J Pediatr Genet 2014; 03(03): 157-162
DOI: 10.3233/PGE-14095
Georg Thieme Verlag KG Stuttgart – New York

A recurrent fibrillin-1 mutation in severe early onset Marfan syndrome

Dimple Sureka
a  Department of Pediatrics, Division of Medical Genetics, Stanford University School of Medicine, Stanford, CA, USA
,
Chantal Stheneur
b  Public Hospital Network of Paris, Hospital Ambroise Paré, Pediatric Service, Boulogne, France
,
Sylvie Odent
c  Clinical Genetics Unit, Rennes Sud University Hospital, UMR 6290 CNRS, Rennes University, Rennes, France
,
Gavin Arno
d  Division of Cardiac and Vascular Sciences, St George's University of London, London, UK
,
Daniel Murphy
e  Department of Pediatrics, Division of Cardiology, Stanford University School of Medicine, Stanford, CA, USA
,
Jonathan A. Bernstein
a  Department of Pediatrics, Division of Medical Genetics, Stanford University School of Medicine, Stanford, CA, USA
› Author Affiliations

Subject Editor:
Further Information

Publication History

17 October 2014

01 November 2014

Publication Date:
27 July 2015 (online)

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.