Distinct Clinical Effects of Two RP1L1 Hotspots in East Asian Patients With Occult Macular Dystrophy (Miyake Disease): EAOMD Report 4.

Purpose: To characterize the clinical effects of two RP1L1 hotspots in patients with East Asian occult macular dystrophy (OMD). Methods: Fifty-one patients diagnosed with OMD harboring monoallelic pathogenic RP1L1 variants (Miyake disease) from Japan, South Korea, and China were enrolled. Patients were classified into two genotype groups: group A, p.R45W, and group B, missense variants located between amino acids (aa) 1196 and 1201. The clinical parameters of the two genotypes were compared, and deep learning based on spectral-domain optical coherence tomographic (SD-OCT) images was used to distinguish the morphologic differences. Results: Groups A and B included 29 and 22 patients, respectively. The median age of onset in groups A and B was 14.0 and 40.0 years, respectively. The median logMAR visual acuity of groups A and B was 0.70 and 0.51, respectively, and the survival curve analysis revealed a 15-year difference in vision loss (logMAR 0.22). A statistically significant difference was observed in the visual field classification, but no significant difference was found in the multifocal electroretinographic classification. High accuracy (75.4%) was achieved in classifying genotype groups based on SD-OCT images using machine learning. Conclusions: Distinct clinical severities and morphologic phenotypes supported by artificial intelligence-based classification were derived from the two investigated RP1L1 hotspots: a more severe phenotype (p.R45W) and a milder phenotype (1196-1201 aa). This newly identified genotype-phenotype association will be valuable for medical care and the design of therapeutic trials.

The difference between induced insight by hints and induced insight by answers: an event-related potential study.

We can solve insight problems by ourselves, by hints or by answers. This study compared the temporal features of different types of insight (spontaneous insight, induced insight by hints and induced insight by answers). Fifteen college students participated in the Chinese Remote Association Task. If they did not come up with an answer, the cue word was presented. Finally, they needed to judge whether the answer was correct or not. Participants' brain electroencephalography-event-related potentials (ERPs) were recorded. Induced insight by hints elicited a more negative ERP deflection than spontaneous insight within 260-400 ms (N2). Induced insight by hints and induced insight by answers elicited a more negative late negative component (LNC) than spontaneous insight. Induced insight by hints elicited a more positive ERP deflection than induced insight by answers and spontaneous insight in the right frontal area. Spontaneous insight and induced insight by answers elicited a more positive ERP deflection than induced insight by hints in the right part of the central region. When solving insight problems, the N2 may be related to representation restructuring. The first LNC may be related to the breaking of mental set. The positive component of the right frontal area before pressing the button may be related to the formation of novel associations, and the positive component of the right part of the central region may be related to the intensity of the 'Aha!' experience.

Occult Macular Dysfunction Syndrome: Identification of Multiple Pathologies in a Clinical Spectrum of Macular Dysfunction with Normal Fundus in East Asian Patients: EAOMD Report No. 5.

Occult macular dystrophy (OMD) is the most prevalent form of macular dystrophy in East Asia. Beyond RP1L1, causative genes and mechanisms remain largely uncharacterised. This study aimed to delineate the clinical and genetic characteristics of OMD syndrome (OMDS). Patients clinically diagnosed with OMDS in Japan, South Korea, and China were enrolled. The inclusion criteria were as follows: (1) macular dysfunction and (2) normal fundus appearance. Comprehensive clinical evaluation and genetic assessment were performed to identify the disease-causing variants. Clinical parameters were compared among the genotype groups. Seventy-two patients with OMDS from fifty families were included. The causative genes were RP1L1 in forty-seven patients from thirty families (30/50, 60.0%), CRX in two patients from one family (1/50, 2.0%), GUCY2D in two patients from two families (2/50, 4.0%), and no genes were identified in twenty-one patients from seventeen families (17/50, 34.0%). Different severities were observed in terms of disease onset and the prognosis of visual acuity reduction. This multicentre large cohort study furthers our understanding of the phenotypic and genotypic spectra of patients with macular dystrophy and normal fundus. Evidently, OMDS encompasses multiple Mendelian retinal disorders, each representing unique pathologies that dictate their respective severity and prognostic patterns.

Dual-amplification colorimetric detection of bisphenol A based on catalytic hairpin assembly and DNAzyme-caused fragment self-assembly hybridization chain reaction.

