Publications by authors named "Kari Branham"

83 Publications

A Novel Think Tank Program to Promote Innovation and Strategic Planning in Ophthalmic Surgery.

Perioper Care Oper Room Manag 2021 Mar 10;22. Epub 2020 Nov 10.

Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI, USA.

Background: Continuous quality improvement is a pillar of all surgical groups. Innovation is a critical aspect to continuously improve, but traditional staff retreats have several disadvantages which limit their utility in identifying needs and developing innovative solutions. To address these challenges, we designed the novel Think Tank Program to spur innovation and strategic planning for an academic ophthalmology department including the Kellogg Eye Center 6 operating rooms.

Methods: The Think Tank program is a structured seven-phase program for faculty in small teams to identify, innovate, and implement meaningful change. Participants brainstormed problems and possible solutions to those problems, formed teams, acquired data, and implemented meaningful change in clinical care, research, education, and administration.

Results: The program generated 19 novel proposals and significant faculty engagement and discussion in improving the department. A case example of improving the operating room (OR) utilization resulted in improved OR utilization from 63.8% to 74.6% over a 3 month period before and after implementation. It also resulted in a reduction of cancelled or rescheduled surgeries within 2 weeks or surgery from 29.8% to 15.2%. This resulted in an estimated positive financial margin of over $141,000 to the institution in addition to improvement in patient, surgeon, and staff satisfaction with the quality of care.

Conclusions: Engaged faculty, critical data analysis, and value proposition analysis with data-driven metrics and accountability can result in a significant increase in OR utilization and reduction in surgical cancellations. Think Tank serves as a model transformative program to assist practices and institutions to best fulfill their mission while actively engaging and retaining their members.
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http://dx.doi.org/10.1016/j.pcorm.2020.100147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993645PMC
March 2021

Association of No-Cost Genetic Testing Program Implementation and Patient Characteristics With Access to Genetic Testing for Inherited Retinal Degenerations.

JAMA Ophthalmol 2021 Mar 4. Epub 2021 Mar 4.

W. K. Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor.

Importance: The benefits of no-cost genetic testing initiatives have not been characterized. The no-cost My Retina Tracker Genetic Testing Study (MRT-GTS) research registry for inherited retinal degenerations (IRDs) was launched in 2017 in the US.

Objective: To investigate the associations of MRT-GTS implementation and patient characteristics with access to genetic testing for IRDs.

Design, Setting, And Participants: In a cross-sectional design, analysis of new patients evaluated 12 months before (July 1, 2016, to June 13, 2017) and 12 months after (June 14, 2017, to June 30, 2018) MRT-GTS implementation at a single academic referral eye center was conducted. Participants included 369 patients with IRD. Data analysis was conducted from February to June 2020.

Main Outcomes And Measures: Change in rates of successfully obtaining genetic testing, odds ratios (ORs) of association between patient characteristics and obtaining testing, and days elapsed from clinic visit to reporting of results.

Results: Among 369 patients (mean [SD] age, 39.5 [20.8] years; 193 [52.3%] women), 144 were evaluated in the pre-MRT-GTS period and 225 in the post-MRT-GTS period. The baseline rate of successfully obtaining testing was 51.4% (95% CI, 42.6%-60.2%). The initiation of MRT-GTS was associated with a 28.9-percentage point increase in testing rate (95% CI, 16.7%-41.1%; P < .001). Patient characteristics that increased the odds of obtaining testing were eligibility for MRT-GTS (OR, 14.15; 95% CI, 7.36-27.24; P < .001) and worse visual acuity (logMAR +1.0; Snellen equivalent decrease from 20/20 to 20/200) in the better-seeing eye (OR, 1.92; 95% CI, 1.27-2.91; P < .01). Patients had decreased odds when identifying as Black or African American (OR, 0.10; 95% CI, 0.04-0.24; P < .001) or other race (OR, 0.37; 95% CI, 0.15-0.91; P = .03) compared with White race, and when the primary language was not English (OR, 0.13; 95% CI, 0.03-0.55; P < .01). The proportion of test results reported within 90 days was 81.5% (95% CI, 74.8%-86.4%) when eligible for MRT-GTS compared with 48.1% (95% CI, 35.6%-58.1%) when not eligible (P < .001).

Conclusions And Relevance: In this study, the implementation of MRT-GTS was associated with an increase in the proportion of patients who successfully obtained testing, suggesting the potential clinical value of this approach. Patient-level demographic and clinical factors appear to be associated with decisions to pursue testing.
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http://dx.doi.org/10.1001/jamaophthalmol.2021.0004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934082PMC
March 2021

Clinical trial design for neuroprotection in autosomal dominant retinitis pigmentosa; outcome measure considerations.

Ophthalmic Genet 2021 Apr 6;42(2):170-177. Epub 2021 Jan 6.

Department of Ophthalmology and Visual Sciences, University of Michigan Medical School, Ann Arbor, MI, USA.

: To identify structural and functional outcome measures among patients with Rho-positive autosomal dominant Retinitis Pigmentosa (adRP) to aid neuroprotection trial design.: This was a retrospective cohort study of 52 patients with Rho-positive adRP. We measured Goldmann Visual Fields (GVF) constriction in four sectors (nasal, temporal, inferior, superior), and sectoral Ellipsoid Zone (EZ) width degeneration using Spectral Domain Optical Coherence Tomography (OCT) scans. Disease progression trajectories were projected using mixed effects modeling.: Superior GVF was most constricted at presentation and had the shallowest trajectory (less steep negative slope); Inferior GVF was less constricted (corrected < .001) and had a steeper negative slope (corrected = .019) than superior GVF. Temporal EZ was most stable on OCT with a relatively shallow negative trajectory (corrected = .011).: Patients' superior visual fields presented with more constriction and subsequently had a shallow negative slope suggesting the corresponding inferior retina may be "burned out" at presentation. Targeted therapies for adRP will likely show a greater efficacy signal if delivered to the superior and nasal retina, which may demonstrate more change on OCT and GVF over the course of a neuroprotection trial.: Mixed effects analysis of sectoral visual field constriction and EZ degeneration in Rho-positive adRP can prove useful in monitoring therapeutic efficacy and identifying targets for local therapies.
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http://dx.doi.org/10.1080/13816810.2020.1867752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987885PMC
April 2021

The Michigan Vision-Related Anxiety Questionnaire: A Psychosocial Outcomes Measure for Inherited Retinal Degenerations.

Am J Ophthalmol 2020 Dec 9;225:137-146. Epub 2020 Dec 9.

Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan Medical School, Ann Arbor, Michigan, USA. Electronic address:

Objective: We sought to construct and validate a patient-reported outcome measure for screening and monitoring vision-related anxiety in patients with inherited retinal degenerations.

