Common and rare variants in patients with early onset drusen maculopathy

Abstract

Early onset drusen maculopathy (EODM) can lead to advanced macular degeneration at a young age, affecting quality of life. However, the genetic causes of EODM are not well studied. We performed whole genome sequencing in 49 EODM patients. Common genetic variants were analysed by calculating genetic risk scores based on 52 age-related macular generation (AMD)-associated variants, and we analysed rare variants in candidate genes to identify potential deleterious variants that might contribute to EODM development. We demonstrate that the 52 AMD-associated variants contributed to EODM, especially variants located in the complement pathway. Furthermore, we identified 26 rare genetic variants predicted to be pathogenic based on in silico prediction tools or based on reported pathogenicity in literature. These variants are located predominantly in the complement and lipid metabolism pathways. Last, evaluation of 18 genes causing inherited retinal dystrophies that can mimic AMD characteristics, revealed 11 potential deleterious variants in eight EODM patients. However, phenotypic characteristics did not point towards a retinal dystrophy in these patients. In conclusion, this study reports new insights into rare variants that are potentially involved in EODM development, and which are relevant for future studies unravelling the aetiology of EODM.

Keywords: age-related macular degeneration; complement pathway; early onset drusen maculopathy; genetic variation; lipid metabolism; whole genome sequencing.

FIGURE 1

Contribution of AMD‐associated variants to EODM. Mean GRS, complement GRS, and lipid GRS in EODM cases (blue) and control individuals (grey). Error bars: mean ± SD. ***p < 0.001. GRS, genetic risk score; ns, not significant [Colour figure can be viewed at wileyonlinelibrary.com]

FIGURE 2

GRS distribution among disease stages. GRS, complement GRS, and lipid GRS among disease stages in EODM patients (A) and in the AMD case–control reference cohort (B). Error bars: mean ± SD. AMD, age‐related macular degeneration; CNV, choroidal neovascularization; GA, geographic atrophy; GRS, genetic risk score [Colour figure can be viewed at wileyonlinelibrary.com]

FIGURE 3

EODM Patients Carrying the Same Rare Variant in LDLR and ACAT1. (A) LDLR c.47 T > C (p.Leu16Pro) carriers. (A1) Patient with a central GA lesion (right eye) and intermediate/large drusen (left eye). (A2) Patient with small drusen, RPE alterations and atrophic areas (both eyes). (B) ACAT1 c.1217A > G (p.Glu406Gly) carriers. (B1,B2) Numerous cuticular drusen spread across the posterior pole (both eyes) on colour fundus photographs and fluorescein angiography. Upper right corner = age; Bottom right corner = GRS; GRS, genetic risk score [Colour figure can be viewed at wileyonlinelibrary.com]