An efficient and innovative strategy for colorimetric detection of bisphenol A (BPA) is shown here based on target-induced catalytic hairpin assembly (CHA) and DNAzyme-caused fragment self-assembly hybridization chain reaction (HCR). BPA can bind with its aptamer hairpin to trigger CHA, thus forming Y-shaped DNA nanostructures with an enzyme-strand (E-DNA) tail. Subsequently, the E-DNA can cyclically cleave the substrate hairpin, generating many fragments which can cause self-assembly HCR to form long strand DNA. Finally, the formed long strand DNA can hybridize with short single strand DNA on AuNPs, causing the color change of AuNPs from red to blue. Six important detection conditions of the proposed aptasensor were optimized. Under optimal conditions, the biosensor has high sensitivity for BPA detection at concentrations ranging from 0.8 pM to 500 pM and the detection limit is as low as 0.2 pM, providing a promising prospective ultrasensitive detection of BPA.

Target controlled alternative hybridization chain reaction for fluorescent detection of dual mycotoxins.

A target controlled alternative hybridization chain reaction (HCR) was developed for fluorescent detection of multiple mycotoxin. Ochratoxin A (OTA) and aflatoxin B1 (AFB1) can bind with their specific aptamer on the gold nanoparticles and cause the releasing of the short DNA sequences. The short DNA sequences can trigger different reaction route of HCR and thus produce two kinds of side-chain sequences. The side-chain sequences can cause the opening of the DNA tweezers and result the recovery of fluorescent signals. Good linear relationships were obtained in the range of 0.06-2 ng/mL (R2 = 0.994) for OTA and 0.005-1 ng/mL (R2 = 0.992) for AFB1 with limit of detection of 0.02 ng/mL for OTA and 0.002 ng/mL for AFB1. Importantly, it showed great sensitivity and excellent selectivity in practical food sample analysis for simultaneous detection of OTA and AFB1.

A versatile Y shaped DNA nanostructure for simple, rapid and one-step detection of mycotoxins.

A versatile Y shaped DNA nanostructure has been developed for simple, rapid and one-step simultaneous detection aflatoxin B1 (AFB1) and ochratoxin A (OTA). Y shaped duplex DNA arms was formed with two DNA tweezer at the ends. The aptamer sequence at the third end can bind to its target mycotoxins with strong affinity and then release the two DNA fragments. The released DNA fragments can open the DNA tweezers at the ends of Y shaped DNA arm. The amounts of AFB1 and OTA can be quantitative detection through the recovery of the fluorescent intensities. This strategy is simple and rapid with self-powered DNA hybridization reaction to control the "open" of Y shaped DNA tweezers. Furthermore, it can be finished in 60 min with only one-step of operation. The linear range of AFB1 was from 0.5 to 200 ng/mL (R2 = 0.995) and linear relationship of OTA was obtained from 4 to 300 ng/mL (R2 = 0.990). It also has been successfully applied for mycotoxins detection in real food samples. Importantly, the target mycotoxins can be extended to others by simply replacing the corresponding aptamer sequences.

Ocular Ischemic Syndrome and Its Related Experimental Models.

Ocular ischemic syndrome (OIS) is one of the severe ocular disorders occurring from stenosis or occlusion of the carotid arteries. As the ophthalmic artery is derived from the branch of the carotid artery, stenosis or occlusion of the carotid arteries could induce chronic ocular hypoperfusion, finally leading to the development of OIS. To date, the pathophysiology of OIS is still not clearly unraveled. To better explore the pathophysiology of OIS, several experimental models have been developed in rats and mice. Surgical occlusion or stenosis of common carotid arteries or internal carotid arteries was conducted bilaterally or unilaterally for model development. In this regard, final ischemic outcomes in the eye varied depending on the surgical procedure, even though similar findings on ocular hypoperfusion could be observed. In the current review, we provide an overview of the pathophysiology of OIS from various experimental models, as well as several clinical cases. Moreover, we cover the status of current therapies for OIS along with promising preclinical treatments with recent advances. Our review will enable more comprehensive therapeutic approaches to prevent the development and/or progression of OIS.

Visual Field Characteristics in East Asian Patients With Occult Macular Dystrophy (Miyake Disease): EAOMD Report No. 3.