Design: Item-response theory and graded response modeling to quantitatively validate questionnaire items generated from qualitative interviews and patient feedback.

Methods: Patients at the Kellogg Eye Center (University of Michigan, Ann Arbor, Michigan, USA) with a clinical diagnosis of an inherited retinal degeneration (n = 128) participated in an interviewer-administered questionnaire. The questionnaire consisted of 166 items, 26 of which pertained to concepts of "worry" and "anxiety." The subset of vision-related anxiety questions was analyzed by a graded response model using the Cai Metropolis-Hastings Robbins-Monro algorithm in the R software mirt package. Item reduction was performed based on item fit, item information, and item discriminability. To assess test-retest variability, 25 participants completed the questionnaire a second time 4 to 16 days later.

Results: The final questionnaire consisted of 14 items divided into 2 unidimensional domains: rod function anxiety and cone function anxiety. The questionnaire exhibited convergent validity with the Patient Health Questionnaire for symptoms of depression and anxiety. This vision-related anxiety questionnaire has high marginal reliability (0.81 for rod-function anxiety, 0.83 for cone-function anxiety) and exhibits minimal test-retest variability (ρ = 0.81 [0.64-0.91] for rod-function anxiety and ρ = 0.83 [0.68-0.92] for cone-function anxiety).

Conclusions: The Michigan Vision-Related Anxiety Questionnaire is a psychometrically validated 14-item patient-reported outcome measure to be used as a psychosocial screening and monitoring tool for patients with inherited retinal degenerations. It can be used in therapeutic clinical trials for measuring the benefit of an investigational therapy on a patient's vision-related anxiety.
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http://dx.doi.org/10.1016/j.ajo.2020.12.001DOI Listing
December 2020

Genetic testing for inherited retinal degenerations: Triumphs and tribulations.

Am J Med Genet C Semin Med Genet 2020 09 31;184(3):571-577. Epub 2020 Aug 31.

Department of Ophthalmology and Visual Sciences, University of Michigan, Kellogg Eye Center, Ann Arbor, Michigan, USA.

Inherited retinal degenerations (IRDs) are a genotypically and phenotypically diverse group of conditions. Great strides have been made toward identifying the genetic basis for these conditions over the last 30 years-more than 270 different genes involved in syndromic and nonsyndromic forms of retinal dystrophies have now been identified. The identification of these genes and the improvement of clinical laboratory techniques have led to the identification of the genetic basis of disease in 56-76% of patients with IRDs through next generation sequencing and copy number variant analysis. Genetic testing is an essential part of clinical care for patients affected with IRDs and is required to confirm the diagnosis, understand the inheritance of the condition, and determine eligibility for gene-specific treatments or clinical trials. Despite the success achieved in determining the genetic cause of these conditions, several challenges remain, which must be considered when providing genetic testing and genetic counseling to patients. For this reason, an integrated team of ophthalmic and genetic clinicians who are familiar with these challenges is necessary to provide optimal comprehensive care to these patients.
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http://dx.doi.org/10.1002/ajmg.c.31835DOI Listing
September 2020

The Michigan Retinal Degeneration Questionnaire: A Patient-Reported Outcome Instrument for Inherited Retinal Degenerations.

Am J Ophthalmol 2021 02 26;222:60-68. Epub 2020 Aug 26.

Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan Medical School, Ann Arbor, Michigan, USA. Electronic address:

Purpose: To create a psychometrically validated patient-reported outcome measure for inherited retinal degenerations.

Design: Qualitative and quantitative patient-reported outcome (PROs) questionnaire development using item response theory validation.

Methods: One hundred twenty-eight patients with a diagnosis of an inherited retinal degeneration at the Kellogg Eye Center (University of Michigan) were recruited and administered a 166-item questionnaire comprising 7 expert-defined domains. The questionnaire was re-administered 4-16 days later to a subset of 25 participants to assess test-retest variability. Graded response models were fit by Cai's Metropolis-Hastings Robbins-Monro algorithm using the R (version 3.6.3) package mirt. Model data were fit to assess questionnaire dimensionality, to estimate item information, and to score participants. Poorly functioning items were removed, and the model was refit to create the final questionnaire.

Results: The psychometrically validated PROs measure was reduced to a 59-item questionnaire measuring 7 unidimesnional domains: central vision, color vision, contrast sensitivity, scotopic function, photopic peripheral vision, mesopic peripheral vision, and photosensitivity. A total of 39 items were removed because of poor factor loading, low item information, poor person-ability differentiation, or high item-level interdependence. This novel questionnaire produces a reliable domain score for person ability that does not show significant test-retest variability across repeated administration.

Conclusions: The final PRO questionnaire, known as the Michigan Retinal Degeneration Questionnaire, is psychometrically validated and available for use in the evaluation of patients with inherited retinal degenerations.
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http://dx.doi.org/10.1016/j.ajo.2020.08.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907279PMC
February 2021

Advancing Clinical Trials for Inherited Retinal Diseases: Recommendations from the Second Monaciano Symposium.

Transl Vis Sci Technol 2020 06 3;9(7). Epub 2020 Jun 3.

Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan Medical School, Ann Arbor, MI, USA.

Major advances in the study of inherited retinal diseases (IRDs) have placed efforts to develop treatments for these blinding conditions at the forefront of the emerging field of precision medicine. As a result, the growth of clinical trials for IRDs has increased rapidly over the past decade and is expected to further accelerate as more therapeutic possibilities emerge and qualified participants are identified. Although guided by established principles, these specialized trials, requiring analysis of novel outcome measures and endpoints in small patient populations, present multiple challenges relative to study design and ethical considerations. This position paper reviews recent accomplishments and existing challenges in clinical trials for IRDs and presents a set of recommendations aimed at rapidly advancing future progress. The goal is to stimulate discussions among researchers, funding agencies, industry, and policy makers that will further the design, conduct, and analysis of clinical trials needed to accelerate the approval of effective treatments for IRDs, while promoting advocacy and ensuring patient safety.
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http://dx.doi.org/10.1167/tvst.9.7.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414644PMC
June 2020

Implementation of a registry and open access genetic testing program for inherited retinal diseases within a non-profit foundation.

Am J Med Genet C Semin Med Genet 2020 09 11;184(3):838-845. Epub 2020 Aug 11.

Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, USA.

The Foundation Fighting Blindness is a 50-year old 501c(3) non-profit organization dedicated to supporting the development of treatments and cures for people affected by the inherited retinal diseases (IRD), a group of clinical diagnoses that include orphan diseases such as retinitis pigmentosa, Usher syndrome, and Stargardt disease, among others. Over $760 M has been raised and invested in preclinical and clinical research and resources. Key resources include a multi-national clinical consortium, an international patient registry with over 15,700 members that is expanding rapidly, and an open access genetic testing program that provides no cost comprehensive genetic testing to people clinically diagnosed with an IRD living in the United States. These programs are described with particular focus on the challenges and outcomes of establishing the registry and genetic testing program.
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http://dx.doi.org/10.1002/ajmg.c.31825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540299PMC
September 2020

Rapid visual field constriction in a patient with retinitis pigmentosa and pituitary adenoma.

