore, clinicians should be aware of the possibility of LV dilatation developing in these patients even in the absence of predisposing factors like valvular pathology.