Genetic screening for macular dystrophies in patients clinically diagnosed with dry age-related macular degeneration.

Kersten E1, Geerlings MJ1, Pauper M1,2, Corominas J1,2, Bakker B1, Altay L3, Fauser S3,4, de Jong EK1, Hoyng CB1, Hollander AI1,2.

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Abstract

It can be clinically challenging to distinguish dry age-related macular degeneration (AMD) from AMD-mimicking dystrophies, and sometimes misdiagnosis occurs. With upcoming therapies for dry AMD it is important to exclude patients with a different retinal disease from clinical trials. In this study we evaluated the occurrence of AMD-mimicking dystrophies in an AMD cohort. Whole-exome sequencing (WES) was performed in 218 patients with intermediate AMD or geographic atrophy secondary to AMD and 133 control individuals. WES data was analyzed for rare variants in nineteen genes associated with autosomal dominant and recessive macular dystrophies mimicking AMD. In three (1.4%) of 218 cases we identified a pathogenic heterozygous variant (PRPH2 c.424C>T; p.R142W) causal for autosomal dominant central areolar choroidal dystrophy (CACD). Phenotypically, these patients all presented with geographic atrophy. In twelve (5.5%) of 218 cases we identified a heterozygous variant of unknown clinical significance, but predicted to be highly deleterious, in genes previously associated with autosomal dominant macular dystrophies. The distinction between AMD and AMD-mimicking dystrophies, such as CACD, can be challenging based on fundus examination alone. Genetic screening for genes associated with macular dystrophies, especially PRPH2, can be beneficial to help identify AMD-mimicking dystrophies. This article is protected by copyright. All rights reserved.

KEYWORDS:

AMD; Age-related macular degeneration; CACD; PRPH2; WES; central areolar choroidal dystrophy; genetic screening; macular dystrophies; whole exome sequencing