Am J Ophthalmol Case Rep 2020 Sep 2;19:100762. Epub 2020 Jun 2.

Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan, 1000 Wall Street, Ann Arbor, MI, 48105, USA.

Purpose: To report a case of pituitary adenoma in a patient with retinitis pigmentosa (RP) and consequent rapid constriction of the visual field in each eye, which is atypical for either of these pathologies.

Observations: A 45-year old male, with a long-standing history of RP, presented with rapid vision loss over 3 months. Examination revealed a severe drop in visual acuity and significant progression of concentric visual field constriction in each eye compared to 3 months prior. MRI revealed a pituitary macroadenoma compressing the optic chiasm. The patient underwent endoscopic trans-sphenoidal resection of the tumor and experienced partial recovery of visual acuity but not visual field.

Conclusions And Importance: The visual field deficit in this patient was atypical for pituitary adenoma or optic neuropathy. The pattern was most consistent with RP, but the rate of progression was not. In a patient with chiasmal pathology in the setting of pre-existing retinopathy, visual field progression may not be limited exclusively to the bitemporal regions. Rapid constriction of the visual field in a patient with RP should prompt a work-up for alternative etiologies which includes neuro-imaging.
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http://dx.doi.org/10.1016/j.ajoc.2020.100762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296332PMC
September 2020

Coats-like Exudative Vitreoretinopathy in Retinitis Pigmentosa: Ocular Manifestations and Treatment Outcomes.

Ophthalmol Retina 2021 Jan 9;5(1):86-96. Epub 2020 Apr 9.

W. K. Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan. Electronic address:

Purpose: To provide a comprehensive review of the ocular manifestations, outcomes, and genetic findings in patients with Coats-like retinitis pigmentosa (RP).

Design: Multicenter, retrospective, nonconsecutive case series.

Participants: Patients with a diagnosis of RP demonstrating Coats-like exudative vitreoretinopathy between January 1, 2008, and October 1, 2019.

Methods: Evaluation of ocular findings at RP diagnosis and at time of presentation of Coats-like exudative vitreoretinopathy, pedigree analysis, genetic testing, retinal imaging, and anatomic outcomes after treatment.

Main Outcome Measures: Visual acuity, ophthalmoscopy results, OCT results, fluorescein angiography results, and identification of genetic mutations.

Results: Nine patients diagnosed with RP and demonstrating Coats-like exudative vitreoretinopathy were included. Median age at time of RP diagnosis was 8 years (range, 1-22 years), and median age at presentation of Coats-like exudative vitreoretinopathy was 18 years (range, 1-41 years). Seven patients were female, and 2 were male. The genetic cause of disease was identified in 6 patients. Three patients demonstrated Coats-like fundus findings at the time of RP diagnosis. Exudative retinal detachment (ERD) localized to the infratemporal periphery was present in all patients, with bilateral disease observed in 7 patients. In all treated patients, focal laser photocoagulation was used to treat leaking telangiectasias and to limit further ERD expansion. Cystoid macular edema refractory to carbonic anhydrase inhibitor therapy and ultimately amenable to treatment with intravitreal anti-vascular endothelial growth factor injection was observed in 4 patients.

Conclusions: Coats-like vitreoretinopathy is present in up to 5% of all RP patients. The term Coats-like RP is used colloquially to describe this disease state, which can present at the time of RP diagnosis or, more commonly, develops late during the clinical course of patients with longstanding RP. Coats-like RP is distinct from Coats disease in that exudative pathologic features occur exclusively in the setting of a coexisting RP diagnosis, is restricted to the infratemporal retina, can affect both eyes, and does not demonstrate a male gender bias. Given the risk of added vision loss posed by exudative vitreoretinopathy in patients with RP, a heightened awareness of this condition is critical in facilitating timely intervention.
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http://dx.doi.org/10.1016/j.oret.2020.03.026DOI Listing
January 2021

Surgical outcomes of Glaucoma associated with Axenfeld-Rieger syndrome.

BMC Ophthalmol 2020 May 1;20(1):172. Epub 2020 May 1.

Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, 1000 Wall Street, Ann Arbor, MI, 48105, USA.

Background: The surgical management of glaucoma associated with Axenfeld-Rieger Syndrome (ARS) is poorly described in the literature. The goal of this study is to compare the effectiveness of various glaucoma surgeries on intraocular pressure (IOP) management in ARS.

Methods: Retrospective cohort study at a university hospital-based practice of patients diagnosed with ARS between 1973 and 2018. Exclusion criterion was follow-up less than 1 year. The number of eyes with glaucoma (IOP ≥ 21 mmHg with corneal edema, Haabs striae, optic nerve cupping or buphthalmos) requiring surgery was determined. The success and survival rates of goniotomy, trabeculotomy±trabeculectomy (no antifibrotics), cycloablation, trabeculectomy with anti-fibrotics, and glaucoma drainage device placement were assessed. Success was defined as IOP of 5-20 mmHg and no additional IOP-lowering surgery or visually devastating complications. Kaplan-Meier survival curves and the Wilcoxon test were used for statistical analysis.

Results: In 32 patients identified with ARS (median age at presentation 6.9 years, 0-58.7 years; median follow-up 5.4 years, 1.1-43.7 years), 23 (71.9%) patients were diagnosed with glaucoma at median age 6.3 years (0-57.9 years). In glaucomatous eyes (46 eyes), mean IOP at presentation was 21.8 ± 9.3 mmHg (median 20 mmHg, 4-45 mmHg) on 1.0 ± 1.6 glaucoma medications. Thirty-one eyes of 18 patients required glaucoma surgery with 2.2 ± 1.2 IOP-lowering surgeries per eye. Goniotomy (6 eyes) showed 43% success with 4.3 ± 3.9 years of IOP control. Trabeculotomy±trabeculectomy (6 eyes) had 17% success rate with 14.8 ± 12.7 years of IOP control. Trabeculectomy with anti-fibrotics (14 eyes) showed 57% success with 16.5 ± 13.5 years of IOP control. Ahmed© (FP7 or FP8) valve placement (8 eyes) had 25% success rate with 1.7 ± 1.9 years of IOP control. Baerveldt© (250 or 350) device placement (8 eyes) showed 70% success with 1.9 ± 2.3 years of IOP control. Cycloablation (4 eyes) had 33% success rate with 2.7 ± 3.5 years of IOP control. At final follow-up, mean IOP (12.6 ± 3.8 mmHg, median 11.8 mmHg, 7-19 mmHg) in glaucomatous eyes was significantly decreased (p < 0.0001), but there was no difference in number of glaucoma medications (1.6 ± 1.5, p = 0.1).

