Epistatic Gene-Based Interaction Analyses for Glaucoma in eMERGE and NEIGHBOR Consortium.

Primary open angle glaucoma (POAG) is a complex disease and is one of the major leading causes of blindness worldwide. Genome-wide association studies have successfully identified several common variants associated with glaucoma; however, most of these variants only explain a small proportion of the genetic risk. Apart from the standard approach to identify main effects of variants across the genome, it is believed that gene-gene interactions can help elucidate part of the missing heritability by allowing for the test of interactions between genetic variants to mimic the complex nature of biology. To explain the etiology of glaucoma, we first performed a genome-wide association study (GWAS) on glaucoma case-control samples obtained from electronic medical records (EMR) to establish the utility of EMR data in detecting non-spurious and relevant associations; this analysis was aimed at confirming already known associations with glaucoma and validating the EMR derived glaucoma phenotype. Our findings from GWAS suggest consistent evidence of several known associations in POAG. We then performed an interaction analysis for variants found to be marginally associated with glaucoma (SNPs with main effect p-value <0.01) and observed interesting findings in the electronic MEdical Records and GEnomics Network (eMERGE) network dataset. Genes from the top epistatic interactions from eMERGE data (Likelihood Ratio Test i.e. LRT p-value <1e-05) were then tested for replication in the NEIGHBOR consortium dataset. To replicate our findings, we performed a gene-based SNP-SNP interaction analysis in NEIGHBOR and observed significant gene-gene interactions (p-value <0.001) among the top 17 gene-gene models identified in the discovery phase. Variants from gene-gene interaction analysis that we found to be associated with POAG explain 3.5% of additional genetic variance in eMERGE dataset above what is explained by the SNPs in genes that are replicated from previous GWAS studies (which was only 2.1% variance explained in eMERGE dataset); in the NEIGHBOR dataset, adding replicated SNPs from gene-gene interaction analysis explain 3.4% of total variance whereas GWAS SNPs alone explain only 2.8% of variance. Exploring gene-gene interactions may provide additional insights into many complex traits when explored in properly designed and powered association studies.

Biology-Driven Gene-Gene Interaction Analysis of Age-Related Cataract in the eMERGE Network.

Bioinformatics approaches to examine gene-gene models provide a means to discover interactions between multiple genes that underlie complex disease. Extensive computational demands and adjusting for multiple testing make uncovering genetic interactions a challenge. Here, we address these issues using our knowledge-driven filtering method, Biofilter, to identify putative single nucleotide polymorphism (SNP) interaction models for cataract susceptibility, thereby reducing the number of models for analysis. Models were evaluated in 3,377 European Americans (1,185 controls, 2,192 cases) from the Marshfield Clinic, a study site of the Electronic Medical Records and Genomics (eMERGE) Network, using logistic regression. All statistically significant models from the Marshfield Clinic were then evaluated in an independent dataset of 4,311 individuals (742 controls, 3,569 cases), using independent samples from additional study sites in the eMERGE Network: Mayo Clinic, Group Health/University of Washington, Vanderbilt University Medical Center, and Geisinger Health System. Eighty-three SNP-SNP models replicated in the independent dataset at likelihood ratio test P < 0.05. Among the most significant replicating models was rs12597188 (intron of CDH1)-rs11564445 (intron of CTNNB1). These genes are known to be involved in processes that include: cell-to-cell adhesion signaling, cell-cell junction organization, and cell-cell communication. Further Biofilter analysis of all replicating models revealed a number of common functions among the genes harboring the 83 replicating SNP-SNP models, which included signal transduction and PI3K-Akt signaling pathway. These findings demonstrate the utility of Biofilter as a biology-driven method, applicable for any genome-wide association study dataset.

Pneumatic Retinopexy with Focal Laser Photocoagulation for Myopic Foveoschisis with Macular Detachment.

PURPOSE: To describe the clinical course and imaging of a case of myopic foveoschisis (MF) with macular detachment (MD), microbreak and epiretinal membrane (ERM) managed with pneumatic retinopexy (PR) and focal laser photocoagulation (FLP) of the microbreak. METHODS: Retrospective Case Review of a highly myopic, phakic Caucasian man who developed vision loss due to MF with MD. RESULTS: 66 year old phakic man with a refractive error of -13.25-2.25x150 in his left eye (OS) and one month visual loss who was diagnosed with MF with MD, microbreak and ERM developed recurrent, isolated, posterior, partial macular detachment one month after PR. CMT was 901um. Repeat PR with supplemental FLP surrounding the inferior macular periarteriolar microbreak achieved re-attachment and improvement in the retinoschisis with return of visual acuity from 20/150 to baseline 20/40+ at 18 month follow-up. CONCLUSION: PR with FLP may provide an alternative to vitrectomy and MP for the repair of MF with MD and ERM.

