A Long-Term Retrospective Natural History Study of EFEMP1-Associated Autosomal Dominant Drusen.

Purpose: To analyze the natural history of EFEMP1-associated autosomal dominant drusen (ADD). Methods: In this retrospective observational study of molecularly confirmed patients with ADD, data and retinal imaging were extracted from an in-house database. The main outcome measurements were best-corrected visual acuity (BCVA), refraction, and retinal imaging, including quantitative analyses of the outer nuclear layer (ONL) thickness and pigmented epithelium detachment area, as well as qualitative analyses. Results: The study included 44 patients (34 females and 10 males). The mean ± SD age of symptom onset was 40.1 ± 6.59 years of age (range, 25-52). Fourteen patients were asymptomatic during their entire follow-up. The most common symptoms at presentation were reduced vision (70%) and distortion in central vision (53%). Most subjects were emmetropic. The mean BCVA (logMAR) at baseline was 0.27 ± 0.41 (range, -0.1 to 2.1) in right eyes and was 0.19 ± 0.32 (range, -0.2 to 1.3) in left eyes. After a mean follow-up of 7.9 years, BCVA was reduced to 0.59 ± 0.66 (range, -0.1 to 2.1) in right eyes and 0.5 ± 0.72 (range, -0.1 to 2.4) in left eyes, values that were significantly different than baseline (P < 0.0001 and P < 0.0014, respectively). Fifteen eyes showed active or inactive choroidal neovascularization (CNV). BCVA differed significantly (P = 0.0004) between eyes with and without CNV at a comparable mean age. The ONL had a slow rate of thinning longitudinally, which significantly correlated with BCVA. Conclusions: Despite the late onset and relatively good prognosis of ADD, CNVs are more frequent than previously reported and are associated with a worse prognosis. Further research is necessary to elucidate gender associations.

Age-Related Macular Degeneration and Extramacular Drusen: Genetic Associations in the Coimbra Eye Study.

Purpose: To explore the association between the genetics of age-related macular degeneration (AMD) and extramacular drusen (EMD) in patients with and without AMD. Methods: We included 1753 eyes (912 subjects) with phenotypic characterization regarding AMD and EMD. Genetic sequencing and the genetic risk score (GRS) for AMD were performed according to the EYE-RISK consortium methodology. To test for differences in the GRS from EMD cases, AMD cases, and controls, a clustered Wilcoxon rank-sum test was used. The association of AMD, EMD, and the GRS was evaluated using logistic regression models adjusted for age and sex. Individual associations of common risk variants for AMD with EMD were explored. Results: EMD were found in 755 eyes: 252 (14.4%) with AMD and 503 (28.7%) without. In total, 122 eyes (7.0%) had only AMD, and 876 (50.0%) were controls. EMD were strongly associated with AMD (odds ratio [OR], 3.333; 95% confidence interval [CI], 2.356-4.623; P < 0.001). The GRS was associated with an increased risk of AMD (OR, 1.416; 95% CI, 1.218-1.646; P < 0.001) but not with EMD. Individually, the common risk variants ARMS2 rs10490924 (P = 0.042), C3 rs2230199 (P = 0.042), and CETP rs5817082 (P = 0.042) were associated with EMD, after adjustment for AMD, sex, and age. Conclusions: We found a strong association between EMD and AMD, suggesting a common pathogenesis. The GRS for AMD was not associated with EMD, but a partially overlapping genetic basis was suggested when assessing individual risk variants. We propose that EMD per se do not represent an increase in the global genetic risk for AMD.

CFH Haploinsufficiency and Complement Alterations in Early-Onset Macular Degeneration.