Conclusions: In our series, greater than 70% of patients with ARS have secondary glaucoma that often requires multiple surgeries. Trabeculectomy with anti-fibrotics and Baerveldt glaucoma drainage devices showed the greatest success in obtaining IOP control.
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http://dx.doi.org/10.1186/s12886-020-01417-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193416PMC
May 2020

Family-based exome sequencing identifies rare coding variants in age-related macular degeneration.

Hum Mol Genet 2020 Jul;29(12):2022-2034

Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen 6500, The Netherlands.

Genome-wide association studies (GWAS) have identified 52 independent variants at 34 genetic loci that are associated with age-related macular degeneration (AMD), the most common cause of incurable vision loss in the elderly worldwide. However, causal genes at the majority of these loci remain unknown. In this study, we performed whole exome sequencing of 264 individuals from 63 multiplex families with AMD and analyzed the data for rare protein-altering variants in candidate target genes at AMD-associated loci. Rare coding variants were identified in the CFH, PUS7, RXFP2, PHF12 and TACC2 genes in three or more families. In addition, we detected rare coding variants in the C9, SPEF2 and BCAR1 genes, which were previously suggested as likely causative genes at respective AMD susceptibility loci. Identification of rare variants in the CFH and C9 genes in our study validated previous reports of rare variants in complement pathway genes in AMD. We then extended our exome-wide analysis and identified rare protein-altering variants in 13 genes outside the AMD-GWAS loci in three or more families. Two of these genes, SCN10A and KIR2DL4, are of interest because variants in these genes also showed association with AMD in case-control cohorts, albeit not at the level of genome-wide significance. Our study presents the first large-scale, exome-wide analysis of rare variants in AMD. Further independent replications and molecular investigation of candidate target genes, reported here, would assist in gaining novel insights into mechanisms underlying AMD pathogenesis.
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http://dx.doi.org/10.1093/hmg/ddaa057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390936PMC
July 2020

X-Chromosome Inactivation Is a Biomarker of Clinical Severity in Female Carriers of RPGR-Associated X-Linked Retinitis Pigmentosa.

Ophthalmol Retina 2020 05 18;4(5):510-520. Epub 2019 Nov 18.

Department of Genetics, University of Texas Health Science Center, Houston, Texas.

Purpose: X-linked retinitis pigmentosa can manifest in female carriers with widely variable severity, whereas others remain unaffected. The contribution of X-chromosome inactivation (XCI) to phenotypic variation has been postulated but not demonstrated. Furthermore, the impact of genotype and genetic modifiers has been demonstrated in affected males but has not been well established in female carriers. The purpose of this study was to describe the scope of clinical phenotype in female carriers with mutations in RPGR and quantify the contribution of genotype, genetic modifiers, and XCI to phenotypic severity.

Design: Cohort study.

Participants: Seventy-seven female carriers with RPGR mutations from 41 pedigrees.

Methods: Coding single nucleotide polymorphisms were sequenced in candidate genetic modifier genes encoding known RPGR-interacting proteins. X-chromosome inactivation ratios were determined in genomic DNA isolated from blood (n = 42) and saliva (n = 20) using methylation status of X-linked polymorphic repeats. These genetic data were compared with disease severity based on quantitative clinical parameters.

Main Outcome Measures: Visual acuity, Humphrey visual field (HVF) results, full-field electroretinography results, and dark adaptation.

Results: Most individuals at all ages were mildly affected or unaffected, whereas those who progressed to moderate or severe vision loss were older than 30 years. RPGR genotype was not associated with clinical severity. The D1264N variant in RPGRIP1L was associated with more severe disease. Skewed XCI toward inactivation of the normal RPGR allele was associated with more severe disease. The XCI ratio in both blood and saliva was a predictor of visual function as measured by HVF diameter, rod amplitude, flicker amplitude, and flicker implicit time. For carriers with extreme XCI skewing of 80:20 or more, 57% were affected severely compared with 8% for those with XCI of less than 80:20 (P = 0.002).

Conclusions: Female carriers with mutations in RPGR demonstrate widely variable clinical severity. X-chromosome inactivation ratios correlate with clinical severity and may serve as a predictor of clinically significant disease. Because RPGR gene therapy trials are underway, a future imperative exists to determine which carriers require intervention and when to intervene. X-chromosome inactivation analysis may be useful for identifying candidates for early intervention.
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http://dx.doi.org/10.1016/j.oret.2019.11.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211129PMC
May 2020

Deep-intronic variants in CNGB3 cause achromatopsia by pseudoexon activation.

Hum Mutat 2020 01 30;41(1):255-264. Epub 2019 Sep 30.

Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany.

Our comprehensive cohort of 1100 unrelated achromatopsia (ACHM) patients comprises a considerable number of cases (~5%) harboring only a single pathogenic variant in the major ACHM gene CNGB3. We sequenced the entire CNGB3 locus in 33 of these patients to find a second variant which eventually explained the patients' phenotype. Forty-seven intronic CNGB3 variants were identified in 28 subjects after a filtering step based on frequency and the exclusion of variants found in cis with pathogenic alleles. In a second step, in silico prediction tools were used to filter out those variants with little odds of being deleterious. This left three variants that were analyzed using heterologous splicing assays. Variant c.1663-1205G>A, found in 14 subjects, and variant c.1663-2137C>T, found in two subjects, were indeed shown to exert a splicing defect by causing pseudoexon insertion into the transcript. Subsequent screening of further unsolved CNGB3 subjects identified four additional cases harboring the c.1663-1205G>A variant which makes it the eighth most frequent CNGB3 variant in our cohort. Compound heterozygosity could be validated in ten cases. Our study demonstrates that whole gene sequencing can be a powerful approach to identify the second pathogenic allele in patients apparently harboring only one disease-causing variant.
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http://dx.doi.org/10.1002/humu.23920DOI Listing
January 2020

Detailed clinical characterisation, unique features and natural history of autosomal recessive -associated retinal degeneration.

Br J Ophthalmol 2019 12 12;103(12):1789-1796. Epub 2019 Apr 12.

Moorfields Eye Hospital NHS Foundation Trust, London, UK.

Background: Defects in retinol dehydrogenase 12 () account for 3.4%-10.5 % of Leber congenital amaurosis and early-onset severe retinal dystrophy (EOSRD) and are a potential target for gene therapy. Clinical trials in inherited retinal diseases have unique challenges, and natural history studies are critical to successful trial design. The purpose of this study was to characterise the natural history of -associated retinal degeneration.

Methods: A retrospective chart review was performed in individuals with retinal degeneration and two likely disease-causing variants in .

