BEST1 Variant Associated with an Atypical Macular and Peripheral Retinal Phenotype.

PURPOSE: Best vitelliform macular dystrophy (BVMD) is an inherited macular dystrophy associated with over 250 pathogenic variants of the Bestrophin-1 (BEST1) gene. While several of the types of lesions of BVMD are well-described, reports of phenotypic variations associated with rare genetic variants are limited. METHODS: Retrospective case-series performed in 2021 at a tertiary eye care center. PATIENTS: Three members of one family referred to a tertiary eye care clinic for evaluation of their autosomal dominant macular dystrophy. RESULTS: Study subjects presented with atypical findings of peripheral schisis-like lesions and atrophy with abnormal electroretinogram (ERG) in addition to typical macular lesions found in BVMD. Genetic analyses identified a heterozygous BEST1 c.227T>A, p.(Ile76Asn) pathogenic variant in all three subjects. CONCLUSIONS: This study represents the first report of the phenotype associated with the c.227T>A, p.(Ile76Asn) BEST1 variant, which - while mentioned twice in the literature - has not been previously described. The phenotype is unique, comprising features of typical BVMD with ERG and peripheral findings, suggestive of a panretinal dysfunction.

A novel ocular phenotype associated with pathogenic variants in MFSD8 leading to macular dystrophy.

BACKGROUND: The major facilitator superfamily domain-containing protein 8 (MFSD8) pathogenic variants are classically associated with autosomal recessive neuronal ceroid lipofuscinosis-7. Case reports have recently demonstrated an association of MFSD8 variants causing autosomal recessive macular dystrophy with central cone involvement without neurologic sequelae. We report a patient with a novel ocular phenotype associated with MFSD8 pathogenic variants causing macular dystrophy without systemic findings. CASE PRESENTATION: A 37-year-old female presented with a 20-year history of progressive bilateral vision loss. Fundus examination was notable for a slight pigmentary ring around the fovea in both eyes. Optical coherence tomography (OCT) of the macula showed bilateral subfoveal ellipsoid zone loss without outer retinal changes. Fundus autofluorescence (FAF) demonstrated foveal hypo-autofluorescence (AF) in both eyes as well as hyper-AF nasally to the optic nerve in the perifoveal area. Full-field and multifocal electroretinography demonstrated cone dysfunction with diffuse macular changes in both eyes. Subsequent genetic testing identified two pathogenic MFSD8 variants. The patient had no neurologic symptoms consistent with variant-late infantile neuronal ceroid lipofuscinosis. CONCLUSION: MFSD8 pathogenic variants are known to cause macular dystrophies. We report a novel MFSD8-associated macular dystrophy phenotype demonstrating foveal-limited disease with cavitary changes on OCT without inner retinal atrophy and foveal-specific changes on FAF. A threshold model can explain how a hypomorphic missense variant heterozygous with a loss-of-function nonsense variant can lead to a predominantly ocular phenotype with preserved neurologic function. We recommend careful monitoring of these patients for future signs of both retinal and systemic disease progression.

TOPICAL CARBONIC ANHYDRASE INHIBITORS IN THE LONG-TERM TREATMENT OF JUVENILE X-LINKED RETINOSCHISIS.

PURPOSE: To describe the response to long-term topical dorzolamide treatment in patients with juvenile X-linked retinoschisis and cystic-like foveal lesions. METHODS: This was a retrospective interventional case series that included 18 eyes of 10 patients with genetically confirmed juvenile X-linked retinoschisis examined at the Cleveland Clinic Cole Eye Institute, a tertiary referral center, between 2005 and 2021. Patients were treated with topical 2% dorzolamide two to three times daily in both eyes. Two eyes were excluded because of retinal detachment. Primary outcome measures were logarithm of minimum angle of resolution visual acuity and optical coherence tomography based central subfield thickness. RESULTS: The mean follow-up was 8.38 years (SD, 3.41 years). The mean baseline and final central subfield thickness was 429.88 µ m (SD, 143.36 µ m) and 372.28 µ m, respectively (SD, 147.13 µ m, P = 0.10). The mean baseline and final logarithm of minimum angle of resolution visual acuity was 0.45 (SD, 0.17) and 0.34, respectively (SD, 0.22, P < 0.01). None of the patients experienced any side effects from topical dorzolamide. CONCLUSION: The study data support previous reports of improved visual acuity in X-linked retinoschisis patients on topical dorzolamide treatment. This is the longest follow-up for a series of juvenile X-linked retinoschisis patients treated with a topical carbonic anhydrase inhibitor to date. A large, prospective, randomized clinical trial is needed to provide stronger evidence regarding the efficacy of topical carbonic anhydrase inhibitors in juvenile X-linked retinoschisis.