Sudden vision loss heralding COVID-19-associated aspergillosis. Report of 2 cases.

Purpose: To describe clinical, radiographic, laboratory and cytopathologic findings in 2 patients who developed vision loss due to endogenous aspergillus endophthalmitis during hospitalization for COVID-19 pneumonia. Observations: Two unvaccinated sexagenarian male smokers lost vision within one month of contracting COVID-19 pneumonia. Initially, both received high dose steroids, nasal cannula oxygen and remdesivir. Immunomodulators tocilizumab or baricitinib were added during week 2 in case 1 and 2 respectively. Upon presentation after discharge from a post-COVID rehabilitation unit, visual acuities were light perception and hand motion. In both cases, inpatient blood and ocular fluid cultures were negative, serum 1,3-beta-D-glucan was positive, and vitreous cytopathology revealed filamentous fungi and PCR was positive for Aspergillus fumigatus. Large solitary intravitreal fungus balls were debulked in patient 1 and excised in patient 2. Final visual acuities were no light perception and 20/200 respectively. MRI revealed previously unsuspected brain and lung lesions consistent with disseminated aspergillosis in patient 2. Conclusions: Vision loss due to fungal endophthalmitis may be the first or only sign of systemic aspergillosis associated with COVID-19 pneumonia. Aspergillosis should be suspected in patients who develop vision loss. Diagnosis limited by negative fungal cultures may be confirmed by vitreous cytopathology and PCR. Systemic imaging for disseminated aspergillosis is indicated. Ultimate visual acuity may depend upon surgical approach.

Role of complement cascade in abdominal aortic aneurysms.

OBJECTIVE: The goal of this study was to investigate the role of complement cascade genes in the pathobiology of human abdominal aortic aneurysms (AAAs). METHODS AND RESULTS: Results of a genome-wide microarray expression profiling revealed 3274 differentially expressed genes between aneurysmal and control aortic tissue. Interestingly, 13 genes in the complement cascade were significantly differentially expressed between AAA and the controls. In silico analysis of the promoters of the 13 complement cascade genes showed enrichment for transcription factor binding sites for signal transducer and activator of transcription (STAT)5A. Chromatin-immunoprecipitation experiments demonstrated binding of transcription factor STAT5A to the promoters of the majority of the complement cascade genes. Immunohistochemical analysis showed strong staining for C2 in AAA tissues. CONCLUSIONS: These results provide strong evidence that the complement cascade plays a role in human AAA. Based on our microarray studies, the pathway is activated in AAA, particularly via the lectin and classical pathways. The overrepresented binding sites of transcription factor STAT5A in the complement cascade gene promoters suggest a role for STAT5A in the coordinated regulation of complement cascade gene expression.

CASE OF METASTATIC UROTHELIAL CARCINOMA OF THE RETINA AND VITREOUS.

PURPOSE: To report a rare case of vitreo-retinal metastasis from urothelial carcinoma of the bladder. METHODS: Case report. RESULTS: A 55-year-old man with a history of bladder cancer developed atypical vitritis and a white fundus mass. Intravenous fluorescein angiography demonstrated connection between the retinal and tumor vasculature consistent with a retinal malignancy. Cytologic analysis of the vitreous sample revealed large, atypical cells with pleomorphic nuclei, mucin vacuoles, and rare mitotic figures. The cells were immunoreactive for cytokeratin markers AE1/AE3, CK7, and CK20 and the urothelial carcinoma marker GATA3. Review of the patient's initial bladder tumor revealed an anaplastic epithelial neoplasm with dyscohesive cells that appeared histologically identical to those in the vitreous biopsy. Despite external beam radiation therapy, the patient's vision declined and the eye became painful and was ultimately enucleated. CONCLUSION: Retinal metastasis from systemic adenocarcinoma is an extremely rare occurrence with poor prognosis for vision.

Prototype Development: Context-Driven Dynamic XML Ophthalmologic Data Capture Application.