Purpose: Complement dysregulation is a key component in the pathogenesis of age-related macular degeneration (AMD) and related diseases such as early-onset macular drusen (EOMD). Although genetic variants of complement factor H (CFH) are associated with AMD risk, the impact of CFH and factor H-like protein 1 (FHL-1) expression on local complement activity in human retinal pigment epithelium (RPE) remains unclear. Methods: We identified a novel CFH variant in a family with EOMD and generated patient induced pluripotent stem cell (iPSC)-derived RPE cells. We assessed CFH and FHL-1 co-factor activity through C3b breakdown assays and measured complement activation by immunostaining for membrane attack complex (MAC) formation. Expression of CFH, FHL-1, local alternative pathway (AP) components, and regulators of complement activation (RCA) in EOMD RPE cells was determined by quantitative PCR, western blot, and immunostaining. Isogenic EOMD (cEOMD) RPE was generated using CRISPR/Cas9 gene editing. Results: The CFH variant (c.351-2A>G) resulted in loss of CFH and FHL-1 expression and significantly reduced CFH and FHL-1 protein expression (∼50%) in EOMD iPSC RPE cells. These cells exhibited increased MAC deposition upon exposure to normal human serum. Under inflammatory or oxidative stress conditions, CFH and FHL-1 expression in EOMD RPE cells paralleled that of controls, whereas RCA expression, including MAC formation inhibitors, was elevated. CRISPR/Cas9 correction restored CFH/FHL-1 expression and mitigated alternative pathway complement activity in cEOMD RPE cells. Conclusions: Identification of a novel CFH variant in patients with EOMD resulting in reduced CFH and FHL-1 and increased local complement activity in EOMD iPSC RPE supports the involvement of CFH haploinsufficiency in EOMD pathogenesis.

Prevalence and determinants of subretinal drusenoid deposits in patients' first-degree relatives.

PURPOSE: Subretinal drusenoid deposits (SDDs) are distinct extracellular alteration anterior to the retinal pigment epithelium (RPE). Given their commonly uniform phenotype, a hereditary predisposition seems likely. Hence, we aim to investigate prevalence and determinants in patients' first-degree relatives. METHODS: We recruited SDD outpatients at their visits to our clinic and invited their relatives. We performed a full ophthalmic examination including spectral domain-optical coherence tomography (SD-OCT) and graded presence, disease stage of SDD as well as percentage of infrared (IR) en face area affected by SDD. Moreover, we performed genetic sequencing and calculated a polygenic risk score (PRS) for AMD. We conducted multivariable regression models to assess potential determinants of SDD and associations of SDD with PRS. RESULTS: We included 195 participants, 123 patients (mean age 81.4 ± 7.2 years) and 72 relatives (mean age 52.2 ± 14.2 years), of which 7 presented SDD, resulting in a prevalence of 9.7%. We found older age to be associated with SDD presence and area in the total cohort and a borderline association of higher body mass index (BMI) with SDD presence in the relatives. Individuals with SDD tended to have a higher PRS, which, however, was not statistically significant in the multivariable regression. CONCLUSION: Our study indicates a potential hereditary aspect of SDD and confirms the strong association with age. Based on our results, relatives of SDD patients ought to be closely monitored for retinal alterations, particularly at an older age. Further longitudinal studies with larger sample size and older relatives are needed to confirm or refute our findings.

Reticular Pseudodrusen Status, ARMS2/HTRA1 Genotype, and Geographic Atrophy Enlargement: Age-Related Eye Disease Study 2 Report 32.