Severe retinal complications in Knobloch Syndrome - Three siblings without clinically apparent occipital defects and a review of the literature.

BACKGROUND: Knobloch syndrome results from recessive mutations in COL18A1 and is characterized by retinopathy and occipital scalp, brain and skull defects. METHODS AND MATERIALS: We report three siblings, born to consanguineous parents, two of whom with genetically confirmed Knobloch syndrome due to a homozygous pathogenic variant c.4054_4055del; p.Leu1352Valfs*72 in COL18A1. RESULTS: With the lack of classic occipital findings, an initial diagnosis of familial exudative vitreoretinopathy was entertained in these siblings because of the history of retinal detachments, retinal pigmentary changes and abnormal vitreous. The diagnosis of Knobloch syndrome was eventually made through molecular genetic testing using an extensive panel. In one patient presenting with acute retinal detachment and posteriorly dislocated intraocular lens implant, reattachment surgery was successful in stabilizing vision. CONCLUSION: The clinical diagnosis of Knobloch syndrome can be difficult to reach in the absence of the typical occipital scalp defects. A careful medical history, detailed clinical examination and molecular genetic testing will reveal the correct diagnosis of Knobloch syndrome in atypical cases.

Germ Line BAP1 Mutation in Patients with Uveal Melanoma and Renal Cell Carcinoma.

Uveal melanoma (UM) and renal cell carcinoma (RCC) can occur sporadically and as a manifestation of BAP1 tumor predisposition syndrome. We aimed to understand the prevalence of germ line BAP1 pathogenic variants in patients with UM and RCC. We reviewed patients managed at Cleveland Clinic between November 2003 and November 2019 who were diagnosed with UM and RCC. Charts were reviewed for demographic and cancer-related characteristics. RCC samples were tested for BAP1 protein expression using immunohistochemical (IHC) staining, and testing for germ line BAP1 pathogenic variants was performed as part of routine clinical care. Thirteen patients were included in the study. The average age at diagnosis of UM was 61.3 years. Seven patients underwent fine-needle aspiration biopsy for prognostic testing of UM (low risk =5, high risk =2). Twelve patients were treated with plaque radiation therapy, and 3 patients developed metastatic disease requiring systemic therapy. The median time to diagnosis of RCC from time of diagnosis of UM was 0 months. RCC samples were available for 7 patients for BAP1 IHC staining (intact =6, loss =1). All patients underwent nephrectomy (total = 3, partial = 8, unknown =2), and 1 received systemic therapy for metastatic RCC. Six patients underwent germ line BAP1 genetic testing. Of these, 1 patient was heterozygous for a pathogenic variant of BAP1 gene: c.1781-1782delGG, p.Gly594Valfs*48. The overall prevalence of germ line BAP1 pathogenic variants in our study was high (1/6; 17%; 95% CI 0-46%). Patients with UM and RCC should be referred for genetic counseling to discuss genetic testing.

Retinoblastoma in twins: Risk assessment of genotypic variants.

Purpose: To describe methods of risk assessment in twins with retinoblastoma (RB). Methods: A case series of four RB probands with a twin sibling. Family status, clinical presentation, and RB1 germline status-based risk assessment were analyzed. Results: Two pairs had a positive family history (unilateral and bilateral RB in one of the parents (#1 and #2, respectively) and two pairs (#3 and #4) were sporadic. One of the familial twins (#1) had a high risk (90%) of manifesting RB in the twin. The other case (#2) with an absent RB1 germline mutation in the twin had a 0% risk of developing RB. Among sporadic cases of twins (#3), genetic testing did not identify a germline mutation (tumor sample unavailable) in the proband which downgraded the risk of germline mutation from 15% to <1%. The twin never developed RB (5 years of age at last follow-up). Pathogenic mosaicism for germline RB1 mutation (c.1723C>T) could be identified (tumor tissue available) in the proband (# 4). Identical germline mutation (and RB tumor) was also noted in the twin. In each case, there was concordance between the assessed risk and manifestation of RB. Conclusion: Assessment of risk of RB in a twin presents with a unique challenge. Depending upon the genotype variant, the risk of developing RB can vary from 0% to 90%. In addition to family history, clinical manifestation in the proband, zygosity status, and RB1 germline status are critical in formulating risk-appropriate surveillance guidelines.