BACKGROUND: The capture and integration of structured ophthalmologic data into electronic health records (EHRs) has historically been a challenge. However, the importance of this activity for patient care and research is critical. OBJECTIVE: The purpose of this study was to develop a prototype of a context-driven dynamic extensible markup language (XML) ophthalmologic data capture application for research and clinical care that could be easily integrated into an EHR system. METHODS: Stakeholders in the medical, research, and informatics fields were interviewed and surveyed to determine data and system requirements for ophthalmologic data capture. On the basis of these requirements, an ophthalmology data capture application was developed to collect and store discrete data elements with important graphical information. RESULTS: The context-driven data entry application supports several features, including ink-over drawing capability for documenting eye abnormalities, context-based Web controls that guide data entry based on preestablished dependencies, and an adaptable database or XML schema that stores Web form specifications and allows for immediate changes in form layout or content. The application utilizes Web services to enable data integration with a variety of EHRs for retrieval and storage of patient data. CONCLUSIONS: This paper describes the development process used to create a context-driven dynamic XML data capture application for optometry and ophthalmology. The list of ophthalmologic data elements identified as important for care and research can be used as a baseline list for future ophthalmologic data collection activities.

A CASE OF METASTATIC UROTHELIAL CARCINOMA OF THE RETINA AND VITREOUS.

PURPOSE: To report a rare case of vitreoretinal metastasis from urothelial carcinoma of the bladder. METHODS: Case report. RESULTS: A 55-year-old male with a history of bladder cancer developed atypical vitritis and a white fundus mass. IV fluorescein angiography demonstrated connection between the retinal and tumor vasculature consistent with a retinal malignancy. Cytologic analysis of the vitreous sample revealed large atypical cells with pleomorphic nuclei, mucin vacuoles, and rare mitotic figures. The cells were immunoreactive for cytokeratin markers AE1/AE3, CK7, and CK20 and urothelial carcinoma marker GATA3. Review of the patient's initial bladder tumor revealed an anaplastic epithelial neoplasm with dyscohesive cells that appeared histologically identical to those in the vitreous biopsy. Despite external beam radiation therapy, the patient's vision declined and the eye became painful and was ultimately enucleated. CONCLUSION: Retinal metastasis from systemic adenocarcinoma is extremely rare occurrence with poor prognosis for vision.

Cancer-associated retinopathy with unusual retinal whitening.

PURPOSE: To describe the clinical characteristics and results of ocular and systemic testing in an atypical case of cancer-associated retinopathy. METHODS: This study is a retrospective case report of a female patient. RESULTS: Rapidly progressive visual loss, vitritis, white, ring- and coin-shaped retinal lesions, and panretinal optical coherence tomography thinning preceded the diagnosis of poorly differentiated cervical carcinoma with neuroendocrine features consistent with small-cell carcinoma. CONCLUSION: Cancer-associated retinopathy can present with ring- and coin-shaped retinal lesions, vitritis, and panretinal thinning. The presence of intraocular inflammation and retinal and choroidal vasculopathy may herald more rapid visual demise.

Posterior segment manifestations of HIV/AIDS.

The ocular posterior segment manifestations of AIDS may be divided into four categories: retinal vasculopathy, unusual malignancies, neuro-ophthalmologic abnormalities, and opportunistic infections. Microvasculopathy is the most common manifestation. Opportunistic infections, particularly cytomegalovirus retinitis and progressive outer retinal necrosis, are the most likely to result in visual loss due to infection or subsequent retinal detachment. Diagnosis and treatment are guided by the particular conditions and immune status of the patient.

X-linked retinoschisis: a clinical and molecular genetic review.

X-linked retinoschisis is a leading cause of macular degeneration in male children. It is characterized by a high degree of clinical variability. Clinical features include a stellate foveal retinoschisis, with or without peripheral retinoschisis. The schisis occurs within the inner retina, primarily at the level of the nerve fiber layer. The disease-causing gene, X-linked retinoschisis 1, has recently been identified, and is expressed in photoreceptor and bipolar cells. This gene codes for retinoschisin, a secreted protein containing a discoidin domain which may be involved in cellular adhesion or cell-cell interactions. The identification of this gene allows for improved diagnosis and contributes to the understanding of this condition. Visual prognosis is variable, as X-linked retinoschisis exhibits a high degree of phenotypic variability. Although there is no treatment to halt the progressive maculopathy, clinical management is directed toward treatment of amblyopia and surgical correction of certain complications. X-linked retinoschisis is an important condition to study, both to improve the clinical management of this disorder, and to better understand retinal function and development. Herein, we review the clinical, histopathologic, and molecular genetic and treatment options of X-linked retinoschisis.

Exudative retinal detachment due to small noncalcified retinal astrocytic hamartoma.