PURPOSE: To determine whether reticular pseudodrusen (RPD) status, ARMS2/HTRA1 genotype, or both are associated with altered geographic atrophy (GA) enlargement rate and to analyze potential mediation of genetic effects by RPD status. DESIGN: Post hoc analysis of an Age-Related Eye Disease Study 2 cohort. PARTICIPANTS: Eyes with GA: n = 771 from 563 participants. METHODS: Geographic atrophy area was measured from fundus photographs at annual visits. Reticular pseudodrusen presence was graded from fundus autofluorescence images. Mixed-model regression of square root of GA area was performed by RPD status, ARMS2 genotype, or both. MAIN OUTCOME MEASURES: Change in square root of GA area. RESULTS: Geographic atrophy enlargement was significantly faster in eyes with RPD (P < 0.0001): 0.379 mm/year (95% confidence interval [CI], 0.329-0.430 mm/year) versus 0.273 mm/year (95% CI, 0.256-0.289 mm/year). Enlargement was also significantly faster in individuals carrying ARMS2 risk alleles (P < 0.0001): 0.224 mm/year (95% CI, 0.198-0.250 mm/year), 0.287 mm/year (95% CI, 0.263-0.310 mm/year), and 0.307 mm/year (95% CI, 0.273-0.341 mm/year) for 0, 1, and 2, respectively. In mediation analysis, the direct effect of ARMS2 genotype was 0.074 mm/year (95% CI, 0.009-0.139 mm/year), whereas the indirect effect of ARMS2 genotype via RPD status was 0.002 mm/year (95% CI, -0.006 to 0.009 mm/year). In eyes with incident GA, RPD presence was not associated with an altered likelihood of central involvement (P = 0.29) or multifocality (P = 0.16) at incidence. In eyes with incident noncentral GA, RPD presence was associated with faster GA progression to the central macula (P = 0.009): 157 µm/year (95% CI, 126-188 µm/year) versus 111 µm/year (95% CI, 97-125 µm/year). Similar findings were observed in the Age-Related Eye Disease Study. CONCLUSIONS: Geographic atrophy enlargement is faster in eyes with RPD and in individuals carrying ARMS2/HTRA1 risk alleles. However, RPD status does not mediate the association between ARMS2/HTRA1 genotype and faster enlargement. Reticular pseudodrusen presence and ARMS2/HTRA1 genotype are relatively independent risk factors, operating by distinct mechanisms. Reticular pseudodrusen presence does not predict central involvement or multifocality at GA incidence but is associated with faster progression toward the central macula. Reticular pseudodrusen status should be considered for improved predictions of enlargement rate. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Early onset drusen and RPE dysfunction in a patient with NLRP3-AID.

Retinal pigment epithelium (RPE) dysfunction, manifested as drusen formation and RPE mottling, is a characteristic lesion of aging. The mechanism of RPE dysfunction remains unknown. Previous animal studies have proven that the activation of NLRP3 inflammasome in RPE leads to apoptosis and pyroptosis, which may play a very important role in the development of age-related macular degeneration (AMD). However, there is a lack of clinical evidence to support the above hypothesis. Herein, we report a 38-year-old Chinese Han woman who had NLRP3-associated autoinflammatory disease (NLRP3-AID) with widely scattered drusen at the posterior pole in both eyes. NLRP3-AID is a rare disease caused by mutations of the NLRP3 gene, leading to NLRP3 inflammasome activation. This report of early-onset drusen provides clinical evidence that the NLRP3 inflammasome might contribute to the occurrence of RPE dysfunction and is a potential cause of age-related macular degeneration (AMD).

Characteristics of intermediate age-related macular degeneration with hyperreflective foci.

Hyperreflective foci (HRF) are the findings observed in optical coherence tomography (OCT) in several retinal diseases and are believed to be associated with the increased risk of atrophy in eyes with age-related macular degeneration (AMD). In this study, we investigated the clinical and genetic characteristics of intermediate AMD with HRF. We reviewed the medical charts for 155 patients with intermediate AMD, in whom macular neovascularization (MNV) was observed in the contralateral eye. The presence or absence of an HRF was evaluated using a spectral-domain OCT volume scan spanning the macular region. Patients were followed longitudinally for at least 12 months, and the maximum follow-up period was 60 months. Genotyping of ARMS2 A69S and CFH I62V was performed in all participants. Of the 155 patients (mean age: 77.8 ± 7.6 years, male/female: 103/52), HRF was observed in 53 eyes (34.2%) and was significantly associated with type-3 MNV (p = 1.0 × 10-5) in the contralateral eye, pseudodrusen (p = 5.0 × 10-4), thinner subfoveal choroidal thickness (p = 0.013), and risk of ARMS2 A69S (p = 0.023). During follow-up (40.8 ± 17.5), 38 eyes (24.5%) developed advanced AMD. The mean time to the onset of advanced AMD was 29.8 ± 12.9 months in eyes with intermediate AMD. HRF was associated with MNV (p = 1.0 × 10-3), but not with atrophy.

