The Importance of a FBN1 Mutation Database for Screening Relatives in Marfan Syndrome and Ectopia Lentis

Abstract

Purpose:: Mutations in the FBN1 gene have been characterised at the molecular level in patients affected with Marfan syndrome and Marfan-related disorders. The identification of a mutation allows for timely preventive management of mutation carriers and reassurance for unaffected family members. Molecular diagnosis is especially useful for early diagnosis when the clinical signs are not yet evident.

Methods:: We analysed a consecutive series of 508 patients, of which 22 were children less than 5 years old. Starting with genomic DNA extracted from peripheral blood, we analysed all 65 exons of the FBN1 gene using PCR, SSCP and/or dHPLC analysis, and automatic sequencing of abnormal bands/peaks.

Results:: A total of 189 mutations were observed in this study, with 127 of them not previously reported. A total of 324 relatives (of which 49 were infants) of 119 probands for whom a mutation had been identified here or at another facility, were tested for the presence of that particular mutation. In addition, 3 prenatal tests have been carried out.Mutations in the ectopia lentis group appeared to display a distinctive distribution: 45.4% of these mutations are confined within the first 15 exons of the gene, while only 11.7% of mutations carried by patients with mainly cardiac manifestations are found in the same cluster. Moreover, there appears to be a significant prevalence of missense mutations inserting an extra-cysteine in the ectopia lentis group. Our results are comparable with those reported by other groups.

Conclusions:: Mutations in patients whose main health problem is ectopia lentis tend to be mild and cluster in the first 15 exons. Because of the occasional occurrence of late-onset aortic aneurysm in members of ectopia lentis families, echocardiograms every 5 years throughout life are recommended. Prenatal and postnatal screening in Marfan syndrome are very straightforward, underlining the importance of knowing in advance the location of the putative mutation.

Keywords: gene screening • mutations • genetics