Results: 57 subjects were enrolled from nine countries. 33 subjects had clinical records available from childhood. The data revealed an EOSRD, with average age of onset of 4.1 years. Macular atrophy was a universal clinical finding in all subjects, as young as 2 years of age. Scotopic and photopic electroretinography (ERG) responses were markedly reduced in all subjects, and a non-recordable ERG was documented as young as 1 year of age. Assessment of visual acuity, visual field and optical coherence tomography revealed severe loss of function and structure in the majority of subjects after the age of 10 years. Widefield imaging in 23 subjects revealed a unique, variegated watercolour-like pattern of atrophy in 13 subjects and sparing of the peripapillary area in 18 subjects.

Conclusions: This study includes the largest collection of phenotypic data from children with -associated EOSRD and provides a comprehensive description of the timeline of vision loss in this severe, early-onset condition. These findings will help identify patients with -associated retinal degeneration and will inform future design of therapeutic trials.
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http://dx.doi.org/10.1136/bjophthalmol-2018-313580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053401PMC
December 2019

Contrast sensitivity deficits in patients with mutation-proven inherited retinal degenerations.

BMC Ophthalmol 2018 Dec 7;18(1):313. Epub 2018 Dec 7.

Department of Ophthalmology and Visual Sciences, W. K. Kellogg Eye Center, University of Michigan, Ann Arbor, MI, 48150, USA.

Background: Patients with retinal diseases frequently complain of poor visual function even when visual acuity is relatively unaffected. This clinical finding has been attributed to deficits in contrast sensitivity (CS). The purpose of our study was to evaluate the CS in patients with clinical and genetic diagnosis of inherited retinal degeneration (IRD) and relatively preserved visual acuity.

Methods: Seventeen patients (30 eyes) with IRD and visual acuity of 20/40 or better, and 18 controls (18 eyes) without any ocular condition underwent slit lamp examination, visual acuity testing via standard Snellen chart testing, CS testing via the Quick Contrast Sensitivity Function (QCSF), and Spectral Domain Optical Coherence Tomography (SD-OCT). CS were measured at 1.0, 1.5, 3.0, 6.0, 12.0, and 18.0 cycles per degree (cpd). T tests with general estimated equations were used to compare CS between groups. Wald chi square followed by pairwise comparisons was used to compare CS between multiple groups.

Results: We included 12 patients with rod-cone dystrophy (RCD), 3 patients with Stargardt disease (STGD) and 2 patients with Best disease. Patients with IRD had significantly worse CS than controls (p < 0.001) in all spatial frequencies. Patients with STGD had more marked deficits in CS than patients with Best disease (p < 0.001) and RCD (p < 0.001) despite having similar visual acuities.

Conclusion: Patients with IRD, especially patients with STGD with relatively preserved visual acuity have marked deficits in CS when measured across a range of spatial frequencies. We recommend that clinical trials for STGD incorporate CS measured over a range of spatial frequencies as a secondary clinical endpoint for monitoring visual function. CS may provide an explanation for complaints of visual dysfunction when visual acuity is not significantly altered.
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http://dx.doi.org/10.1186/s12886-018-0982-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286564PMC
December 2018

Retinal detachment and infantile-onset glaucoma in Stickler syndrome associated with known and novel COL2A1 mutations.

Ophthalmic Genet 2018 10 21;39(5):615-618. Epub 2018 Aug 21.

a Kellogg Eye Center, Department of Ophthalmology and Visual Sciences , University of Michigan , Ann Arbor , MI , USA.

Background: Few reports on surgical outcomes after retinal detachment in Stickler syndrome exist. Also, infantile-onset glaucoma associated with Stickler syndrome has been rarely reported and no reports exist that examine outcomes after glaucoma surgery. This study describes the clinical and genetic associations and the long-term outcomes of retinal detachment repair or glaucoma surgery in patients with Stickler syndrome.

Materials And Methods: Retrospective, single-center, case series of patients with Stickler syndrome. Demographics, clinical features, genetic mutations, and long-term surgical outcomes of eyes that experienced retinal detachment or diagnosed with infantile-onset glaucoma were assessed.

Results: Fifteen patients were identified with a mean age of 13 years at presentation and followed for a mean of 6 years. Two-thirds were male. Genetic analysis was performed as part of routine examination in nine patients from eight families. All were identified as having variants in COL2A1, three of which were novel. Six eyes of six patients experienced retinal detachment. Fifty percent of eyes without prophylactic laser treatment experienced retinal detachment, whereas only 5% of eyes that underwent prophylactic therapy detached. Despite surgical intervention for retinal detachment, five eyes became phthisical. Five eyes of three patients were diagnosed with infantile-onset glaucoma. All five eyes required multiple glaucoma surgeries, and three eyes became phthisical.

Conclusions: This study illustrates the surgical challenges encountered in patients with Stickler syndrome. Additionally, infantile-onset glaucoma may be more prevalent than previously reported and presents a challenge in terms of management. A multidisciplinary approach is recommended to provide optimal care to these patients.
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http://dx.doi.org/10.1080/13816810.2018.1509355DOI Listing
October 2018

Mutations in the gene PDE6C encoding the catalytic subunit of the cone photoreceptor phosphodiesterase in patients with achromatopsia.

Hum Mutat 2018 10 22;39(10):1366-1371. Epub 2018 Aug 22.

Institute for Ophthalmic Research, Centre for Ophthalmology, University Tuebingen, Tuebingen, Germany.

Biallelic PDE6C mutations are a known cause for rod monochromacy, better known as autosomal recessive achromatopsia (ACHM), and early-onset cone photoreceptor dysfunction. PDE6C encodes the catalytic α'-subunit of the cone photoreceptor phosphodiesterase, thereby constituting an essential part of the phototransduction cascade. Here, we present the results of a study comprising 176 genetically preselected patients who remained unsolved after Sanger sequencing of the most frequent genes accounting for ACHM, and were subsequently screened for exonic and splice site variants in PDE6C applying a targeted next generation sequencing approach. We were able to identify potentially pathogenic biallelic variants in 15 index cases. The mutation spectrum comprises 18 different alleles, 15 of which are novel. Our study significantly contributes to the mutation spectrum of PDE6C and allows for a realistic estimate of the prevalence of PDE6C mutations in ACHM since our entire ACHM cohort comprises 1,074 independent families.
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http://dx.doi.org/10.1002/humu.23606DOI Listing
October 2018

Contribution of noncoding pathogenic variants to RPGRIP1-mediated inherited retinal degeneration.

Genet Med 2019 03 3;21(3):694-704. Epub 2018 Aug 3.

Ocular Genomics Institute, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, USA.