Genomewide Association Study of Retinal Traits in the Amish Reveals Loci Influencing Drusen Development and Link to Age-Related Macular Degeneration.

Purpose: The purpose of this study was to identify genetic risk loci for retinal traits, including drusen, in an Amish study population and compare these risk loci to known risk loci of age-related macular degeneration (AMD). Methods: Participants were recruited from Amish communities in Ohio, Indiana, and Pennsylvania. Each participant underwent a basic health history, ophthalmologic examination, and genotyping. A genomewide association analysis (GWAS) was conducted for the presence and quantity of each of three retinal traits: geographic atrophy, drusen area, and drusen volume. The findings were compared to results from a prior large GWAS of predominantly European-ancestry individuals. Further, a genetic risk score for AMD was used to predict the presence and quantity of the retinal traits. Results: After quality control, 1074 participants were included in analyses. Six single nucleotide polymorphisms (SNPs) met criteria for genomewide significance and 48 were suggestively associated across three retinal traits. The significant SNPs were not highly correlated with known risk SNPs for AMD. A genetic risk score for AMD provided significant predictive value of the retinal traits. Conclusions: We identified potential novel genetic risk loci for AMD in a midwestern Amish study population. Additionally, we determined that there is a clear link between the genetic risk of AMD and drusen. Further study, including longitudinal data collection, may improve our ability to define this connection and improve understanding of the biological risk factors underlying drusen development.

The Phenotypic Course of Age-Related Macular Degeneration for ARMS2/HTRA1: The EYE-RISK Consortium.

PURPOSE: Age-related maculopathy susceptibility 2 (ARMS2) is considered the most enigmatic of the genes for age-related macular degeneration (AMD). We investigated the phenotypic course and spectrum of AMD for the risk haplotype at the ARMS2 and high-temperature requirement A serine peptidase 1 (HTRA1) locus in a large European consortium. DESIGN: Pooled analysis of 4 case-control and 6 cohort studies. PARTICIPANTS: Individuals (N = 17 204) aged 55 years or older participating in the European Eye Epidemiology consortium. METHODS: Age-related macular degeneration features and macular thickness were determined on multimodal images; data on genetics and phenotype were harmonized. Risks of AMD features for rs3750486 genotypes at the ARMS2/HTRA1 locus were determined by logistic regression and were compared with a genetic risk score (GRS) of 19 variants at the complement pathway. Lifetime risks were estimated with Kaplan-Meier analyses in population-based cohorts. MAIN OUTCOME MEASURES: Age-related macular degeneration features and stage. RESULTS: Of 2068 individuals with late AMD, 64.7% carried the ARMS2/HTRA1 risk allele. For homozygous carriers, the odds ratio (OR) of geographic atrophy was 8.6 (95% confidence interval [CI], 6.5-11.4), of choroidal neovascularization (CNV) was 11.2 (95% CI, 9.4-13.3), and of mixed late AMD was 12.2 (95% CI, 7.3-20.6). Cumulative lifetime risk of late AMD ranged from 4.4% for carriers of the nonrisk genotype to 9.4% and 26.8% for heterozygous and homozygous carriers. The latter received the diagnosis of late AMD 9.6 years (95% CI, 8.0-11.2) earlier than carriers of the nonrisk genotype. The risk haplotype was not associated with hard or soft drusen < 125 µm (OR, 1.2; 95% CI, 0.9-1.7), but risks increased significantly for soft drusen ≥ 125 µm (OR, 2.1; 95% CI, 1.5-3.0), up to an OR of 7.2 (95% CI, 3.8-13.8) for reticular pseudodrusen. Compared with persons with a high GRS for complement, homozygous carriers of ARMS2/HTRA1 showed a higher risk of CNV (OR, 4.1; 95% CI, 3.2-5.4); risks of other characteristics were not different. CONCLUSIONS: Carriers of the risk haplotype at ARMS2/HTRA1 have a particularly high risk of late AMD at a relatively early age. Data suggest that risk variants at ARMS2/HTRA1 act as a strong catalyst of progression once early signs are present. The phenotypic spectrum resembles that of complement genes, only with higher risks of CNV.

