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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
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Publication History

17 October 2014

01 November 2014

Publication Date:
27 July 2015 (online)

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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