Juvenile Bilateral Lens Dislocation, Corneal Guttatae, and Glaucoma Associated With a Novel Mutation in the FBN1 Gene

Abstract

Abstract: : Purpose: To describe the clinical and ocular findings in multiple members of a family with early–onset and bilateral lens dislocation, corneal guttatae, and open angle glaucoma. To identify the genetic etiology of this syndrome. Methods: All family members underwent physical and ophthalmic examinations. After informed consent was obtained, DNA was extracted from blood samples from eleven family members, eight of whom were affected. A series of polymorphic markers flanking the fibrillin locus were genotyped and results analyzed using the SIMLINK program. PCR amplification of the 65 exons and exon–intron boundaries of the FBN1 gene was performed followed by conformation sensitive gel electrophoresis (CSGE). All fragments with sequence variations were then sequenced. Results: Pedigree analysis revealed a three–generation family with eight of eleven individuals affected by early–onset lens dislocation, high myopia, typical facies, frontal bossing, flexion contractures, PIP joint thickening, corneal guttatae, and glaucoma. Genetic linkage using flanking and intragenic markers for fibrillin 1 demonstrated a peak LOD score of 2.41 out of a maximum possible LOD score of 2.67. Conformation Sequence Gel Electrophoresis (CSGE) analysis suggested a sequence variation in exon 3. Sequencing revealed a C to G substitution changing a serine to cysteine at cDNA position c.311 in all affecteds and none of the unaffecteds. Conclusions: This syndrome is consistent with a novel mutation in the fibrillin 1 locus and appears to represent a variant of Marfan’s syndrome. The early–onset of complete lens dislocation and progressive corneal guttatae is unusual for Marfan’s syndrome. This study demonstrates a possible link between guttatae and fibrillin disorders.

Keywords: genetics • gene mapping • candidate gene analysis