Purpose: The purpose of this study was to investigate the perimetric features and their associations with structural and functional features in patients with RP1L1-associated occult macular dystrophy (OMD; i.e. Miyake disease). Methods: In this international, multicenter, retrospective cohort study, 76 eyes of 38 patients from an East Asian cohort of patients with RP1L1-associated OMD were recruited. Visual field tests were performed using standard automated perimetry, and the patients were classified into three perimetric groups based on the visual field findings: central scotoma, other scotoma (e.g. paracentral scotoma), and no scotoma. The association of the structural and functional findings with the perimetric findings was evaluated. Results: Fifty-four eyes (71.1%) showed central scotoma, 14 (18.4%) had other scotomata, and 8 (10.5%) had no scotoma. Central scotoma was mostly noted in both eyes (96.3%) and within the central 10 degrees (90.7%). Among the three perimetric groups, there were significant differences in visual symptoms, best-corrected visual acuity (BCVA), and structural phenotypes (i.e. severity of photoreceptor changes). The central scotoma group showed worse BCVA often with severe structural abnormalities (96.3%) and a pathogenic variant of p.R45W (72.2%). The multifocal electroretinogram (mfERG) groups largely corresponded with the perimetric groups; however, 8 (10.5%) of 76 eyes showed mfERG abnormalities preceding typical central scotoma. Conclusions: The patterns of scotoma with different clinical severity were first identified in occult macular dystrophy, and central scotoma, a severe pattern, was most frequently observed. These perimetric patterns were associated with the severity of BCVA, structural phenotypes, genotype, and objective functional characteristics which may precede in some cases.

An entropy driven catalytic reaction powered DNA motor for simultaneous detection of ochratoxin A and chloramphenicol in food.

An entropy driven catalytic reaction powered DNA motor was proposed for simultaneous detection of ochratoxin A (OTA) and chloramphenicol (CAP) in food. The dumbbell hairpin structure was formed by the two aptamers of OTA and CAP. The dumbbell hairpin can be opened by the interaction of OTA and CAP with their aptamers. The tails of the end of dumbbell hairpin sequence can induce the entropy driven catalytic reactions on the AuNPs, causing the sustained releasing of the fluorophore labeled DNA sequences. The recovery of fluorescent intensities can be used for quantitative detection of OTA and CAP. The limit of detection reached 2 pM for OTA and 6 pM for CAP respectively, which was great improved by entropy driven amplification of the self-powdered DNA motor. This strategy is simple and sensitive and only needs one-step operation. It exhibits promising potentiality in food quality control and food security supervision.

Simultaneous and ultra-sensitive detection of Cu2+ and Mg2+ in wine and beer based on dual DNA tweezers and entropy-driven three-dimensional DNA nanomachine.

Simultaneous and ultra-sensitive detection strategy of Cu2+ and Mg2+ in wine and beer was developed based on dual DNA tweezers and entropy-driven three-dimensional DNA nanomachine. The dual DNAzyme can simultaneously respond to two kinds of metal ions and cause two kinds of "turn-on" fluorescent signals. The working principle of this strategy was indirectly proven. In addition, some key experimental parameters were also optimized. Under the optimum conditions, the limit of detection was 10 pM for Cu2+ and 2 nM for Mg2+ respectively which was significantly improved by entropy driven amplification. This strategy also showed good selectivity and specificity. It was successfully used to detect of Cu2+ and Mg2+ in wine and beer with 5.26% to 9.12% of relative standard deviation and 90.4% to 110.5% of recoveries.

Prediction of causative genes in inherited retinal disorder from fundus photography and autofluorescence imaging using deep learning techniques.

BACKGROUND/AIMS: To investigate the utility of a data-driven deep learning approach in patients with inherited retinal disorder (IRD) and to predict the causative genes based on fundus photography and fundus autofluorescence (FAF) imaging. METHODS: Clinical and genetic data from 1302 subjects from 729 genetically confirmed families with IRD registered with the Japan Eye Genetics Consortium were reviewed. Three categories of genetic diagnosis were selected, based on the high prevalence of their causative genes: Stargardt disease (ABCA4), retinitis pigmentosa (EYS) and occult macular dystrophy (RP1L1). Fundus photographs and FAF images were cropped in a standardised manner with a macro algorithm. Images for training/testing were selected using a randomised, fourfold cross-validation method. The application program interface was established to reach the learning accuracy of concordance (target: >80%) between the genetic diagnosis and the machine diagnosis (ABCA4, EYS, RP1L1 and normal). RESULTS: A total of 417 images from 156 Japanese subjects were examined, including 115 genetically confirmed patients caused by the three prevalent causative genes and 41 normal subjects. The mean overall test accuracy for fundus photographs and FAF images was 88.2% and 81.3%, respectively. The mean overall sensitivity/specificity values for fundus photographs and FAF images were 88.3%/97.4% and 81.8%/95.5%, respectively. CONCLUSION: A novel application of deep neural networks in the prediction of the causative IRD genes from fundus photographs and FAF, with a high prediction accuracy of over 80%, was highlighted. These achievements will extensively promote the quality of medical care by facilitating early diagnosis, especially by non-specialists, access to care, reducing the cost of referrals, and preventing unnecessary clinical and genetic testing.