Heritability of retinal drusen in the Copenhagen Twin Cohort Eye Study.

PURPOSE: To study age- and sex-adjusted heritability of small hard drusen and early age-related macular degeneration (AMD) in a population-based twin cohort. METHODS: This was a single-centre, cross-sectional, classical twin study with ophthalmic examination including refraction, biometry, best-corrected visual acuity assessment, colour and autofluorescence fundus photography, and fundus optical coherence tomography. Grading and categorization of drusen was by diameter and location. RESULTS: The study enrolled 176 same-sex pairs of twins of mean (SD) age 58.6 (9.9) years. The prevalence of the four phenotypes ≥20 small hard macular drusen (largest diameter < 63 µm), ≥20 small hard extramacular drusen, intermediate drusen (63-125 µm) anywhere, and large drusen (>125 µm) anywhere was 12.4%, 36.4%, 5.8%, and 8.4%, respectively, and the respective heritabilities, adjusted for age and sex, were 78.2% [73.5-82.9], 69.1% [62.3-75.9], 30.1% [4.1-56.1], and 65.6% [26.4-100]. Age trajectory analysis supported a gradual transition to larger numbers of small hard drusen with increasing age. The heritability of ≥20 small hard drusen was markedly lower than the 99% found in the 40% overlapping twin cohort that was seen 20 years earlier. CONCLUSION: Numerous (≥20) small hard drusen and larger drusen that fit the definition of dry AMD were highly heritable. Small hard drusen counts increased with age. Decreasing heritability with increasing age suggests that the impact of behavioural and environmental factors on the development of small hard drusen increases with age.

Genetics of reticular pseudodrusen in age-related macular degeneration.

Reticular pseudodrusen (RPD) are subretinal deposits that, when observed with age-related macular degeneration (AMD), form a distinct phenotype, often associated with late-stage disease. To date, RPD genetic risk associations overlap six well-established AMD-risk regions. Determining RPD-specific underlying genetic causes by using adequate imaging methods should improve our understanding of the pathophysiology of RPD.

North Carolina macular dystrophy shows a particular drusen phenotype and atrophy progression.

BACKGROUND/AIM: To provide a comprehensive multimodal retinal imaging characterisation of patients with North Carolina macular dystrophy (NCMD). METHODS: Clinical evaluation and retinal imaging in six families. RESULTS: Twenty-one subjects showed phenotypic characteristics of NCMD . Small drusen-like deposits were found in all affected individuals, either tightly grouped in the macula, or surrounding atrophic or fibrotic macular alterations. These small subretinal lesions showed an increased fundus autofluorescence and were associated with only mild irregularities on optical coherence tomography imaging. Similar drusen-like deposits were regularly seen in the peripheral fundus, predominantly temporally and often with a radial distribution. Two patients showed a bilateral chorioretinal atrophy and two had a macular neovascularisation (MNV). Findings from follow-up examinations were available from 11 patients. The retinal phenotype remained overall stable, except for two patients: one patient with atrophy showed a distinct growth of the atrophic lesions on longitudinal AF imaging over a review period of 14 years. One patient with MNV showed a unilateral decline of best-corrected visual acuity. Genetic testing identified the single nucleotide variant chr6:100040987G>C upstream of the PRDM13 gene in all family members with NCMD phenotype. CONCLUSION: Patients with NCMD show a characteristic retinal phenotype and distribution of drusen that differ from drusen in patients with age-related macular degeneration. Although the prognosis of this developmental condition is overall better than for other macular diseases with drusen, patients may be at risk of developing MNV or enlargement of pre-existing atrophy.