Purpose: With the advent of gene therapies for inherited retinal degenerations (IRDs), genetic diagnostics will have an increasing role in clinical decision-making. Yet the genetic cause of disease cannot be identified using exon-based sequencing for a significant portion of patients. We hypothesized that noncoding pathogenic variants contribute significantly to the genetic causality of IRDs and evaluated patients with single coding pathogenic variants in RPGRIP1 to test this hypothesis.

Methods: IRD families underwent targeted panel sequencing. Unsolved cases were explored by exome and genome sequencing looking for additional pathogenic variants. Candidate pathogenic variants were then validated by Sanger sequencing, quantitative polymerase chain reaction, and in vitro splicing assays in two cell lines analyzed through amplicon sequencing.

Results: Among 1722 families, 3 had biallelic loss-of-function pathogenic variants in RPGRIP1 while 7 had a single disruptive coding pathogenic variants. Exome and genome sequencing revealed potential noncoding pathogenic variants in these 7 families. In 6, the noncoding pathogenic variants were shown to lead to loss of function in vitro.

Conclusion: Noncoding pathogenic variants were identified in 6 of 7 families with single coding pathogenic variants in RPGRIP1. The results suggest that noncoding pathogenic variants contribute significantly to the genetic causality of IRDs and RPGRIP1-mediated IRDs are more common than previously thought.
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http://dx.doi.org/10.1038/s41436-018-0104-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399075PMC
March 2019

IFT88 mutations identified in individuals with non-syndromic recessive retinal degeneration result in abnormal ciliogenesis.

Hum Genet 2018 Jul 5;137(6-7):447-458. Epub 2018 Jul 5.

Shiley Eye Institute, University of California San Diego, 9415 Campus Point Drive, JRC 206, La Jolla, CA, 92093, USA.

Whole genome sequencing (WGS) was performed to identify the variants responsible for inherited retinal degeneration (IRD) in a Caucasian family. Segregation analysis of selected rare variants with pathogenic potential identified a set of compound heterozygous changes p.Arg266*:c.796C>T and p.Ala568Thr:c.1702G>A in the intraflagellar transport protein-88 (IFT88) gene segregating with IRD. Expression of IFT88 with the p.Arg266* and p.Ala568Thr mutations in mIMDC3 cells by transient transfection and in HeLa cells by introducing the mutations using CRISPR-cas9 system suggested that both mutations result in the formation of abnormal ciliary structures. The introduction of the IFT88 p.Arg266* variant in the homozygous state in HeLa cells by CRISPR-Cas9 genome-editing revealed that the mutant transcript undergoes nonsense-mediated decay leading to a significant depletion of IFT88 transcript. Additionally, abnormal ciliogenesis was observed in these cells. These observations suggest that the rare and unique combination of IFT88 alleles observed in this study provide insight into the physiological role of IFT88 in humans and the likely mechanism underlying retinal pathology in the pedigree with IRD.
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http://dx.doi.org/10.1007/s00439-018-1897-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150774PMC
July 2018

Molecular Findings in Families with an Initial Diagnose of Autosomal Dominant Retinitis Pigmentosa (adRP).

Adv Exp Med Biol 2018 ;1074:237-245

The Retina Foundation of the Southwest, Dallas, TX, USA.

Genetic testing of probands in families with an initial diagnosis of autosomal dominant retinitis pigmentosa (adRP) usually confirms the diagnosis, but there are exceptions. We report results of genetic testing in a large cohort of adRP families with an emphasis on exceptional cases including X-linked RP with affected females; homozygous affected individuals in families with heterozygous, dominant disease; and independently segregating mutations in the same family. Genetic testing was conducted in more than 700 families with a provisional or probable diagnosis of adRP. Exceptions to the proposed mode of inheritance were extracted from our comprehensive patient and family database. In a subset of 300 well-characterized families with a probable diagnosis of adRP, 195 (70%) have dominant mutations in known adRP genes but 25 (8%) have X-linked mutations, 3 (1%) have multiple segregating mutations, and 3 (1%) have dominant-acting mutations in genes previously associated with recessive disease. It is currently possible to determine the underlying disease-causing gene and mutation in approximately 80% of families with an initial diagnosis of adRP, but 10% of "adRP" families have a variant mode of inheritance. Informed genetic diagnosis requires close collaboration between clinicians, genetic counselors, and laboratory scientists.
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http://dx.doi.org/10.1007/978-3-319-75402-4_29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138351PMC
May 2019

Identification of Novel Deletions as the Underlying Cause of Retinal Degeneration in Two Pedigrees.

Adv Exp Med Biol 2018 ;1074:229-236

Shiley Eye Institute, University of California San Diego, La Jolla, CA, USA.

Retinal dystrophies are a phenotypically and genetically complex group of conditions. Because of this complexity, it can be challenging in many families to determine the inheritance based on pedigree analysis alone. Clinical examinations were performed and blood samples were collected from a North American (M1186) and a consanguineous Pakistani (PKRD168) pedigree affected with two different retinal dystrophies (RD). Based on the structure of the pedigrees, inheritance patterns in the families were difficult to determine. In one family, linkage analysis was performed with markers on X-chromosome. In the second family, whole-exome sequencing (WES) was performed. Subsequent Sanger sequencing of genes of interest was performed. Linkage and haplotype analysis localized the disease interval to a 70 Mb region on the X chromosome that encompassed RP2 and RPGR in M1186 . The disease haplotype segregated with RD in all individuals except for an unaffected man (IV:3) and his affected son (V:1) in this pedigree. Subsequent analysis identified a novel RPGR mutation (p. Lys857Glu fs221X) in all affected members of M1186 except V:1. This information suggests that there is an unidentified second cause of retinitis pigmentosa (RP) within the family. A novel two-base-pair deletion (p. Tyr565Ter fsX) in CHM (choroideremia) was found to segregate with RD in PKRD168. This paper highlights the challenges of interpreting family history in families with RD and reports on the identification of novel mutations in two RD families.
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http://dx.doi.org/10.1007/978-3-319-75402-4_28DOI Listing
May 2019

Peripheral Pigmented Retinal Lesions in Stargardt Disease.

Am J Ophthalmol 2018 04 27;188:104-110. Epub 2017 Dec 27.

W.K. Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan. Electronic address:

Purpose: To investigate the prevalence of peripheral pigmented retinal lesions and associated clinical findings in patients with Stargardt disease.

Design: Retrospective case series.

Methods: Records at a single academic institution were reviewed for patients with genetically confirmed Stargardt disease with peripheral pigmented retinal lesions on wide-field retinal imaging. For this cohort we described demographics, clinical features, and pathogenic variants.

Results: Out of 62 patients with Stargardt disease and wide-field retinal imaging, 14 had peripheral pigmented retinal lesions. These flat, subretinal lesions were located in the mid or far periphery and had well-defined borders, resembling congenital hypertrophy of retinal pigment epithelium (CHRPE) lesions. For this group of 14 patients, median age at initial diagnosis of Stargardt disease was 9.5 years, and the median duration of disease was 21.5 years. Median Snellen visual acuity was 20/200, and median central scotoma size was 20.0 degrees. All 14 patients had electroretinographic abnormalities. Four out of 14 patients developed new lesions during clinical follow-up.

