Looking for the Missing Links
Challenges in the Search for Genotype–Phenotype Correlation in Marfan Syndrome
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See Article by Takeda, Inuzuka, and Maemura et al
Since the middle of the past century, identification of the causal gene for monogenic disorders has undoubtedly led to improvement in diagnostics and knowledge of the pathophysiological mechanisms underlying these disorders. Yet an explanation for the often extensive variability in the clinical expression of diseases caused by variants in the same gene often remains elusive, and this is no less the case for Marfan syndrome (MFS). MFS is an autosomal dominant inherited connective tissue disorder, caused by pathogenic variants in the fibrillin 1 gene (FBN1). This gene encodes the extracellular matrix protein, fibrillin1, which plays an essential structural role in the assembly of the microfibrils, as well as a functional role in the regulation of growth factors, such as transforming growth factor β and bone morphogenetic protein.1
MFS is a pleiotropic disease affecting predominantly the ocular, skeletal, and cardiovascular systems. Survival of patients with MFS is mainly determined by the degree of cardiovascular involvement. Progressive enlargement of the aortic root at the level of the sinuses of Valsalva in particular accounts for excess mortality because it may lead to life-threatening aortic dissection or rupture. Whereas the prognosis for people with MFS was initially bleak, mainly because of aortic complications, this has improved significantly for the past decades.2 This positive trend is not only because of optimization of medical and surgical treatment but also related to increased awareness and better diagnostics. Other cardiovascular features, present in a variable amount of patients, include mitral valve prolapse and myocardial dysfunction.3,4
To date, treatment of cardiovascular manifestations in patients with MFS is fairly uniform, with guidelines for medical treatment and (prophylactic) surgery based on simple parameters, such as age, body surface, and aortic diameters. Nevertheless, we know that not everyone …