Widening the Spectrum of Disease Expression due to Heterozygous Variants in EFEMP1

What is the spectrum of phenotype caused by EFEMP1 variants? In this case series of 3 unrelated families, EFEMP1 p.Arg140Trp segregated with a late-onset, predominantly peripheral retinal degeneration, and heterozygous carriers showed severe rod dysfunction with markedly delayed dark adaptation kinetics at retinal loci without clinically visible atrophy, while central acuity, structure, and L/M-cone function remained normal. This study found that EFEMP1 p.Arg140Trp causes a late-onset, predominantly peripheral retinal degeneration distinct from canonical Doyne honeycomb retinal dystrophy or malattia leventinese (DHRD/ML), whereas published and current results in DHRD/ML caused by EFEMP1 p.Arg345Trp, show a central predilection with peripheral preservation, suggesting that early rod dysfunction preceding outer nuclear layer loss provides a potential intervention window.

Corresponding Authors: Maximilian Pfau, MD, Department of Ophthalmology, University of Bonn, Rheinische Friedrich-Wilhelms-Universitat Bonn, Venusberg-Campus 1, Bonn 53127, Germany (maximilian.pfau@ukbonn.de); Artur V. Cideciyan, PhD, Center for Hereditary Retinal Degenerations, Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, 51 North 39th Street, Philadelphia, PA, 19104; (cideciya@pennmedicine.upenn.edu)

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