Correlation between Argus II array-retina distance and electrical thresholds of stimulation is improved by measuring the entire array.

PURPOSE: To describe two methods of measuring Argus II array-retina distance and to correlate array-retina distance to electrode stimulation thresholds. METHODS: This was a case series of eight patients implanted with the Argus II. Spectral domain-optical coherence tomography array-retina distance was measured by two methods and correlated to corresponding electrode thresholds: (1) array-retina distance at each array corner and the largest array-retina distance and (2) using manual optical coherence tomography segmentation, the average array-retina distance was determined for each group of four electrodes. Patients 1-5 and 6-8 were analyzed separately due to a different threshold programming software. RESULTS: The Spearman's rank coefficient between array-retina distance and thresholds was -0.006 (p = 0.98) for patients 1-5, and 0.16 (p = 0.59) for patients 6-8 with the first method. The Spearman's rank coefficient was 0.25 (p < 0.001) for patients 1-5 and 0.36 (p < 0.001) for patients 6-8 with the second method. CONCLUSION: There is a positive correlation between array-retina distance and threshold measurements when measuring the entire array but not when using a faster measurement method of four corners and largest array-retina distance.

Cellular Changes in Retinas From Patients With BEST1 Mutations.

Best disease (BD), also known as vitelliform macular dystrophy, is an inherited disease of the central retina caused by more than 300 pathogenic variants in the BEST1 gene. The phenotype of BD is variable, and there are just a few reports on the histopathology of eyes from donors with BD. Here, we describe the histopathological comparison of donor's eyes from two patients with BD. Eyes obtained from 85-year-old (donor 1) and 65-year-old (donor 2) donors were fixed within 25 h postmortem. Perifoveal and peripheral retinal regions were processed for histology and immunocytochemistry using retinal-specific and retinal pigment epithelium (RPE)-specific antibodies. Three age-matched normal eyes were used as controls. DNA was obtained from donor blood samples. Sequence analysis of the entire BEST1 coding region was performed and identified a c.886A > C (p.Asn296His) variant in donor 1 and a c.602T > C (p.Ile201Thr) variant in donor 2; both mutations were heterozygous. Fundus examination showed that donor 1 displayed a macular lesion with considerable scarring while donor 2 displayed close to normal macular morphology. Our studies of histology and molecular pathology in the perifovea and periphery of these two BD donor eyes revealed panretinal abnormalities in both photoreceptors and RPE cellular levels in the periphery; donor 1 also displayed macular lesion. Our findings confirm the phenotypic variability of BD associated with BEST1 variants.

Evidence of complement dysregulation in outer retina of Stargardt disease donor eyes.

Stargardt macular degeneration (STGD) is a central blinding disease caused by loss of or dysfunctional ABCA4 transporter in both photoreceptors and retinal pigment epithelial (RPE) cells. Toxic bisretinoid-lipofuscin buildup in the RPE cells is a pathological hallmark of STGD patients and its mouse model, the Abca4-/-. These vitamin A-derived fluorophores have been shown to induce oxidative stress, stimulate complement activity, and cause chronic inflammation of the RPE. In vivo modulation of complement regulatory pathway in the STGD mouse model has partially rescued the STGD phenotype suggesting that complement attack on the RPE is an important etiologic factor in disease pathogenesis. While bisretinoid-dependent complement activation was further evidenced in cultured RPE cells, this pathway has never been investigated directly in the context of RPE from STGD donor eyes. In the current study, we evaluate the complement reactivity in postmortem donor eyes of clinically diagnosed STGD patients. All three STGD donor eyes RPE displayed strong immunoreactivity for an antibody specific to 4-Hydroxynonenal, a lipid peroxidation byproduct. Also, unlike the control eyes, all three STGD donor eyes showed significantly increased membrane attack complex deposition on the RPE cells. In STGD eyes, increased MAC accumulation was mirrored by elevated C3 fragments internalized by the RPE and inversely correlated with the levels of complement factor H, a major complement regulatory protein. Here, we report the first direct evidence of RPE complement dysregulation as a causative factor in developing Stargardt phenotype.

An Online Application for Retinoblastoma Surveillance.

