Clinical and Genetic Characteristics of East Asian Patients with Occult Macular Dystrophy (Miyake Disease)

Abstract

study group zPurpose: To describe the clinical and genetic characteristics of the cohort enrolled in the East Asian studies of occult macular dystrophy (OMD).Design: International, multicenter, retrospective cohort studies.Participants: A total of 36 participants from 21 families with a clinical diagnosis of OMD and harboring pathogenic RP1L1 variants (i.e., Miyake disease) were enrolled from 3 centers in Japan, China, and South Korea.Methods: A detailed history was obtained, and comprehensive ophthalmological examinations including spectral-domain OCT were performed. All detected sequence variants in the RP1L1 gene were reviewed, and in silico analysis was performed, including allele frequency analyses and pathogenicity predictions.Main Outcome Measures: Onset of disease, visual acuity (VA) converted to the logarithm of the minimum angle of resolution (logMAR), OCT findings, and effect of detected variants.Results: Eleven families from Japan, 6 from South Korea, and 4 from China were recruited. There were 12 female and 24 male participants. The median age of onset was 25.5 years (range, 2e73), and the median age at the latest examination was 46.0 years (range, 11e86). The median VA (logMAR) was 0.65 (range, e0.08e1.22) in the right eye and 0.65 (e0.08e1.10) in the left eye. A significant correlation between onset of disease and VA was revealed. The Classical morphologic phenotype showing both blurred ellipsoid zone and absence of interdigitation zone of the photoreceptors was demonstrated in 30 patients (83.3%), and subtle photoreceptor architectural changes were demonstrated in 6 patients (16.6%). Eight pathogenic RP1L1 variants were identified, including 6 reported variants and 1 novel variant: p.R45W, p.T1194M/p.T1196I (complex), p.S1199C, p.G1200A, p.G1200D, p.V1201G, and p.S1198F, respectively. Two variants were recurrent: p.R45W (11 families, 52.4%) and p.S1199C (5 families, 23.8%). The pathogenic missense variants in 10 families (47.6%) were located within the previously reported unique motif, including 6 amino acids (1196e1201).Conclusions: There is a large spectrum of clinical findings in Miyake disease, including various onset of disease and VA, whereas the characteristic photoreceptor microstructures were shared in most cases. Two hot spots including amino acid numbers 45 and 1196e1201 in the RP1L1 gene were confirmed in the East Asian population.

Clinical and Genetic Characteristics of Chinese Patients with Occult Macular Dystrophy

“…In this cohort, visual acuity varied widely from 0.04 to 0.5; however, no significant correlation was found between visual acuity and onset and duration, unlike the results of previous studies. 4,8 This may be related to the small number of patients included in this study. Another limitation of our study is that it is a cross-sectional retrospective study, and more accurate data regarding disease progression could not be obtained.…”

“…The vari-ant p.S1199C is not found in the ExAC or 1000 Genomes Project database, but all 12 reported patients harboring this variant were East Asian. 4,19,20 This indicated that these two variants were more common in the East Asian population than in other populations. Previous studies showed that the penetrance of the variant p.R45W was incomplete, ranging from 38% to 85%.…”

“…The most frequent variant was p.R45W (71/101 families, 70.3%), followed by p.S1199C (7/101 families, 6.9%), located within two previously reported mutation hotspots. 4 A schematic diagram showing the location of all previously reported RP1L1 variants is presented in Figure 5. Five of the 26 variants (19.2%) were located in two DCX domains (residues 33-133 and 147-228), and these domains in combination with the RP1 domain appeared to be necessary for localization of RP1L1 to the outer segment axoneme of photoreceptors.…”

“…In addition, spectral-domain optical coherence tomography (SD-OCT) shows the absence of the interdigitation zone (IZ) and blurring of the ellipsoid zone (EZ) of photoreceptors at the macula. 3,4 Retinitis pigmentosa 1-like 1 (RP1L1, OMIM 608581) is the only confirmed gene associated with OMD. 5 It is mapped to human chromosome 8p and spans 50 kb of genomic DNA; it is composed of four exons, but exon 1 is noncoding.…”

“…10,13,14 To date, numerous studies describing OMD patients with RP1L1 mutations have been reported, but limited data are available for the Chinese population. 4,15,16 Thus, this study aims to investigate the clinical and genetic characteristics of a small cohort of Chinese OMD patients.…”