Conclusions: Wide-field retinal imaging revealed the presence of peripheral pigmented retinal lesions resembling CHRPE lesions in a subset of patients with genetically confirmed Stargardt disease. Presence of these lesions may be associated with severe phenotypes of the disease.
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http://dx.doi.org/10.1016/j.ajo.2017.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994923PMC
April 2018

Peripheral Visual Fields in ABCA4 Stargardt Disease and Correlation With Disease Extent on Ultra-widefield Fundus Autofluorescence.

Am J Ophthalmol 2017 Dec 14;184:181-188. Epub 2017 Oct 14.

Department of Ophthalmology and Visual Sciences, University of Michigan Medical School, Ann Arbor, Michigan. Electronic address:

Purpose: To evaluate the disease extent on ultra-widefield fundus autofluorescence (UWF-FAF) in patients with ABCA4 Stargardt disease (STGD) and correlate these data with functional outcome measures.

Design: Retrospective cross-sectional study.

Methods: Setting: Kellogg Eye Center, University of Michigan.

Study Population: Sixty-five patients with clinical diagnosis and proven pathogenic variants in the ABCA4 gene. Observational Procedures: The UWF-FAF images were obtained using Optos (200 degrees) and classified into 3 types. Functional testing included kinetic widefield perimetry, full-field electroretinogram (ffERG), and visual acuity (VA). All results were evaluated with respect to UWF-FAF classification.

Main Outcome Measures: Classification of UWF-FAF; area comprising the I4e, III4e, and IV4e isopters; ffERG patterns; and VA.

Results: For UWF-FAF, 27 subjects (41.5%) were classified as type I, 17 (26.2%) as type II, and 21 (32.4%) as type III. The area of each isopter correlated inversely with the extent of the disease and all isopters were able to detect differences among UWF-FAF types (IV4e, P = .0013; III4e, P = .0003; I4e, P < .0001 = 3.93e). ffERG patterns and VA were also different among the 3 UWF-FAF types (P < .001 = 6.61e- and P < .001 = 7.3e, respectively).

Conclusion: Patients with widespread disease presented with more constriction of peripheral visual fields and had more dysfunction on ffERG and worse VA compared to patients with disease confined to the macula. UWF-FAF images may provide information for estimating peripheral and central visual function in STGD.
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http://dx.doi.org/10.1016/j.ajo.2017.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5997299PMC
December 2017

C2orf71 Mutations as a Frequent Cause of Autosomal-Recessive Retinitis Pigmentosa: Clinical Analysis and Presentation of 8 Novel Mutations.

Invest Ophthalmol Vis Sci 2017 08;58(10):3840-3850

Institute of Medical Molecular Genetics, University of Zurich, Schlieren, Switzerland 11Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland 12Neuroscience Center Zurich, University and ETH Zurich, Zurich, Switzerland.

Purpose: To define the phenotype of C2orf71 associated retinopathy and to present novel mutations in this gene.

Methods: A retrospective multicenter study of patients with retinopathy and identified C2orf71 mutations was performed. Ocular function (visual acuity, visual fields, electroretinogram [ERG] responses); retinal morphology (fundus, optical coherence tomography); and underlying mutations were analyzed.

Results: Thirteen patients from 11 families, who were aged 7 to 63 years (mean: 32.1 years) at their first examination with presumed compound heterozygous (6/13 patients) or homozygous (7/13 patients) C2orf71 mutations were identified. Eight of the mutations were novel. Truncation mutations were responsible in all cases. Nyctalopia was observed in less than 50% of patients. Visual acuity ranged from 20/20 to light perception. Severe visual loss was associated with atrophic maculopathy. Full-field ERG responses showed severe progressive cone-rod or rod-cone dysfunction. Typical fundus changes were progressive symmetrical retinopathy with an early mild maculopathy and patchy circular midperipheral RPE atrophy. Normal retinal lamination was preserved despite early disruption of the ellipsoid zone and RPE irregularities. Outer retinal tubulations were associated with better-preserved visual acuity.

Conclusions: On the basis of our multicenter analysis, C2orf71 might represent a more frequently mutated gene in autosomal recessive retinitis pigmentosa in some populations. The phenotype analysis over a wide age range showed a variable and progressive retinal degeneration with early onset maculopathy and a better visual potential before the age of 30 years.
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http://dx.doi.org/10.1167/iovs.17-21597DOI Listing
August 2017

Double hyperautofluorescent ring on fundus autofluorescence in ABCA4.

Ophthalmic Genet 2018 Jan-Feb;39(1):87-91. Epub 2017 Jul 20.

a Department of Ophthalmology and Visual Sciences , University of Michigan Medical School , Ann Arbor , Michigan , USA.

We report an unusual phenotype in a child with a clinical diagnosis of recessive Stargardt disease (STGD1) and two pathogenic variants in the ABCA4 gene. Typically, the diagnosis of early-onset STGD1 is challenging because children may present with a variety of fundus changes and a variable rate of progression. At the time of his initial visit, the 6-year-old boy presented with 20/200 OD (right eye) and 20/150 OS (left eye), symmetrical mild foveal atrophy without flecks on fundus exam, and foveal hypoautofluorescence surrounded by a homogeneous hyperautofluorescent background on wide-field fundus autofluorescence. Over 4 years of follow-up, the retinal atrophy continued to progress, resulting in two well-defined and concentric hyperautofluorescent rings: one ring located at the posterior pole and the other located around the peripapillary region. Visual acuity also deteriorated to counting fingers at 4ft OD and 20/500 OS. To the best of our knowledge, this phenotype has not been previously described with the ABCA4 gene.
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http://dx.doi.org/10.1080/13816810.2017.1335330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5950710PMC
March 2018

Reliability of kinetic visual field testing in children with mutation-proven retinal dystrophies: Implications for therapeutic clinical trials.

Ophthalmic Genet 2018 Jan-Feb;39(1):22-28. Epub 2017 Jul 13.

a Department of Ophthalmology and Visual Sciences , W. K. Kellogg Eye Center, University of Michigan Medical School , Ann Arbor , Michigan , USA.

Purpose: Kinetic visual field testing is used to monitor disease course in retinal dystrophy clinical care and treatment response in treatment trials, which are increasingly recruiting children. This study investigates Goldmann visual field (GVF) changes in young children with mutation-proven retinal dystrophies as they age and with progression of the retinal degeneration.

Methods: Retrospective review of children ≤ 17 years old with a mutation-proven retinal dystrophy. Objective clinical disease activity was assessed by a retinal degeneration specialist masked to GVF results. Digital quantification of GVF area was performed.