BACKGROUND: Retinoblastoma (RB) is a potentially heritable childhood cancer that is vision- and life-threatening. Assessing the risk of inheriting RB is important for structuring ophthalmic and genetic screening of family members. PURPOSE: To create a free online application that integrates phenotypic, genetic, and familial relationships with clinical best practice surveillance guidelines for families with RB. METHODS: The risk of germline RB1 gene mutation was assessed for first- and second-degree relatives of a proband under variable clinical scenarios, integrating age, phenotype, relationship data, and genotype (germline RB1 mutation status: detected, undetected, not tested). Based on the assessed risk of a germline RB1 mutation, recommendations regarding further genetic testing as well as ophthalmic surveillance were derived from consensus guidelines. RESULTS: The recommendations depend on the RB1 germline mutation status (detected, undetected, not tested), which were further subcategorized by the results of tumor phenotype, relationship to proband, age of the relative, and family structure. The online application is available at https://nakul-singh.shinyapps.io/RB_Screening_rec/. CONCLUSIONS: The assessed risk of germline RB1 mutation determines ophthalmic surveillance recommendations. The tool may have most value in regions where access to specialized care is limited.

Inherited retinal degeneration current genetics practices - a needs assessment.

BACKGROUND: Clinical assessment of patients with IRD often includes thorough documentation of medical and ocular history in addition to genetics related practices like assessing the family history and genetic testing. Previous studies have demonstrated the genetic counseling needs of IRD patients are not being fully met, but there is a lack of literature showing the current genetics practices of ophthalmologists and optometrists in the U.S. The goal of this study is to assess the current genetics related practices being provided to patients with IRD. METHODS: Data from 51 survey participants were included in the analysis. The survey assessed their current practices of risk counseling to patients with IRD, their confidence level of ocular genetics, and resources they may utilize in the future. Descriptive statistics were used to summarize quantitative data while data from open ended responses were coded using thematic analysis generated through grounded theory. RESULTS: Responses suggest some discussion of genetics is occurring with IRD patients. However, there are limitations to these discussions given time constraints and lack of understanding of the genetics of IRDs and available testing. The study also revealed that there are minimal referrals to genetic counseling being made at this time, though there is interest in working with genetic counselors. Additionally, there is a need for continued education regarding the genetics related to IRDs. CONCLUSION: Future larger-scale studies are warranted to provide additional insight into these genetics related practices and where genetic counselors are needed in this field.

A novel TIMP3 mutation associated with a retinitis pigmentosa-like phenotype.

BACKGROUND: Sorsby Fundus Dystrophy is an inherited macular degeneration caused by pathogenic variants in the TIMP3 gene. Clinical exam findings typically drusen -like deposits beneath the RPE or reticular pseudo drusen deposits above the RPE with a majority of patients developing choroidal neovascularization. MATERIALS AND METHODS: Case report of two members of a family that present with atypical clinical exam findings. Protein modeling of the novel Y137CTIMP3 variant was performed and compared with other known variants. RESULTS: In this study we describe a father and son initially diagnosed with retinitis pigmentosa of unknown genetic origin. More recent genetic testing of the patients, identified a novel c.410A>G; p.Tyr137Cys variant of uncertain clinical significance in the Tissue Inhibitor of Metalloproteinase-3 (TIMP3) gene. The atypical clinical findings led us to compare the theoretical molecular effects of this variant on the TIMP3 protein structure and interactions with other proteins using homology modeling and machine learning predictions. CONCLUSIONS: It is important to consider mutations in TIMP3 in atypical cases of Retinitis Pigmentosa particularly in the absence of known variants.

Hickam's Dictum: Pseudoxanthoma elasticum and Usher syndrome in a single patient.

BACKGROUND: To report the case of a patient with two distinct genetic systemic diseases - pseudoxanthoma elasticum (PXE) and Usher syndrome - confirmed by genetic testing. MATERIALS AND METHODS: Single Retrospective Case Report. RESULTS: A 36-year-old woman presented with acute central vision loss of the left eye (OS). Fundus exam revealed choroidal neovascularization OS in the setting of angioid streaks secondary to an underlying diagnosis of PXE. Unexpectedly, she also exhibited peripheral bony spicules with significant visual field constriction. Physical exam revealed skin papules on her neck and hearing loss. The presence of angioid streaks and skin findings was compatible with PXE; the etiology of her pigmentary retinopathy and hearing loss was elucidated using genetic testing. The patient was found to be compound heterozygous for pathogenic variants in both the ABCC6 and USH2A genes, confirming the diagnosis of two rare disorders in a single patient. CONCLUSIONS: PXE and Usher syndrome are rare systemic disorders that cause distinctive retinal abnormalities. This report highlights the importance of genetic testing in diagnosing uncommon hereditary retinal disorders and outlines the progression of disease over 6 years.