Reticular pseudodrusen: A critical phenotype in age-related macular degeneration.

Reticular pseudodrusen (RPD), or subretinal drusenoid deposits (SDD), refer to distinct lesions that occur in the subretinal space. Over the past three decades, their presence in association with age-related macular degeneration (AMD) has become increasingly recognized, especially as RPD have become more easily distinguished with newer clinical imaging modalities. There is also an increasing appreciation that RPD appear to be a critical AMD phenotype, where understanding their pathogenesis will provide further insights into the processes driving vision loss in AMD. However, key barriers to understanding the current evidence related to the independent impact of RPD include the heterogeneity in defining their presence, and failure to account for the confounding impact of the concurrent presence and severity of AMD pathology. This review thus critically discusses the current evidence on the prevalence and clinical significance of RPD and proposes a clinical imaging definition of RPD that will help move the field forward in gathering further key knowledge about this critical phenotype. It also proposes a putative mechanism for RPD formation and how they may drive progression to vision loss in AMD, through examining current evidence and presenting novel findings from preclinical and clinical studies.

Evaluating the Occurrence of Rare Variants in the Complement Factor H Gene in Patients With Early-Onset Drusen Maculopathy.

IMPORTANCE: Early-onset drusen maculopathy (EODM) is a severe disease and can lead to advanced macular degeneration early in life; however, genetic and phenotypic characteristics of individuals with EODM are not well studied. OBJECTIVE: To identify genotypic and phenotypic characteristics of individuals with EODM. DESIGN, SETTING, AND PARTICIPANTS: This case-control study collected data from the European Genetic Database from September 2004 to October 2019. A total of 89 patients with EODM diagnosed at 55 years or younger and 91 patients with age-related macular degeneration (AMD) diagnosed at 65 years or older were included. EXPOSURES: Coding regions of CFH, CFI, C3, C9, CFB, ABCA4, PRPH2, TIMP3, and CTNNA1 genes were sequenced, genetic risk scores (GRS) were calculated based on 52 AMD-associated variants, and phenotypic characteristics on color fundus photographs were analyzed comparing patients with EODM and AMD. MAIN OUTCOMES AND MEASURES: GRS, frequency of rare genetic complement variants, and phenotypic characteristics. RESULTS: This case-control study included 89 patients with EODM (mean [SD] age, 51.8 [8.7] years; 58 [65.2%] were female) and 91 patients with AMD (mean [SD] age, 77.6 [6.1] years; 45 [49.5%] female). At a mean (SD) age of 56.4 (7.3) years, 40 of 89 patients with EODM (44.9%) were affected by geographic atrophy or choroidal neovascularization. A lower GRS was observed in patients with EODM compared with patients with AMD (1.03 vs 1.60; P = .002), and 27 of 89 patients with EODM (30.3%) carried rare variants in the CFH gene compared with 7 of 91 patients with AMD (7.7%). Carriership of a rare CFH variant was associated with EODM (odds ratio, 7.2; 95% CI, 2.7-19.6; P < .001). A large macular drusen area (more than 50% covered with drusen) was observed in patients with EODM (24 of 162 eyes [14.8%]) compared with patients with AMD (9 of 164 eyes [5.5%]) (odds ratio, 4.57; 95% CI, 1.5-14.1; P = .008). CONCLUSIONS AND RELEVANCE: A large proportion of patients with EODM in this study carried rare CFH variants, with most of the identified CFH variants clustered in the first 7 complement control protein domains affecting factor H and factor H-like 1. Because EODM frequently leads to advanced macular degeneration at an early age and can result in many years of vision loss, this study supports targeting the complement system and sequencing the CFH gene in patients with EODM to improve genetic counseling and future treatments for AMD.

