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

Doyne honeycomb retinal dystrophy or malattia leventinese (DHRD/ML) is an autosomal dominant retinal disorder caused by a single recurrent p.Arg345Trp (NM_001039348.3:c.1033C>T) variant in EFEMP1 and characterized by early-onset, nearly confluent, large central retinal drusen. Other variants in EFEMP1 have not been reported to cause retinal disease.

To define the topography of the anatomical and functional phenotype of another variant in EFEMP1, p.Arg140Trp (c.418C>T), associated with retinal degeneration.

This multi-institutional case series was conducted at 3 inherited retinal disease clinics (Philadelphia, Pennsylvania; Basel, Switzerland; and Prague, Czech Republic) from October 1998 to May 2026. Participants included 3 unrelated families with the p.Arg140Trp variant and 1 comparator family with canonical DHRD/ML caused by the p.Arg345Trp variant. Analyses were conducted from November 2019 to May 2026.

Heterozygosity for pathogenic EFEMP1 variants.

Color fundus photography and optical coherence tomography, light- and dark-adapted chromatic perimetry, and rod-mediated dark adaptation kinetics.

The EFEMP1 p.Arg140Trp variant segregated with disease in all 3 families. In family 1, the index case developed nyctalopia in the sixth decade with progressive field loss and abnormal ERG. Among 5 at-risk relatives (ages 50 to 58 years), 4 heterozygous carriers had delayed rod-mediated dark adaptation kinetics despite best-corrected visual acuity of 20/20 OU and normal fundus appearance; the noncarrier had normal imaging and function. Additional heterozygous carriers from families 2 (age 42 years; symptom onset at 40 years) and 3 (age 69 years; symptom onset at 55 years) had nyctalopia and peripheral lobular chorioretinal atrophy initially labeled gyrate atrophy-like or choroideremia-like. Topographically matched testing in temporal retina without visible atrophy showed severe rod dysfunction and markedly delayed dark adaptation at 15°, 30°, and 46° with increasing severity toward the periphery. For comparison, the patient with DHRD/ML exhibited normal light- and dark-adapted visual function outside the central 10° and an increasing delay in rod recovery kinetics toward the fovea.

This study found that the EFEMP1 p.Arg140Trp variant was associated with a late-onset, predominantly peripheral retinal degeneration with features overlapping the late-onset retinal degeneration phenotype and was distinct from canonical DHRD/ML; it spares relatively central macular structure and function while preferentially affecting the periphery. Functional evidence suggests preferential rod involvement, with rod dysfunction observed at retinal loci without detectable outer nuclear layer loss.