Results: Twenty-nine children (58 eyes), ages 5-16, were identified. GVF area increased with age despite progression in 20 children and clinical stability in nine children. Mean ± standard error increase in GVF area/year was 333 ± 130 mm (I4e, p = 0.012), 720 ± 155 mm (III4e, p < 0.001), and 759 ± 167 mm (IV4e, p < 0.001), with greater increases at earlier ages. Repeatability coefficients were 7381 mm (I4e), 9379 mm (III4e), and 10346 mm (IV4e), indicating a large variability. At 2.5 years after the baseline GVF the area increased ≥ 20%, the criterion for positive treatment outcome defined in recent published therapeutic trials, in 38% (I4e), 34% (III4e), and 33% (IV4e) of eyes.

Conclusion: In a substantial proportion of children with mutation-proven retinal dystrophies, there is a significant increase in GVF area with age, particularly those < 12 years, despite progression or stability of disease. These findings suggest that change in GVF area in children with retinal dystrophies can be an unreliable measure of response to treatment and on which to base appropriate counseling about visual impairment.
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http://dx.doi.org/10.1080/13816810.2017.1329447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938742PMC
March 2018

A Novel Dominant Mutation in SAG, the Arrestin-1 Gene, Is a Common Cause of Retinitis Pigmentosa in Hispanic Families in the Southwestern United States.

Invest Ophthalmol Vis Sci 2017 05;58(5):2774-2784

Human Genetics Center, School of Public Health, The University of Texas Health Science Center, Houston, Texas, United States 5Ruiz Department of Ophthalmology and Visual Science, McGovern Medical School, The University of Texas Health Science Center, Houston, Texas, United States.

Purpose: To identify the causes of autosomal dominant retinitis pigmentosa (adRP) in a cohort of families without mutations in known adRP genes and consequently to characterize a novel dominant-acting missense mutation in SAG.

Methods: Patients underwent ophthalmologic testing and were screened for mutations using targeted-capture and whole-exome next-generation sequencing. Confirmation and additional screening were done by Sanger sequencing. Haplotypes segregating with the mutation were determined using short tandem repeat and single nucleotide variant polymorphisms. Genealogies were established by interviews of family members.

Results: Eight families in a cohort of 300 adRP families, and four additional families, were found to have a novel heterozygous mutation in the SAG gene, c.440G>T; p.Cys147Phe. Patients exhibited symptoms of retinitis pigmentosa and none showed symptoms characteristic of Oguchi disease. All families are of Hispanic descent and most were ascertained in Texas or California. A single haplotype including the SAG mutation was identified in all families. The mutation dramatically alters a conserved amino acid, is extremely rare in global databases, and was not found in 4000+ exomes from Hispanic controls. Molecular modeling based on the crystal structure of bovine arrestin-1 predicts protein misfolding/instability.

Conclusions: This is the first dominant-acting mutation identified in SAG, a founder mutation possibly originating in Mexico several centuries ago. The phenotype is clearly adRP and is distinct from the previously reported phenotypes of recessive null mutations, that is, Oguchi disease and recessive RP. The mutation accounts for 3% of the 300 families in the adRP Cohort and 36% of Hispanic families in this cohort.
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http://dx.doi.org/10.1167/iovs.16-21341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455168PMC
May 2017

Cystoid macular changes on optical coherence tomography in a patient with maternally inherited diabetes and deafness (MIDD)-associated macular dystrophy.

Ophthalmic Genet 2017 Sep-Oct;38(5):467-472. Epub 2017 Jan 31.

a Kellogg Eye Center , University of Michigan , Ann Arbor , Michigan , USA.

The clinical presentation and optical coherence tomography findings in a patient with maternally inherited diabetes and deafness (MIDD) are presented to highlight the presence of macular cystoid spaces in some patients with this disease. Typically, patients with MIDD demonstrate progression of a pigmentary maculopathy into areas of geographic macular atrophy. At the time of initial visit, the 30-year-old patient had large macular cystoid changes in addition to retinal pigmentary changes in both eyes. The cystoid changes responded to treatment with systemic immunosuppression and a topical carbonic anhydrase inhibitor (CAI), recurred when treated with topical CAI monotherapy, and finally resolved after an intravitreal triamcinolone acetonide injection. Over time, the retinal atrophy continued to progress, but the macular cysts did not recur. The patient received systemic immunosuppression for renal transplantation due to renal failure resulting from focal glomerulosclerosis. There was no evidence of diabetic retinopathy at any time during the five-and-a-half-year follow-up, and the patient retained good visual acuity in both eyes.
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http://dx.doi.org/10.1080/13816810.2016.1253106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568973PMC
December 2017

Genetic analysis of 10 pedigrees with inherited retinal degeneration by exome sequencing and phenotype-genotype association.

Physiol Genomics 2017 Apr 27;49(4):216-229. Epub 2017 Jan 27.

Shiley Eye Institute, University of California San Diego, La Jolla, California;

Our purpose was to identify causative mutations and characterize the phenotype associated with the genotype in 10 unrelated families with autosomal recessive retinal degeneration. Ophthalmic evaluation and DNA isolation were carried out in 10 pedigrees with inherited retinal degenerations (IRD). Exomes of probands from eight pedigrees were captured using Nimblegen V2/V3 or Agilent V5+UTR kits, and sequencing was performed on Illumina HiSeq. The gene was screened for mutations in the remaining two pedigrees with Ashkenazi Jewish ancestry. Exome variants were filtered to detect candidate causal variants using exomeSuite software. Segregation and ethnicity-matched control sample analysis were performed by dideoxy sequencing. Retinal histology of a patient with mutation was studied by microscopy. Genetic analysis identified six known mutations in (p.Gly1961Glu, p.Ala1773Val, c.5461-10T>C), (p.Tyr249Cys, p.Gly484Asp), (p.Lys706Ter) and (p.Lys42Glu) and ten novel potentially pathogenic variants in (p.Met323Val fsX20), (p.Phe252Ser, Thr454Leu fsX31), (p.Arg121His), (p.Gly3142Ter, p.Cys3294Trp), (p.Gln652Ter), and (p.Thr206Ala) genes. Among these, variants/mutations in two separate genes were observed to segregate with IRD in two pedigrees. Retinal histopathology of a patient with a mutation showed severe degeneration of retinal layers with relative preservation of the retinal pigment epithelium. Analysis of exome variants in ten pedigrees revealed nine novel potential disease-causing variants and nine previously reported homozygous or compound heterozygous mutations in the , , , , and genes. Mutations that could be sufficient to cause pathology were observed in more than one gene in one pedigree.
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http://dx.doi.org/10.1152/physiolgenomics.00096.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5407181PMC
April 2017