Intravitreal enzyme replacement for inherited retinal diseases.

PURPOSE OF REVIEW: This paper provides an update on intravitreal (IVT) enzyme replacement therapy (ERT) in metabolic retinal diseases; particularly neuronal ceroid lipofuscinosis type 2 (CLN2) also known as Batten disease. RECENT FINDINGS: ERT is being explored in CLN2 related Batten disease, a fatal neurodegenerative condition associated with retinopathy and blindness that is caused by the deficiency of lysosomal enzyme TPP1. Cerliponase alfa, a recombinant human tripeptidyl-peptidase1 (rhTPP1) administered by intraventricular infusions has been demonstrated to slow the rate of neurodegenerative decline but not retinopathy. A preclinical study of IVT rhTPP1 in a CLN2 canine model demonstrated efficacy in preserving retinal function and retinal morphology shown on histology. More recently, intravitreal (IVT) administration of rhTPP1 was reported in a first-in-human compassionate use study. Patients received 12-18 months of 8-weekly IVT ERT (0.2 mg rhTPP-1 in 0.05 ml) in one eye. No significant ocular adverse reactions were reported. Treatment decreased the rate of retinal thinning but modestly. SUMMARY: The evidence suggests that IVT ERT with rhTPP1 may be a safe and effective treatment for CLN2 retinopathy. However, the optimal dosage and frequency to achieve the best possible outcomes requires further investigation as does patient selection.

First in man study of intravitreal tripeptidyl peptidase 1 for CLN2 retinopathy.

BACKGROUND/OBJECTIVES: CLN2 Batten Disease is a fatal neurodegenerative condition of childhood associated with retinal dystrophy and blindness. Intracerebroventricular infusion of rhTPP1 greatly slows the rate of neurodegenerative decline but not retinopathy. Intravitreal rhTPP1 is known to slow retinal degeneration in a canine model of CLN2. We report a first-in-man controlled clinical trial of intravitreal rhTPP1 for CLN2 associated retinal dystrophy. SUBJECTS/METHODS: 8 children aged 5-9 with CLN2 Batten Disease were prospectively enroled. Severely affected patients were preferentially selected, provided that vision was better than no perception of light. Children underwent 8 weekly intravitreal injections of rhTPP1 (0.2 mg in 0.05 ml) into the right eye for 12-18 months. The left eye was untreated and acts as a paired control. The primary outcome was safety based on the clinical detection of complications. A secondary outcome was paracentral macular volume (PMV) measured by spectral domain OCT. Linear regression/paired t tests were used to compare rates of decline. RESULTS: No severe adverse reactions (uveitis, raised IOP, media opacity) occurred. The mean baseline PMV was 1.28 mm3(right), 1.27 mm3(left). 3 of the youngest patients exhibited bilateral progressive retinal thinning (p < 0.05), whereas retinal volume was stable in the remaining 5 patients. In the 3 patients undergoing retinal degeneration, the rate of PMV loss was slower in the treated vs. untreated eye (p = 0.000042, p = 0.0011, p = 0.00022). CONCLUSIONS: Intravitreal rhTPP1 appears to be a safe and effective treatment for CLN2 related retinopathy however commencement of treatment early in the course of disease is more likely to be efficacious.

First-in-Human Gene Therapy Trial of AAV8-hCARp.hCNGB3 in Adults and Children With CNGB3-associated Achromatopsia.

PURPOSE: To assess the safety and efficacy of AAV8-hCARp.hCNGB3 in participants with CNGB3-associated achromatopsia (ACHM). DESIGN: Prospective, phase 1/2 (NCT03001310), open-label, nonrandomized clinical trial. METHODS: The study enrolled 23 adults and children with CNGB3-associated ACHM. In the dose-escalation phase, adult participants were administered 1 of 3 AAV8-hCARp.hCNGB3 dose levels in the worse-seeing eye (up to 0.5 mL). After a maximum tolerated dose was established in adults, an expansion phase was conducted in children ≥3 years old. All participants received topical and oral corticosteroids. Safety and efficacy parameters, including treatment-related adverse events and visual acuity, retinal sensitivity, color vision, and light sensitivity, were assessed for 6 months. RESULTS: AAV8-hCARp.hCNGB3 (11 adults, 12 children) was safe and generally well tolerated. Intraocular inflammation occurred in 9 of 23 participants and was mainly mild or moderate in severity. Severe cases occurred primarily at the highest dose. Two events were considered serious and dose limiting. All intraocular inflammation resolved following topical and systemic steroids. There was no consistent pattern of change from baseline to week 24 for any efficacy assessment. However, favorable changes were observed for individual participants across several assessments, including color vision (n = 6/23), photoaversion (n = 11/20), and vision-related quality-of-life questionnaires (n = 21/23). CONCLUSIONS: AAV8-hCARp.hCNGB3 for CNGB3-associated ACHM demonstrated an acceptable safety and tolerability profile. Improvements in several efficacy parameters indicate that AAV8-hCARp.hCNGB3 gene therapy may provide benefit. These findings, with the development of additional sensitive and quantitative end points, support continued investigation.

Is RPGR-related retinal dystrophy associated with systemic disease? A case series.

