Phenotypic Characterization of Complement Factor H R1210C Rare Genetic Variant in Age-Related Macular Degeneration

Abstract

IMPORTANCE The complement factor H R1210C rare variant confers the strongest genetic risk for age-related macular degeneration and earlier age at onset; however, its associated phenotype has not been well characterized. OBJECTIVE To describe specific fundus features of a white population with the R1210C rare variant. DESIGN, SETTING, AND PARTICIPANTS Fundus features specific for diagnosis and disease staging were retrospectively characterized by systematic review of all available fundus images for each patient, including color photography, fluorescein angiography, fundus autofluorescence, and optical coherence tomography, at a tertiary ophthalmologic referral center. For this retrospective observational study conducted from 2012 to 2014, enrolled patients with the variant and their family members without the variant were identified from the Age-Related Macular Degeneration Study for a family-based study arm. For patients with the variant but without a family member enrolled in the study, age-matched comparison individuals without the variant were selected randomly from the database. MAIN OUTCOMES AND MEASURES The presence of drusen in the macula (macular drusen score) and estimated number (total macular drusen score) were assessed. The presence of drusen in the extramacular regions (extramacular drusen score), pigmentary abnormalities, and disease staging were also evaluated. Binary logistic regression models were used to evaluate the association between rare variant status and ocular phenotypes. RESULTS Images from a total of 143 patients (283 eyes), including 62 patients with the rare variant, were analyzed. Drusen score covariates were associated with the R1210C rare variant. A larger proportion of patients carrying the variant had the highest level of macular and total macular drusen scores compared with those without the variant (57.9% vs 16.7% and 52.9% vs 14.2%, respectively; P for trend < .001 for both scores). Patients carrying the rare variant had a much greater likelihood of having advanced disease (odds ratio, 7.0; 95% CI, 3.1-16.2; P < .001). A higher prevalence of geographic atrophy was observed among patients carrying the variant (odds ratio, 13.7; 95% CI, 5.0-37.7; P < .001). CONCLUSIONS AND RELEVANCE The typical phenotype of the complement factor H R1210C rare variant is associated with extensive drusen accumulation in the macula and throughout the fundus, as well as with a high risk for having advanced disease. Better characterization of genetic profiles in age-related macular degeneration may be important for screening and future therapeutic strategies for this vision-threatening condition.

Mapping rare, deleterious mutations in Factor H: Association with early onset, drusen burden and lower antigenic levels in familial AMD

“…In addition to these variants being associated with more advanced AMD within these families, carriers also had earlier age of onset of advanced disease (mean age = 59.2) compared to individuals with advanced AMD without rare CFH variants (mean age at diagnosis in our AMD database = 69.6, n = 1,627)26. We also explored disease symmetry, and among affected individuals carrying a rare CFH variant in these families, 75% (n = 9 of 12 carriers) exhibited a symmetric fundus phenotype.…”

Differentiating drusen: Drusen and drusen-like appearances associated with ageing, age-related macular degeneration, inherited eye disease and other pathological processes

“…R1210C is also associated with atypical hemolytic uremic syndrome (OMIM 134371). The drusen phenotype associated with the R1210C risk allele has recently been described (Ferrara and Seddon, 2015). The authors identified widespread soft drusen, both at the macular and outside the arcades, an unusual combination as such drusen are rarely observed in the peripheral retina.…”

Genetics and genetic testing for age-related macular degeneration

“…Carriers of rare variants appear to have differing phenotypes compared with non-carriers. A number of studies have shown rare variants to be associated with earlier onset of advanced AMD [48,58,59,62,63]. Carriers of rare CFH variants have increased drusen load, are more likely to have extramacular drusen, drusen nasal to the optic disc, and crystalline or calcified drusen [62,63,64].…”

“…A number of studies have shown rare variants to be associated with earlier onset of advanced AMD [48,58,59,62,63]. Carriers of rare CFH variants have increased drusen load, are more likely to have extramacular drusen, drusen nasal to the optic disc, and crystalline or calcified drusen [62,63,64]. In addition, rare variants in CFH, CFI, C9, and C3 have been more frequently observed in patients with GA than those with nvAMD [58,63].…”