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Stargardt disease is one of the most common forms of inherited retinal disease and leads to permanent vision loss. A diagnostic feature of the disease is retinal flecks, which appear hyperautofluorescent in fundus autofluorescence (FAF) imaging. The size and number of these flecks increase with disease progression. Manual segmentation of flecks allows monitoring of disease, but is time-consuming. Herein, we have developed and validated a deep learning approach for segmenting these Stargardt flecks (1750 training and 100 validation FAF patches from 37 eyes with Stargardt disease). Testing was done in 10 separate Stargardt FAF images and we observed a good overall agreement between manual and deep learning in both fleck count and fleck area. Longitudinal data were available in both eyes from 6 patients (average total follow-up time 4.2 years), with both manual and deep learning segmentation performed on all (n = 82) images. Both methods detected a similar upward trend in fleck number and area over time. In conclusion, we demonstrated the feasibility of utilizing deep learning to segment and quantify FAF lesions, laying the foundation for future studies using fleck parameters as a trial endpoint.

PurposeThis study investigates whether subordinates who rate their managers higher on narcissism are also more likely to view their managers as abusive. In particular, the study explores the extent to which managers whom subordinates rate higher on narcissism use certain behaviors (self-promotion and unpredictability) that mediate the relationship between narcissism and perceived abuse.Design/methodology/approachSurvey participants (n = 949) rated their most-destructive manager in terms of self-promotion, unpredictability, narcissism and abusiveness. A bootstrap analysis assessed the positive, mediating effects of leader self-promotion and unpredictability on the narcissism–abuse relationship.FindingsDegree of perceived supervisor narcissism predicted subordinates' perceptions of abusive supervision. However, the supervisor's self-promotion activities and unpredictability fully mediated this relationship.Research limitations/implicationsThis study identifies perceived narcissism as an antecedent of abusive supervision and identifies two mediators relevant to subordinates' perceptions of abuse. Using multiple methods and multiple sources, the authors recommend that scholars identify additional mediators. Further research should consider variables such as gender, organizational culture and occupational status.Practical implicationsFindings highlight how subordinates connect supervisor narcissism to abuse; this allows human resource practitioners to better predict and address subordinates' perceptions of their managers and to design interventions for improving supervisors' behaviors.Originality/valueThis study helps in explaining destructive leadership by empirically examining perceptions of narcissism as a driver of abusive supervision. Also, the study reveals the characteristics of narcissistic managers that impede productive relationships with subordinates.

Purpose Missing heritability in human diseases represents a major challenge, and this is particularly true for ABCA4 -associated Stargardt disease (STGD1). We aimed to elucidate the genomic and transcriptomic variation in 1054 unsolved STGD and STGD-like probands. Methods Sequencing of the complete 128-kb ABCA4 gene was performed using single-molecule molecular inversion probes (smMIPs), based on a semiautomated and cost-effective method. Structural variants (SVs) were identified using relative read coverage analyses and putative splice defects were studied using in vitro assays. Results In 448 biallelic probands 14 known and 13 novel deep-intronic variants were found, resulting in pseudoexon (PE) insertions or exon elongations in 105 alleles. Intriguingly, intron 13 variants c.1938-621G>A and c.1938-514G>A resulted in dual PE insertions consisting of the same upstream, but different downstream PEs. The intron 44 variant c.6148-84A>T resulted in two PE insertions and flanking exon deletions. Eleven distinct large deletions were found, two of which contained small inverted segments. Uniparental isodisomy of chromosome 1 was identified in one proband. Conclusion Deep sequencing of ABCA4 and midigene-based splice assays allowed the identification of SVs and causal deep-intronic variants in 25% of biallelic STGD1 cases, which represents a model study that can be applied to other inherited diseases.

To present en face optical coherence tomography (OCT) images generated by graph-search theory algorithm-based custom software and examine correlation with other imaging modalities. En face OCT images derived from high density OCT volumetric scans of 3 healthy subjects and 4 patients using a custom algorithm (graph-search theory) and commercial software (Heidelberg Eye Explorer software (Heidelberg Engineering)) were compared and correlated with near infrared reflectance, fundus autofluorescence, adaptive optics flood-illumination ophthalmoscopy (AO-FIO) and microperimetry. Commercial software was unable to generate accurate en face OCT images in eyes with retinal pigment epithelium (RPE) pathology due to segmentation error at the level of Bruch's membrane (BM). Accurate segmentation of the basal RPE and BM was achieved using custom software. The en face OCT images from eyes with isolated interdigitation or ellipsoid zone pathology were of similar quality between custom software and Heidelberg Eye Explorer software in the absence of any other significant outer retinal pathology. En face OCT images demonstrated angioid streaks, lesions of acute macular neuroretinopathy, hydroxychloroquine toxicity and Bietti crystalline deposits that correlated with other imaging modalities. Graph-search theory algorithm helps to overcome the limitations of outer retinal segmentation inaccuracies in commercial software. En face OCT images can provide detailed topography of the reflectivity within a specific layer of the retina which correlates with other forms of fundus imaging. Our results highlight the need for standardization of image reflectivity to facilitate quantification of en face OCT images and longitudinal analysis.

