Novel Frameshift, Nonsense and Splice Site Mutations in the Complement Factor H Gene in Patients With Age-Related Maculopathy

Abstract

Purpose: : The present study was conducted to identify novel complement factor H (CFH) mutations in patients with age-related maculopathy and to describe the associated retinal phenotypes.

Methods: : All subjects were derived from EUGENDA, a multicenter database for clinical and molecular analysis of age-related macular degeneration (AMD). In brief, ophthalmic examinations, non-stereoscopic 30° color fundus photography, and fluorescein angiography were performed. In addition, patients were interviewed with a questionnaire. Venous blood samples were drawn for genomic DNA extraction from peripheral blood leukocytes. The CFH gene was analyzed by direct sequencing.

Results: : In four patients we identified novel heterozygous mutations in the CFH gene: p.Ile184fsX, p.Lys204fsX, p. Trp436X, and c.1697-17_-8del. In addition, the patients carried the AMD risk allele p.Tyr402His in heterozygous or homozygous state. The patients had drusen and and/or pigment epithelial detachment (PED) in the macular area. One patient had the basal laminar drusen (BLD) phenotype and reported an end stage membranoproliferative glomerulonephritis type II (MPGN II) in his medical history.

Conclusions: : Our findings confirm that AMD and the BLD phenotype belong to a spectrum of diseases associated with either monogenic or multifactorial inheritance of variants and mutations of the CFH gene. These insights may provide us with tools for risk estimation in the near future by genetic screening.

Keywords: age-related macular degeneration • mutations