Study Reveals Importance of Genetic Findings in Marfan Diagnosis and Management


A study published this week in the Orphanet Journal of Rare Diseases confirmed the importance of genetic findings in the diagnosis of Marfan syndrome.

A study published this week in the Orphanet Journal of Rare Diseases confirmed the importance of genetic findings in the diagnosis of Marfan syndrome, as well as the risk stratification and clinical management of patients with it.

The study enrolled 90 patients with Fibrillin-1 (FBN-1) gene mutations matching 58 non-interrelated families. Of the 57 FBN-1 variants found, 25 (43.9%) had previously been described, 23 of which had been identified and associated with Marfan syndrome.

There is no single test that can identify Marfan syndrome, and clinicians currently use a set of guidelines called “Ghent” criteria to assist in the diagnosis. A clinician experienced with connective tissue disorders can often recognize the condition via: detailed medical and family history, a complete physical examination, echocardiogram, electrocardiogram, eye exam, and a CT or MRI of the lower back.

Symptoms among patients with Marfan syndrome vary, but common presentations include long limbs and digits, a curved spine, flexible joints, and crowded teeth. Current standard of care focuses on preventing complications, and without proper treatment, the condition can lead to heart and respiratory problems and difficulties pertaining to vision.

The objective of the study, conducted by Victor Manuel Becerra-Munoz of the Unidad de Gestion Clinica cel Corazon and colleagues was to summarize the different FBN-1 variants and establish a genotype-phenotype correlation in a broad population of patients with Marfan syndrome, with a focus on the onset of aortic events. All patients had a transthoracic echocardiogram at each visit, and once blood samples for genetic analysis had been taken, they were studied in a single reference laboratory, using a massive parallel sequencing library that included 30 genes associated with aneurysm and aortic dissection, of which FBN-1 is one. If the variants met the criteria for causal FBN-1 mutations in accordance with modified Ghent criteria, they were classified as pathogenic. If findings showed a pathogenic genetic variant, first degree relatives began a cascade screening to inspect for the same FBN-1 variant found in the index case.

For 84 of the 90 patients enrolled (93.3%) with FBN-1 variants, it was possible to give a definite diagnosis of Marfan syndrome in accordance with modified Ghent criteria.

“As in classic studies of MFS, the clinical heterogeneity of our patients is worthy of note: we found cases ranging from mild forms with aortic diameters that were normal or only slightly larger than normal, to forms with a higher phenotypical expression with or without aortic events,” the researchers noted in the publication of their data.

While phenotypes varied greatly between patients, those with confirmed Marfan syndrome and truncating variants presented a higher proportion of aortic events. This means that genetic findings could potentially have significance in risk stratification and in the clinical management in suspected patients with Marfan syndrome.

“The finding of one or other type of variant has prognostic implications and should guide clinical management,” the researchers stated. “Some individuals could also benefit from closer follow-up, recommendations for an appropriate lifestyle, and a more vigorous medical treatment that helps reduce the progression of this disorder towards potentially fatal aortic events.”

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