Affiliations: Department of Pediatrics, Division of Medical Genetics, Stanford University School of Medicine, Stanford, CA, USA | Public Hospital Network of Paris, Hospital Ambroise Paré, Pediatric Service, Boulogne, France | Clinical Genetics Unit, Rennes Sud University Hospital, UMR 6290 CNRS, Rennes University, Rennes, France | Division of Cardiac and Vascular Sciences, St George's University of London, London, UK | Department of Pediatrics, Division of Cardiology, Stanford University School of Medicine, Stanford, CA, USA
Note: [] Corresponding author: Jonathan A. Bernstein, MD, 300 Pasteur Dr. H-315, Stanford, CA 94305, USA, Tel.: +1 650 498 4937; Fax: +1 650 498 4555; E-mail: [email protected]
Abstract: The recurrent substitution of isoleucine for threonine at codon 1048 (I1048T) substitution has been linked to severe, early onset Marfan syndrome, however, the existence of strong genotype-phenotype associations in Marfan syndrome (MFS) is not widely agreed upon. Our aim is to substantiate the association between the I1048T substitution and a severe clinical presentation to facilitate care planning and genetic counseling. We review the clinical findings from seven cases of early-onset MFS with a recurrent I1048T substitution. The presented findings include those from one newly diagnosed case, significant new detail from three additional cases, and a review of published findings in three cases. All seven individuals with the I1048T substitution had mitral insufficiency, arachnodactyly and characteristic facies consistent with early-onset MFS. Our findings support the existence of a genotype-phenotype correlation between the I1048T substitution and early-onset MFS. Recognition of this relationship has implications for genetic counseling and clinical care. Additionally, exploration of how the I1048T substitution results in a severe phenotype may lead to further insight into the pathophysiology of MFS.
Keywords: FBN1, genotype-phenotype correlation, Marfan syndrome, severe early onset