Ectopia lentis phenotypes and the FBN1 gene

Mutations of the fibrillin-1 (FBN1) gene on chromosome 15 have been described in patients with classical Marfan syndrome (MFS), neonatal MFS, the "MASS" phenotype, autosomal dominant ascending aortic aneurysms, autosomal dominant ectopia lentis (EL), Marfanoid skeletal features Milewicz et al., 1995: J Clin Invest 95:2373-2378, familial arachnodactyly, Shprintzen-Goldberg syndrome Hayward et al., 1994: Mol Cell Probes 8:325-327; Furthmayr and Francke, 1997: Semin Thorac Cardiovasc Surg 9:191-205, and severe progressive kyphoscoliosis Adès et al., 2002: Am J Med Genet 109:261-270. We report the use of denaturing high performance liquid chromatography (DHPLC) to facilitate the characterization of a previously elusive FBN1 mutation in the large autosomal dominant EL kindred described by Edwards et al. 1994: Am J Med Genet 53:65-71. This isolated EL kindred remains the largest for which detailed clinical data is available. Nine years on, we present an update of the clinical status of the family. We report a recurrent FBN1 mutation, R240C, in the kindred. This mutation has been reported three times before, once in a family with classic MFS Loeys et al., 2001: Arch Intern Med 161:2447-2454, once in one member of a multi-generation EL kindred, Körkkö et al., 2002: J Med Genet 39:34-41, and once in an adult from a familial EL kindred who had EL, and involvement of the integument, without cardiovascular involvement Comeglio et al., 2002: Br J Ophthalmol 86:1359-1362. This is the second report of the R240C mutation in association with isolated EL, and supports the existing evidence that the R240C mutation can result in two quite distinct, yet related, phenotypes. It also raises the possibility that R240C may prove to be a relative mutational "hot-spot" for isolated EL. We review the current literature regarding EL (isolated and other) and FBN1 mutations.