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C. J. Boon, B. J. Klevering, C. B. Hoyng, M. N. Zonneveld-Vrieling, S. B. Nabuurs, E. Blokland, F. P. M. Cremers, A. I. den Hollander; Basal Laminar Drusen Caused by Compound Heterozygous Variants in the CFH Gene. Invest. Ophthalmol. Vis. Sci. 2008;49(13):466. doi: https://doi.org/.
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To analyze the CFH gene and assess the retinal and functional abnormalities in 30 unrelated patients with basal laminar drusen.
Thirty probands were diagnosed with an early-onset drusen phenotype resembling basal laminar drusen, based on ophthalmoscopic and fluorescein angiographic findings. In addition to an extensive ophthalmologic examination, blood samples were obtained for analysis of the coding regions of the CFH gene. The effect of amino acid variants in CFH were evaluated by molecular modelling.
We identified the CFH Tyr402His variant in 50% of CFH alleles of the patients with basal laminar drusen. This variant was previously found to be strongly associated with age-related macular degeneration (AMD). In seven patients from two drusen families, we identified a heterozygous CFH Gln408X nonsense mutation in combination with the Tyr402His AMD risk allele (Fig. 1: pedigrees A and B). Three individuals with drusen from a third family carried a heterozygous Arg1078Ser variant on one allele, and the Tyr402His variant on the other allele (Fig. 1: family C). A homology model of the Arg1078Ser variant indicated that this change may interfere with the different interactions in which CFH participates. Two other heterozygous CFH variants were identified in two unrelated patients carrying the Tyr402His risk allele, that may interfere with normal CFH function. Patients with these CFH variants show confluent macular drusen and many small drusen in the (mid-)peripheral retina, that may show an evolution towards extensive chorioretinal atrophy.
These findings strongly suggest that autosomal recessive inheritance of severe and mild CFH variants can result in basal laminar drusen in young adults, which may progress to age-related maculopathy and severe vision loss later in life. As the mild variant (Tyr402His) has a high prevalence, families often will show a pseudodominant inheritance.
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