Two-color, ultra-sensitive fluorescent strategy for Ochratoxin A detection based on hybridization chain reaction and DNA tweezers.

A two-color fluorescent DNA tweezers was developed for ultrasensitive detection of Ochratoxin A (OTA) based on hairpin-locked aptamer and hybridization chain reaction (HCR) amplification strategy. OTA can bind with hairpin-locked aptamer and then trigger the HCR reaction to produce a long double-strand DNA. The side-chains of the long duplex can separately hybridize with the two locker sequences of DNA tweezer, causing the opening of DNA tweezer and the recovery of two-color fluorescent signals. It shows a good linear range from 0.02 to 0.8 ppb with limit of detection of 0.006 ppb for FAM and 0.014 ppb for Cy5, which is beyond the requirement of actual application. In addition, the two-color fluorescent strategy can greatly reduce the false positive rate. It shows excellent performance for detection of OTA in practical food sample.

Spatial Functional Characteristics of East Asian Patients With Occult Macular Dystrophy (Miyake Disease); EAOMD Report No. 2.

PURPOSE: To describe the functional phenotypic features of East Asian patients with RP1L1-associated occult macular dystrophy (ie, Miyake disease). DESIGN: An international multicenter retrospective cohort study. METHODS: Twenty-eight participants (53 eyes) with Miyake disease were enrolled at 3 centers (in Japan, China, and South Korea). Ophthalmologic examinations including spectral-domain optical coherence tomography (SDOCT) and multifocal electroretinogram (mfERG) were performed. Patients were classified into 3 functional groups based on mfERG: Group 1, paracentral dysfunction with relatively preserved central/peripheral function; Group 2, homogeneous central dysfunction with preserved peripheral function; and Group 3, widespread dysfunction over the recorded area. Three functional phenotypes were compared in clinical parameters and SDOCT morphologic classification (severe phenotype, blurred/flat ellipsoid zone and absence of the interdigitation zone; mild phenotype, preserved ellipsoid zone). RESULTS: There were 8 eyes in Group 1, 40 eyes in Group 2, and 5 eyes in Group 3. The patients in Group 1 showed significantly later onset (P = .005) and shorter disease duration (P = .002), compared with those in Group 2. All 8 eyes in Group 1 showed the mild morphologic phenotype, while 43 of 45 eyes in Groups 2 and 3 presented the severe phenotype, which identified a significant association between the functional grouping and the morphologic classification (P < .001). CONCLUSIONS: A spectrum of functional phenotypes of Miyake disease was first documented with identification of 3 functional subtypes. Patients with paracentral dysfunction had the mildest phenotype, and those with homogeneous central or widespread dysfunction showed overlapping clinical findings with severe photoreceptor changes, suggesting various extents of visual impairment.

Simultaneous detection of aflatoxin B1 and ochratoxin A in food samples by dual DNA tweezers nanomachine.

a dual DNA tweezers nanomachine was developed for one-step simultaneous detection of aflatoxin B1 (AFB1) and ochratoxin A (OTA) in food samples. The dual DNA tweezers are locked by the aptamers of mycotoxins, resulting the "turn off" of fluorescent signal. In the presence of AFB1 and OTA, the aptamers can bind with their corresponding targets, resulting the "open" of DNA tweezers and the "turn on" of the fluorescent signals. The limits of detections were 3.5 × 10-2 ppb for AFB1 and 0.1 ppb for OTA. Moreover, the applicability of the method was further demonstrated by conducting a limited survey on 5 samples collected from various sources. The recoveries of this method change from 90.0% to 110.0% for simultaneous detection of AFB1 or OTA and the RSDs vary from 4.1% to 9.2%. Detection uncertainties were within 5% (with a 95% confidence level).