Towards safe operation of an active retinal prosthesis during functional MRI and diffusion tensor imaging.

OBJECTIVE: To determine if the Argus II retinal prosthesis can operate during functional MRI (fMRI) and diffusion tensor imaging (DTI) acquisitions and if currents induced in the prosthesis by imaging are at safe levels. MATERIALS AND METHODS: One Argus II retinal prosthesis was modified to enable current measurements during imaging. Active electronics were modified to enable operation during scans. Induced current was measured during diagnostic scans, which were previously shown to be safe for implanted patients, and during fMRI and DTI scans. All measurements were performed using an ASTM phantom to ensure reproducible placement. RESULTS: The prosthesis was able to maintain communication with the external RF coil during the fMRI and DTI scans except briefly during pre-scans. Current levels induced during fMRI and DTI scans were consistently below those measured during diagnostic scans. CONCLUSIONS: fMRI and DTI may be safely performed while the Argus II retinal prosthesis is operating.

Investigation of CEP290 genotype-phenotype correlations in a patient with retinitis pigmentosa, infertility, end-stage renal disease, and a novel mutation.

Background: Mutations in CEP290 cause autosomal recessive conditions with a wide range of severity and the lack of strong genotype-phenotype data makes it difficult to provide accurate prognostic data to patients and families.Methods: A retrospective chart review was conducted on a patient with a clinical diagnosis of Senior-Loken Syndrome, molecularly confirmed biallelic nonsense mutations in CEP290,and a recent finding of infertility secondary to non-motile sperm.Results: Here we present the case of a patient with a long-standing diagnosis of Senior-Loken syndrome due to findings of early-onset retinitis pigmentosa and renal disease. This is a patient who has been followed by ophthalmology and genetics for over 20 years and so provides valuable information on the natural history of CEP290-related ciliopathies. Additionally, we consider how this patient's biallelic nonsense variants in CEP290 affect phenotype severity through nonsense-mediated alternative splicing and how understanding this process could lead to future therapeutic options.Conclusions: CEP290 mutations are associated with a variety of overlapping clinical phenotypes, some of which will become better understood as more patients with these conditions survive to reproductive age. Similarly, increased understanding of the molecular mechanisms that underlie differences in phenotype may provide avenues to consider in future therapies.

Whole Exome Sequencing Identifies Candidate Genes Associated with Hereditary Predisposition to Uveal Melanoma.

PURPOSE: To identify susceptibility genes associated with hereditary predisposition to uveal melanoma (UM) in patients with no detectable germline BAP1 alterations. DESIGN: Retrospective case series from academic referral centers. PARTICIPANTS: Cohort of 154 UM patients with high risk of hereditary cancer defined as patients with 1 or more of the following: (1) familial UM, (2) young age (<35 years) at diagnosis, (3) personal history of other primary cancers, and (4) family history of 2 or more primary cancers with no detectable mutation or deletion in BAP1 gene. METHODS: Whole exome sequencing, a cancer gene panel, or both were carried out. Probands included 27 patients with familial UM, 1 patient with bilateral UM, 1 patient with congenital UM, and 125 UM patients with strong personal or family histories, or both, of cancer. Functional validation of variants was carried out by immunohistochemistry, reverse-transcriptase polymerase chain reaction, and genotyping. MAIN OUTCOME MEASURES: Clinical characterization of UM patients with germline alterations in known cancer genes. RESULTS: We identified actionable pathogenic variants in 8 known hereditary cancer predisposition genes (PALB2, MLH1, MSH6, CHEK2, SMARCE1, ATM, BRCA1, and CTNNA1) in 9 patients, including 3 of 27 patients (11%) with familial UM and 6 of 127 patients (4.7%) with a high risk for cancer. Two patients showed pathogenic variants in CHEK2 and PALB2, whereas variants in the other genes each occurred in 1 patient. Biallelic inactivation of PALB2 and MLH1 was observed in tumors from the respective patients. The frequencies of pathogenic variants in PALB2, MLH1, and SMARCE1 in UM patients were significantly higher than the observed frequencies in noncancer controls (PALB2: P = 0.02; odds ratio, 8.9; 95% confidence interval, 1.5-30.6; MLH1: P = 0.04; odds ratio, 25.4; 95% confidence interval, 1.2-143; SMARCE1: P = 0.001; odds ratio, 2047; 95% confidence interval, 52-4.5e15, respectively). CONCLUSIONS: The study provided moderate evidence of gene and disease association of germline mutations in PALB2 and MLH1 with hereditary predisposition to UM. It also identified several other candidate susceptibility genes. The results suggest locus heterogeneity in predisposition to UM. Genetic testing for hereditary predisposition to cancer is warranted in UM patients with strong personal or family history of cancers, or both.