PurposeThe c.1430A > G (Asp477Gly) variant in RPE65 has been reported in Irish and Scottish families with either an autosomal dominant retinal dystrophy (adRD) that resembles choroideremia, a vitelliform macular dystrophy or an isolated macular atrophy. We report novel features on multimodal imaging and the natural history of a family harbouring this variant in combination with the BEST1 c.37C > T (Arg13Cys) variant.MethodsMembers of a family with an adRD were examined clinically to ascertain phenotype and underwent genetic testing. Multimodal imaging included widefield colour fundus photography, quantitative autofluorescence (qAF) and spectral domain optical coherence tomography. Electrophysiology and microperimetry were also performed.ResultsVision loss was attributed to foveal atrophy in the proband and choroidal neovascularisation and a vitello-eruptive lesion in one affected son. Peripheral retinal white dots corresponding to subretinal deposits were seen in three patients. The median qAF8 values in the proband (I:1) were low (40 and 101 in OD and OS) at age 79. Similarly, the qAF8 values for the middle son (II:2) were also low (100 and 87 in ODS and OS) at age 60. Electrophysiology showed disproportionate reduction in Arden ratio prior to the gradual loss of full-field responses. Microperimetry demonstrated an enlarging scotoma in the proband.ConclusionsThe coexistence of the pathogenic BEST1 c.37C > T variant may modify clinical features observed in RPE65 adRD. This study expands our understanding of RPE65 adRD as a retinoid cycle disorder supported by the reduced qAF, fine white retinal dots and corresponding subretinal deposits on OCT in affected members.

Choroideremia is an X-linked chorioretinal dystrophy caused by mutations in the CHM gene. Several CHM gene replacement clinical trials are in advanced stages. In this study, we report the molecular confirmation of choroideremia in 14 Australian families sourced from the Australian Inherited Retinal Disease Registry and DNA Bank. Sixteen males (14 symptomatic) and 18 females (4 symptomatic; 14 obligate carriers) were identified for analysis. Participants’ DNA was analyzed for disease-causing CHM variants by Sanger sequencing, TaqMan qPCR and targeted NGS. We report phenotypic and genotypic data for the 14 symptomatic males and four females manifesting disease symptoms. A pathogenic or likely pathogenic CHM variant was detected in all families. Eight variants were previously reported, and five were novel. Two de novo variants were identified. We previously reported the molecular confirmation of choroideremia in 11 Australian families. This study expands the CHM genetically confirmed Australian cohort to 32 males and four affected carrier females.Eye disease: Finding new gene variants for choroideremiaAdditional variants of the gene responsible for choroideremia, a rare genetic disease that affects blood flow in the eye, have been identified. Choroideremia is X-linked, which means it is much more likely to manifest in males, who do not have a second X chromosome that could carry a functional gene copy. Over time, choroideremia can cause blindness. Terri McLaren at Sir Charles Gairdner Hospital in Perth, Australia, and co-workers aimed to identify new genetic variants that cause choroideremia. Using gene sequencing technology, they identified affected individuals in 14 Australian families, including five new and eight known variants. Prior to sequencing, other eye diseases (excluding choroideremia) had been diagnosed in over one-third of the families, indicating that choroideremia is underdiagnosed. These results will help to build a database of patients for future genetic and other therapies.