Long-term follow-up of a Chinese patient with KCNV2-retinopathy.

Purpose: To characterize and monitor the clinical and electrophysiological features of a Chinese patient with KCNV2 retinopathy.Methods: A 17-year-old Chinese male with the diagnosis of cone dystrophy with supernormal rod response (CDSRR) was followed-up for 5 years, with full ophthalmological examinations, including decimal best corrected visual acuity (BCVA), fundus photography, fundus autofluorescence (FAF) imaging, spectral-domain optical coherence tomography (SD-OCT), and full-field electroretinogram (ERG). Genetic screening was performed to detect the sequence variations in the retinal dystrophy associated genes in the patient and his parents.Results: The patient demonstrated the characteristic full-field electroretinography (ERG) features of CDSRR, namely a profound enlargement of the dark-adapted ERG b-wave amplitude with increasing flash strength and a broadened a-wave trough; this case also had undetectable light-adapted ERGs. A BCVA of 0.15 was maintained over 5 years in both eyes; while progressive macular atrophy was identified. Molecular genetic analyses revealed two novel disease-causing KCNV2 variants in compound heterozygous state: c.1408 G > C (p.Gly470Arg) and c.1500 C > G (p.Tyr500Ter).Conclusions: This is the first long-term case study of an East Asian patient with molecularly confirmed CDSRR. The progressive atrophy with maintained VA demonstrated in this case will be valuable for increasing the understanding of the natural course of KCNV2 retinopathy and it will help in counselling patients with this disease.

Clinical and genetic analysis of the ABCA4 gene associated retinal dystrophy in a large Chinese cohort.

ABCA4 gene associated retinal dystrophies (ABCA4-RD) are a group of inherited eye diseases caused by ABCA4 gene mutations, including Stargardt disease, cone-rod dystrophy and retinitis pigmentosa. With the development of next-generation sequencing (NGS), numerous clinical and genetic studies on ABCA4-RD have been performed, and the genotype and phenotype spectra have been elucidated. However, most of the studies focused on the Caucasian population and limited studies of large Chinese ABCA4-RD cohorts were reported. In this study, we summarized the phenotypic and genotypic characteristics of 129 Chinese patients with ABCA4-RD. We found a mutation spectrum of Chinese patients which is considerably different from that of the Caucasian population and identified 35 novel ABCA4 mutations. We also reported some rare and special cases, such as, pedigrees with patients in two generations, patients diagnosed with cone-rod dystrophy or retinitis pigmentosa, patients with subretinal fibrosis and patients with preserved foveal structure. At the same time, we focused on the correlation between the genotypes and phenotypes. By the comprehensive analysis of multiple clinical examinations and the application of multiple regression analysis, we proved that patients with two "null" variants had a younger onset age and reached legal blindness earlier than patients with two "none-null" variants. Patients with one or more "none-null" variants tended to have better visual acuity and presented with milder fundus autofluorescence changes and more preserved rod functions on the full-field electroretinography than patients with two "null" variants. Furthermore, most patients with the p.(Phe2188Ser) variant shared a mild phenotype with a low fundus autofluorescence signal limited to the fovea and with normal full-field electroretinography responses. Our findings expand the variant spectrum of the ABCA4 gene and enhance the knowledge of Chinese patients with ABCA4-RD.

A "turn-on" and proximity ligation assay dependent DNA tweezer for one-step amplified fluorescent detection of DNA.

A "turn-on" and proximity ligation assay dependent DNA tweezer was proposed for one-step amplified fluorescent detection of DNA. Target DNA can anneal with capture probe to form an entire long sequence. The formed long sequence can circularly open the hairpin, resulting the "turn-on" of DNA tweezers. A good linear relationship was shown from 40 pM to 20 nM with limit of detection of 10 pM. In addition, it has been successfully utilized to analysis DNA in human serum, representing a great and practical application future.

HnRNPA2/B1 Is a Novel Prognostic Biomarker for Breast Cancer Patients.