Novel mutation in CTNNB1 causes familial exudative vitreoretinopathy (FEVR) and microcephaly: case report and review of the literature.

Purpose: Neonatal retinal folds and/or vitreoretinal traction can be signs of isolated ocular or syndromic disorders. Etiologies include retinopathy of prematurity, perinatal infections or inherited vitreoretinal disorders such as familial exudative vitreoretinopathy (FEVR) or Norrie disease. We present the clinical and genetic findings of a two-month-old infant with microcephaly, mild motor developmental delay, and FEVR, who required urgent surgical interventions.Methods: The patient underwent an initial examination under anesthesia (EUA) with fluorescein angiography (FA) and subsequent medical and surgical treatments. Genetic testing was undertaken to identify the etiology.Results: Examination at 2 months of age demonstrated microcephaly with a head circumference smaller than the 1st percentile. Family history was negative for microcephaly or retinal disease. Anterior segment eye exam was normal OU. There were bilateral macular folds involving the fovea and extending from the disc to the temporal periphery. FA demonstrated bilateral incomplete vascularization of the retina most notable nasally. Indirect laser was applied to ischemic retina OU. Scleral buckling procedures were performed OU as well as a vitrectomy in the left eye. Follow-up examinations demonstrated the stable appearance of the folds and attached retinas OU. Genetic testing identified a novel dominant heterozygous c.2046_2047del [p.Phe683Glnfs*9] mutation in CTNNB1, predicted to result in a frameshift causing a truncated protein.Conclusions: CTNNB1 mutations are an uncommon cause of FEVR with microcephaly.

Computer-Assisted Immersive Visual Rehabilitation in Argus II Retinal Prosthesis Recipients.

PURPOSE: The field of retinal prostheses is expanding. However, the best approach to training and assessing the functional benefit of postoperative vision has not been established. The purpose of this single-center prospective interventional case series was to evaluate the feasibility and effectiveness of using the Computer Assisted Rehabilitation Environment (CAREN) system as a visual rehabilitation tool in Argus II patients. DESIGN: Single-center prospective interventional case series (clinicaltrials.gov identifier, NCT03444961). PARTICIPANTS: Four Argus II recipients (3 men and 1 woman). METHODS: Eight visual rehabilitation sessions using the CAREN system (twice weekly for 4 weeks). MAIN OUTCOME MEASURES: Baseline and postintervention assessments consisted of visual function, mobility, and balance tests. RESULTS: All patients successfully completed training on the CAREN system. While the Argus II device was active, walking speed increased from baseline to immediately after the intervention on flat and undulating surfaces and while localizing objects by 20%, 10%, and 18%, respectively. An improved ability to complete the timed up and go test successfully was observed. CONCLUSIONS: Novel methods of visual rehabilitation for retinal prostheses recipients, such the CAREN system, are feasible and may result in improved ability to use the Argus II while performing functional tasks. Immersive technology may provide a solution for the standardization of effective rehabilitation approaches to augment retinal prosthesis performance. Heterogeneity of results indicates that a larger sample size would be beneficial.

Retinal dystrophy associated with a Kizuna (KIZ) mutation and a predominantly macular phenotype.

Introduction: Mutations in Kizuna (KIZ), a gene involved in ciliary function, have been previously associated with rod-cone dystrophy with relative macular sparing and a number of other systemic abnormalities.Purpose: We present a patient with a phenotype dominated by retinal dystrophy and macular cysts as a result of a homozygous nonsense mutation in KIZ.Methods: A 32-year-old female of Ashkenazi Jewish ancestry presented with progressive central vision loss and peripheral visual field loss following decades of night-blindness. She was noted to have a bull's-eye pattern of macular hyper-autofluorescence, intraretinal cystoid macular changes and outer retinal atrophy in both eyes. Visual fields were constricted to <10 degrees centrally with inferior preserved islands of vision. Genetic testing revealed a homozygous KIZ c.226 C > T (p.Arg76*) nonsense mutation. The patient was treated with topical dorzolamide and showed significant improvement in the degree of macular cysts.Conclusion: Mutations in KIZ can present with a predominantly macular phenotype and develop cystoid macular changes responsive to carbonic anhydrase inhibitor treatment. Because of the importance of KIZ in cilia function, it is critical to look for associated systemic manifestations to ensure best patient care.