Background Mutations in CLN3 cause Batten disease, however non‐syndromic CLN3 disease, characterized by retinal‐specific degeneration, has been also described. Here, we characterized an induced pluripotent stem cell (iPSC)‐derived disease model derived from a patient with non‐syndromic CLN3‐associated retinopathy. Methods Patient‐iPSC, carrying the 1 kb‐deletion and c.175G>A variants in CLN3, coisogenic iPSC, in which the c.175G>A variant was corrected, and control iPSC were differentiated into neural retinal organoids (NRO) and cardiomyocytes. CLN3 transcripts were analyzed by Sanger sequencing. Gene expression was characterized by qPCR and western blotting. NRO were characterized by immunostaining and electron microscopy. Results Novel CLN3 transcripts were detected in adult human retina and control‐NRO. The major transcript detected in patient‐NRO displayed skipping of exons 2 and 4–9. Accumulation of subunit‐C of mitochondrial ATPase (SCMAS) protein was demonstrated in patient‐derived cells. Photoreceptor progenitor cells in patient‐NRO displayed accumulation of peroxisomes and vacuolization of inner segments. Correction of the c.175G>A variant restored CLN3 mRNA and protein expression and prevented SCMAS and inner segment vacuolization. Conclusion Our results demonstrate the expression of novel CLN3 transcripts in human retinal tissues. The c.175G>A variant alters splicing of the CLN3 pre‐mRNA, leading to features consistent with CLN3 deficiency, which were prevented by gene correction. In this paper, we examined the phenotype of retinal organoids derived from a patient with non‐syndromic CLN3 disease. We showed that accumulation of subunit C of mitochondrial ATPase occurs in patient retinal cells and cardiomyocytes, and could be prevented by gene correction. Additionally, we demonstrated that novel CLN3 transcripts are expressed in the human retina.

Reported growth rates (GR) of atrophic lesions in Stargardt disease (STGD1) vary widely. In the present study, we report the longitudinal natural history of patients with confirmed biallelic ABCA4 mutations from five genotype groups: c.6079C>T, c.[2588G>C;5603A>T], c.3113C>T, c.5882G>A and c.5603A>T. Fundus autofluorescence (AF) 30° × 30° images were manually segmented for boundaries of definitely decreased autofluorescence (DDAF). The primary outcome was the effective radius GR across five genotype groups. The age of DDAF formation in each eye was calculated using the x-intercept of the DDAF effective radius against age. Discordance between age at DDAF formation and symptom onset was compared. A total of 75 eyes from 39 STGD1 patients (17 male [44%]; mean ± SD age 45 ± 19 years; range 21–86) were recruited. Patients with c.3113C>T or c.6079C>T had a significantly faster effective radius GR at 0.17 mm/year (95% CI 0.12 to 0.22; p < 0.001 and 0.14 to 0.21; p < 0.001) respectively, as compared to those patients harbouring c.5882G>A at 0.06 mm/year (95% CI 0.03–0.09), respectively. Future clinical trial design should consider the effect of genotype on the effective radius GR and the timing of DDAF formation relative to symptom onset.

Background Leber congenital amaurosis (LCA) is a severe visual impairment responsible for infantile blindness, representing ~5% of all inherited retinal dystrophies. LCA encompasses a group of heterogeneous disorders, with 24 genes currently implicated in pathogenesis. Such clinical and genetic heterogeneity poses great challenges for treatment, with personalized therapies anticipated to be the best treatment candidates. Unraveling the individual genetic etiology of disease is a prerequisite for personalized therapies, and could identify potential treatment candidates, inform patient management, and discriminate syndromic forms of disease. Methods We have genetically analyzed 45 affected and 82 unaffected individuals from 34 unrelated LCA pedigrees using predominantly next‐generation sequencing and Array CGH technology. Results We present the molecular findings for an Australian LCA cohort, sourced from the Australian Inherited Retinal Disease Registry & DNA Bank. CEP290 and GUCY2D mutations, each represent 19% of unrelated LCA cases, followed by NMNAT1 (12%). Genetic subtypes were consistent with other reports, and were resolved in 90% of this cohort. Conclusion The high resolution rate achieved, equivalent to recent findings using whole exome/genome sequencing, reflects the progression from hypothesis (LCA Panel) to non‐hypothesis (RD Panel) testing and, coupled with Array CGH analysis, is a highly effective first‐tier test for LCA. Leber congenital amaurosis (LCA) is a severe visual impairment responsible for infantile blindness, representing ~5% of all inherited retinal dystrophies. We present the molecular findings for an Australian LCA cohort, sourced from the Australian Inherited Retinal Disease Registry & DNA Bank, which utilized next‐generation sequencing and Array CGH to resolve 90% of this cohort. The high resolution rate achieved, equivalent to recent findings using whole exome/genome sequencing, reflects the progression from hypothesis (LCA Panel) to non‐hypothesis (RD Panel) testing and, coupled with Array CGH analysis, is a highly effective first‐tier test for LCA.