PURPOSE: To report a case of exudative retinal detachment due to small noncalcified retinal astrocytic hamartoma and review pertinent literature. DESIGN: Case report and review of literature. METHODS: Clinical examination, fluorescein angiography, optical coherence tomography, and laser treatment were performed. RESULTS: Exudative macular detachment caused by a small noncalcified retinal astrocytic hamartoma confirmed by optical coherence tomography regressed completely after laser therapy. Visual acuity improved only slightly because lamellar macular thinning developed after subretinal fluid and macular exudates resolved. CONCLUSIONS: Small noncalcified, parafoveal retinal astrocytic hamartomas may cause macular retinal detachment. Optical coherence tomography may aid in the diagnosis of the tumor. Argon laser photocoagulation may induce tumor regression and resolution of exudative detachment. Final visual acuity may be limited in some cases.

Autosomal dominant Stargardt-like macular dystrophy: identification of a new family with a mutation in the ELOVL4 gene.

PURPOSE: To describe the clinical features and identify the mutation responsible for an autosomal dominant macular degeneration occurring in a four-generation family. METHODS: Family members underwent clinical examination and genealogical characterization. Mutation screening of the ELOVL4 gene was performed. RESULTS: Patients reported visual loss occurring at a mean age of 20 years. Fundus examination revealed varying degrees of central macular atrophy with or without flecks in all affected individuals. DNA sequence analysis showed a 5-bp deletion in exon 6 of the ELOVL4 gene, confirming the diagnosis of autosomal dominant Stargardt-like macular dystrophy. Genealogical analysis showed that this family represents a new affected branch of a previously described 12-generation family (31 branches) with this disorder. CONCLUSIONS: We characterized a new branch of a family with autosomal dominant Stargardt-like macular dystrophy. Identification of the disease-causing gene allows for improved genetic counseling of affected individuals.

X-linked retinoschisis: report of a family with a rare deletion in the XLRS1 gene.

PURPOSE: To describe the clinical features and identify the disease causing mutation in a family with X-linked retinoschisis. DESIGN: Cohort study. METHODS: Genealogical investigation and mutation screening of the XLRS1 gene were performed in a four generation family of Icelandic ancestry. Three affected family members were evaluated clinically over a 29-year period. RESULTS: A rarely reported, four base pair deletion (375- 378 del AGAT) in exon 5 of the XLRS1 gene was found in all affected males. A high degree of intrafamilial variability was observed in the progression of the disorder over 29 years. CONCLUSIONS: Identification of the disease causing mutation in this family allows for the diagnosis of individuals at risk for this inherited macular degeneration. Furthermore, the long-term follow-up of subjects with identical mutations helps to better characterize the highly variable clinical course of this disorder.

X-linked retinoschisis: novel mutation in the initiation codon of the XLRS1 gene in a large family.

PURPOSE: To describe a novel point mutation in the initiation codon of the XLRS1 gene in a large family and the clinical features of males affected with X-linked juvenile retino-schisis. METHODS: Genealogic investigation and mutation screening of the XLRS1 gene were performed for a 4-generation family consisting of 72 members. Affected males were evaluated clinically between 1986 and 2004 with up to 18 years of follow-up. RESULTS: We identified a novel point mutation (1A>T transversion) in the initiation codon of the XLRS1 gene in affected males resulting in an amino acid substitution of methionine to leucine (Met1Leu), therefore abolishing the translation initiation Met codon. CONCLUSION: Identification of the disease-causing mutation in this family with long-term follow-up allows for earlier and more accurate identification of individuals at risk for this inherited progressive macular degeneration, provides for more accurate genetic counseling, and contributes to our understanding of the pathophysiology of this disorder.

Voluntary suppression of the multifocal electroretinogram.

OBJECTIVE: To describe multifocal electroretinogram (mfERG) responses in 2 patients with nonorganic visual loss and in 11 eyes of 6 healthy persons who suppressed their mfERG responses. DESIGN: Observational case series. METHODS: The mfERG results were recorded in all individuals using the Veris Science 4.2 instrument. All subjects were instructed to adjust the hexagonal test pattern so that it was in best focus. A second mfERG was recorded subsequently in volunteers who attempted suppression with inattention and poor fixation and by adjusting the focus to greatest blur. MAIN OUTCOME MEASURES: Amplitude and latency of mfERG responses. RESULTS: Suppressed mfERGs in patients with nonorganic visual loss and healthy volunteers demonstrated reduced amplitude, especially centrally. Amplitude reduction was statistically significant in the postsuppression as compared with the presuppression recordings in wave forms N1 and N2. Statistically significant shortening of postsuppression implicit times of P1 and N2 waveforms also was demonstrated. CONCLUSIONS: The mfERG responses may be suppressed voluntarily. Amplitude may be reduced. In contrast to most reported pathologic conditions, the implicit time is shortened.