Clinical and genetic characteristics of 10 Japanese patients with PROM1‐associated retinal disorder: A report of the phenotype spectrum and a literature review in the Japanese population

Abstract

Variants in the PROM1 gene are associated with cone (−rod) dystrophy, macular dystrophy, and other phenotypes. We describe the clinical and genetic characteristics of 10 patients from eight Japanese families with PROM1-associated retinal disorder (PROM1-RD) in a nationwide cohort. A literature review of PROM1-RD in the Japanese population was also performed. The median age at onset/examination of 10 patients was 31.0 (range, 10-45)/44.5 (22-73) years. All 10 patients showed atrophic macular changes. Seven patients (70.0%) had spared fovea to various degrees, approximately half of whom had maintained visual acuity. Generalized cone (−rod) dysfunction was demonstrated in all nine subjects with available electrophysiological data. Three PROM1 variants were identified in this study: one recurrent disease-causing variant (p.Arg373Cys), one novel putative disease-causing variant (p.Cys112Arg), and one novel variant of uncertain significance (VUS; p. Gly53Asp). Characteristic features of macular atrophy with generalized conedominated retinal dysfunction were shared among all 10 subjects with PROM1-RD, and the presence of foveal sparing was crucial in maintaining visual acuity. Together with the three previously reported variants [p.R373C, c.1551+1G>A (pathogenic), p.Asn580His (likely benign)] in the literature of Japanese patients, one prevalent missense variant (p.Arg373Cys, 6/9 families, 66.7%) detected in multiple studies was determined in the Japanese population, which was also frequently detected in the European population.

Characterization of PROM1 p.Arg373Cys Variant in a Cohort of Chinese Patients: Macular Dystrophy Plus Peripheral Bone-Spicule Degeneration

“…11,16 However, one reported Chinese family and eight Japanese families that were identified as having the p.Arg373Cys variant presented only macular atrophy fundus changes, with no mention of retinal peripheral pigment deposits. 10,13 In the current study, in all six affected individuals with the p.Arg373Cys variant who underwent detailed widefield fundus examination, peripheral bone-spicule appearance degeneration was seen, in addition to macular lesions, suggesting that changes resembling retinitis pigmentosa are not an ethnically specific phenotype. In our opinion, typical bone-spicule pigmentation in the peripheral retina may be rarely observed in routine clinical practice, as it is slightly far from the midretina.…”

“…The characteristics of the fundus changes observed in the current study may be of help in explaining the various forms of retinal degeneration associated with the p.Arg373Cys variant, such as Stargardt-like macular dystrophy with yellowish flecks, 3,9 specific bull's eye retinal pigment epithelium dystrophy with central fovea sparing, 3,11,14 and occasionally severe macular dystrophy accompanied by possible pigmentation changes in the peripheral retina. 11,16 Characteristic macular involvement was found in all previously reported patients of 28 families with the p.Arg373Cys variant, 3,[9][10][11][12][13][14][15][16]19,28 which might overlap with cone-rod dystrophy and progression to rod-cone like dystrophy over time. 29 In addition, severe macular dystrophy, bull's eye fundus changes, and cone-rod dystrophy associated with the p.Arg373Cys variant may actually be present in the same eye, between two eyes of the same patient, or among different affected individuals in the same family if they are examined by different methods (with or without ERG or FFA) at different times or by different people.…”

“… 11 , 16 It might be interesting to determine why the same variant results in different phenotypes. Moreover, four novel heterozygous variants: c.2485G>A (p.Asp829Asn), 17 c.734T>C (p.Leu245Pro), 18 c.334T>C (p.Cys112Arg), and c.158G>A (p.Gly53Asp), 10 have recently been reported to cause PROM1 -associated autosomal dominant retinal degeneration.…”

The Association Between the Number of Visual Fields and the Accuracy of Future Prediction in Eyes With Retinitis Pigmentosa

“…RP is genetically heterogeneous, and genetic testing can direct prognosis and clinical management. For instance, variants in many genes, including ABCA4, 38 PRPH2, 39,40 and PROM1 41 genes, are associated with various phenotypes. A better understanding of the in uence of genetics on the VF progression rate would be bene cial.…”

Introduction to the special issue on Ophthalmic Genetics: Vision in 2020

“…The Global Eye Genetics Consortium has emerged as a collaborative research effort spanning Asia, India, and South America with collaborators in Europe and the USA. Two papers from Fujinami et al (2020) describe the largest series of PROM1 ‐related retinopathy and RP2 ‐related X‐linked RP in Japan, and Liu et al (2020) depict the prevalence of Stargardt‐associated pathogenic ABCA4 variants in China. Ophthalmic genetics experiences in New Zealand (Hull et al, 2020), India (Bansal et al, 2020), Brazil (Sallum et al, 2020), and Argentina, Colombia, and Chile (Daich Varela et al, 2020) outline clinical practices and molecular genetic testing algorithms in their counties.…”