Aims: Heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2/B1) is highly expressed in multiple types of tumor tissues and could potentially be used as a biomarker for the early detection of lung cancer. However, there is little evidence supporting its clinical significance as a prognostic marker in breast cancer. Materials and Methods: We retrospectively analyzed the protein expression and localization of hnRNPA2/B1 protein in breast cancer tissues and adjacent normal tissues from 50 patients with Stage II and III breast cancer who were treated at Shanxi Provincial People's Hospital from May 2018 to May 2019 using western blot, and immunofluorescent and immunohistochemical staining assays. In addition, bioinformatic analyses using the Affymetrix Human Genome database were performed to examine the mRNA levels of hnRNPA2/B1 in normal and breast cancer tissues, and to determine their correlation with the survival rates of breast cancer patients. Results: Based on the cohort of 50 patients, HnRNPA2/B1 protein was expressed in both the cytoplasm and nucleus of breast cancer cells. The protein levels of hnRNPA2/B1 in breast cancer tissues were significantly higher than those in adjacent normal tissues (p < 0.001). Furthermore, bioinformatic analyses of hnRNPA2/B1 mRNA expression levels demonstrated that they were negatively correlated with overall survival and disease-specific survival rates in breast cancer patients. Conclusion: Our study indicates that hnRNPA2/B1 could serve as a novel prognostic biomarker for breast cancer.

HER2-positive pure mucinous breast carcinoma: A case report and literature review.

INTRODUCTION: Pure mucinous carcinoma is a rare type of breast carcinoma, but it usually has a favorable prognosis. Tumors of pure mucinous carcinoma are typically positive for both estrogen receptor (ER) and progesterone receptor (PR), and they do not commonly overexpress human epidermal growth factor receptor 2 (HER2). However, when tumors have HER2 overexpression and are progesterone receptor negative, the prognosis is worse. PATIENT CONCERNS: A 59-year-old female reported a slow growth mass of 3 years, which was radiologically diagnosed as fibroadenoma at another institution. The patient came to our institution for treatment and follow-up. She had no salient past history. DIAGNOSIS: Excisional biopsy revealed a pure mucinous breast carcinoma that was ER (100%, moderate-strong intensity), PR(-), 5% Ki-67 (+), and HER2(3+) by immunohistochemistry. The HER2 gene was found to be amplified by fluorescence in situ hybridization (FISH). The clinical staging was T2N0M0, with pathological grade I, subtype luminal B. INTERVENTIONS: After a modified radical mastectomy, she received four 21-day cycles of intravenous docetaxel (75 mg/m), intravenous cyclophosphamide (600 mg/m), and intravenous trastuzumab (8 mg/kg) (loading dose) on day 1 followed by 6 mg/kg every 3 weeks to complete a full year of treatment. She then received 2.5 mg of letrozole daily for 5 years. OUTCOMES: After following up for 2 years, the patient's outcome was survival without recurrence. Cardiac ultrasounds were performed every 3 months and there was no change in the left ventricular ejection fraction (LEVF). CONCLUSION: It is essential to correctly diagnose the ER(+), PR(-) HER2(+) subtype in mucinous carcinoma. This type should be treated with chemotherapy and anti-HER2 therapy, as well as aromatase inhibitor endocrine therapy.

RP2-associated retinal disorder in a Japanese cohort: Report of novel variants and a literature review, identifying a genotype-phenotype association.

The retinitis pigmentosa 2 (RP2) gene is one of the causative genes for X-linked inherited retinal disorder. We characterized the clinical/genetic features of four patients with RP2-associated retinal disorder (RP2-RD) from four Japanese families in a nationwide cohort. A systematic review of RP2-RD in the Japanese population was also performed. All four patients were clinically diagnosed with retinitis pigmentosa (RP). The mean age at examination was 36.5 (10-47) years, and the mean visual acuity in the right/left eye was 1.40 (0.52-2.0)/1.10 (0.52-1.7) in the logarithm of the minimum angle of resolution unit, respectively. Three patients showed extensive retinal atrophy with macular involvement, and one had central retinal atrophy. Four RP2 variants were identified, including two novel missense (p.Ser6Phe, p.Leu189Pro) and two previously reported truncating variants (p.Arg120Ter, p.Glu269CysfsTer3). The phenotypes of two patients with truncating variants were more severe than the phenotypes of two patients with missense variants. A systematic review revealed additional 11 variants, including three missense and eight deleterious (null) variants, and a statistically significant association between phenotype severity and genotype severity was revealed. The clinical and genetic spectrum of RP2-RD was illustrated in the Japanese population, identifying the characteristic features of a severe form of RP with early macular involvement.