WEDNESDAY′S NEWSLETTER 26.02.2020 NO. 01

Understanding the genetic architecture of human retinal degenerations

J. Fielding Hejtmancik and Stephen P. Daiger

PNAS February 25, 2020 117 (8) 3904-3906

Figure: Retinal degradations

Overview of Inherited Retinal Degenerations

Inherited retinal degenerations are a clinically and genetically heterogeneous group of blinding diseases characterized by progressive degeneration of the neuroretina and/or the retinal pigment epithelium. Currently, over 300 genes have been implicated in retinal degenerations (RetNet: https://sph.uth.edu/RetNet/). While mutations, or causative variants, in each of these genes are relatively rare, taken together they are a significant cause of blindness, especially in working-age individuals, which increases their economic and societal impact. Clinically, inherited retinal degenerations vary from retinitis pigmentosa and Leber congenital amaurosis, which are often manifest at birth and initially involve rod photoreceptors in the retinal periphery, to early-onset macular degeneration, which is a progressive degeneration affecting central vision (1). Inherited retinal degenerations can show autosomal-dominant, autosomal-recessive, and X-linked inheritance, as well as more complex or multifactorial inheritance patterns, especially for some of the later-onset progressive diseases. While mutations in the same gene usually show the same inheritance pattern, it is not uncommon for mutations in the same gene to cause two or more forms of retinal disease, complicating the nosology of this group of diseases (2). In addition, the presence of disease-associated alleles at one gene can affect the penetrance or expressivity of mutations at a second, resulting in complicated family histories and in some cases even digenic diallelic (3) or digenic triallelic (4) inheritance. In PNAS, Hanany et al. (5) address this intimidating set of related diseases by developing a system to identify disease alleles at each of the associated genes and, beyond that, to calculate the gene-specific carrier frequency and the prevalence of homozygosity for variants causing autosomal recessive retinal degenerations. While appearing somewhat mundane on the surface, this work actually has far-reaching implications for both the basic science of the retina and the clinical practice of ophthalmology.

►See https://www.pnas.org/content/117/8/3904

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