Clinical and molecular findings in patients with pattern dystrophy.

Purposes: To study the clinical and genetic background of a series of Italian patients affected by pattern dystrophy (PD).Methods: We reviewed patients with a clinical diagnosis of PD examined at the Eye Clinic in Florence from 2012 to 2019. We took into consideration patients with a standard ophthalmological examination, personal and familial ophthalmological history, fundus imaging, and molecular genetic analysis of genes PRPH2 and BEST1. We labelled patients with BEST1 and PRPH2 mutations as m-PD group (mutated) whereas patients with no mutations in these 2 genes as nm-PD group (non-mutated).Results: Seventy-seven PD patients were assessed (average age 59.7 ± 14.2, range 31-88 years). Fifty patients were placed in the nm-PD group and 27 in the m-PD. Pathogenic BEST1 and PRPH2 mutations were detected in 7% and 22% of PD patients, respectively. In total, we reported 1 BEST1 and 8 PRPH2 novel mutations. Ten patients were characterized by drusen in the nm-PD group whereas in no patients in the m-PD group drusen were detected at the fundus.Conclusions: An important proportion of patients affected by PD showed BEST1 or PRPH2 mutations. Patients affected by drusen represent a different sub-phenotype. Genetic examination is recommended for a correct clinical management.

Drusenoid Pigment Epithelial Detachment: Genetic and Clinical Characteristics.

Few studies report drusenoid pigment epithelial detachment (DPED) in Asians. In this multicenter study, we report the clinical and genetic characteristics of 76 patients with DPED, and, for comparison, 861 patients with exudative age-related macular degeneration (AMD) were included. On the initial presentation, the mean best-corrected visual acuity was 0.087 ± 0.17 (logMAR unit), and mean DPED height and width were 210 ± 132 and 1633 ± 1114 µm, respectively. Fifty-one (67%) patients showed macular neovascularization in the contralateral eye. The risk allele frequency of both ARMS2 A69S and CFH I62V was significantly higher in DPED than in typical AMD and polypoidal choroidal vasculopathy (PCV) (ARMS2 A69S risk allele frequency: DPED 77% vs. typical AMD 66% vs. PCV 57%, CFH I62V risk allele frequency: DPED 87% vs. typical AMD 73% vs. PCV 73%), although the risk allele frequency of both genes was similar between the DPED group and retinal angiomatous proliferation (RAP) group (ARMS2 A69S: p = 0.32, CFH I62V, p = 0.11). The prevalence of reticular pseudodrusen (RPD) was highest in RAP (60%), followed by DPED (22%), typical AMD (20%), and PCV (2%). Although the prevalence of RPD differs between DPED and RAP, these entities share a similar genetic background in terms of ARMS2 and CFH genes.

Whole exome sequencing reveals putatively novel associations in retinopathies and drusen formation.

Inherited retinal dystrophies (IRDs) affect 1 in 3000 individuals worldwide and are genetically heterogeneous, with over 270 identified genes and loci; however, there are still many identified disorders with no current genetic etiology. Whole exome sequencing (WES) provides a hypothesis-free first examination of IRD patients in either a clinical or research setting to identify the genetic cause of disease. We present a study of IRD in ten families from Alberta, Canada, through the lens of novel gene discovery. We identify the genetic etiology of IRDs in three of the families to be variants in known disease-associated genes, previously missed by clinical investigations. In addition, we identify two potentially novel associations: LRP1 in early-onset drusen formation and UBE2U in a multi-system condition presenting with retinoschisis, cataracts, learning disabilities, and developmental delay. We also describe interesting results in our unsolved cases to provide further information to other investigators of these blinding conditions.