BACKGROUND: Ciliopathies responsible for retinitis pigmentosa can also cause systemic manifestations. RPGR is a ciliary gene and pathogenic variants in RPGR cause a retinal ciliopathy, the commonest cause of X-linked recessive retinitis pigmentosa. The RPGR protein interacts with numerous other ciliary proteins present in the transition zone of both motile and sensory cilia, and may play an important role in regulating ciliary protein transport. There has been a growing, putative association of RPGR variants with systemic ciliopathies: mainly sino-respiratory infections and primary ciliary dyskinesia. MATERIALS AND METHODS: Retrospective case series of patients with RPGR-RP presenting to Oxford Eye Hospital with systemic disease. RESULTS: We report three children with RPGR-related rod-cone dystrophy, all of whom have mutations in the N-terminus of RPGR. Two cases co-presented with confirmed diagnoses of primary ciliary dyskinesia and one case with multiple sino-respiratory symptoms strongly suggestive of primary ciliary dyskinesia. These and all previously reported RPGR co-pathologies relate to ciliopathies and have no other systemic associations. CONCLUSIONS: The link between RPGR variants and a systemic ciliopathy remains plausible, but currently unproven.

Evolving outcomes of surgery for retinal detachment in retinopathy of prematurity: the need for a national service in the United Kingdom : An audit of surgery for acute tractional retinal detachment complicating ROP in the UK.

OBJECTIVES: To audit the structural and functional outcomes of surgery for acute tractional retinal detachment due to retinopathy or prematurity between 2004 and 2014 in Oxford UK. METHODS: Consecutive operations were identified from a surgical log. Clinical data including demography, perioperative data, and retinal outcomes were extracted into a spreadsheet and compared against two international data sets referenced in the method section. Nonparametric tests (Fisher's exact, and the Mann-Whitney U-tests) were used for statistical analysis with a p-value < 0.05 considered significant. RESULTS: Twenty-nine eyes of 19 babies underwent surgery. The mean age (SD) at final follow-up was 6.4 (3.7) years of age and comparable to the reference data sets. The mean birth weight and gestational age of babies matched the ETROP data set referenced in the method section. Anatomical success was obtained in 16/29 (55.2%) of eyes and more likely with stage 4 ROP than stage 5 disease (p < 0.05). Thirteen of 29 eyes (44.8%) obtained form vision post-operatively. All instances of macular retinal reattachment during follow up were verified with post-operative OCT. CONCLUSIONS: Surgery for stage 5 ROP is not worthwhile. For stage 4 ROP it yielded better visual outcomes than ETROP but registration for visual impairment was not prevented. Innovation such as endoscopic vitrectomy could yield better outcomes. Earlier detection of vitreoretinal fibrosis could result in timelier referral. A formally funded national service is needed to ring-fence resource to avoid delays in access to surgery, which has a narrow surgical window.

SRD5A3-CDG: Emerging Phenotypic Features of an Ultrarare CDG Subtype.

Background: SRD5A3-CDG is a rare N-glycosylation defect caused by steroid 5 alpha reductase type 3 deficiency. Its key feature is an early severe visual impairment with variable ocular anomalies often leading to diagnosis. Additional symptoms are still poorly defined. In this case study, we discuss 11 genetically confirmed cases, and report on emerging features involving other systems in addition to the eye phenotype. Methods: In total, 11 SRD5A3-CDG patients in five sets of sibships were included in the study. Data on 9 of 11 patients are as of yet unpublished. Patients' results on biochemical and genetic investigations and on in-depth phenotyping are presented. Results: Key diagnostic features of SRD5A3-CDG are ophthalmological abnormalities with early-onset retinal dystrophy and optic nerve hypoplasia. SRD5A3-CDG is also characterized by variable neurological symptoms including intellectual disability, ataxia, and hypotonia. Furthermore, ichthyosiform skin lesions, joint laxity, and scoliosis have been observed in our cohort. We also report additional findings including dystonia, anxiety disorder, gastrointestinal symptoms, and MRI findings of small basal ganglia and mal-rotated hippocampus, whereas previous publications described dysmorphic features as a common finding in SRD5A3, which could not be confirmed in our patient cohort. Conclusion: The detailed description of the phenotype of this large cohort of patients with SRD5A3-CDG highlights that the key clinical diagnostic features of SRD5A3-CDG are an early onset form of ophthalmological problems in patients with a multisystem disorder with variable symptoms evolving over time. This should aid earlier diagnosis and confirms the need for long-time follow-up of patients.

An ERG and OCT study of neuronal ceroid lipofuscinosis CLN2 Battens retinopathy.

BACKGROUND: Late infantile neuronal ceroid lipofuscinosis (CLN2 Batten disease) is a rare, progressive neurodegenerative disease of childhood. The natural history of motor and language regression is used to monitor the efficacy of CNS treatments. Less is known about CLN2 retinopathy. Our aim is to elaborate the nature, age of onset, and symmetry of CLN2 retinopathy using visual electrophysiology and ophthalmic imaging. SUBJECTS AND METHODS: We reviewed 22 patients with genetically confirmed CLN2 disease; seventeen showing classical and five atypical disease. Flash electroretinograms (ERGs), flash and pattern reversal visual evoked potentials (VEPs), recorded from awake children were collated. Available fundus images were graded, optical coherence tomography (OCT) central subfoveal thickness (CST) measured, and genotype, age, clinical vision assessment and motor language grades assembled. RESULTS: ERGs show cone/rod system dysfunction preceded by localised macular ellipsoid zone disruption on OCT from 4.8 years. Electroencephalogram (EEG) time-locked spikes confounded both pattern 6/17 (35%) and flash VEPs 12/16 (75%). Paired right eye (RE) and left eye (LE) ERG amplitudes did not differ significantly for each flash stimulus at the p 0.001 level, Wilcoxon ranked signed test. Cone ERGs show a functional deficit before CST thinning in classical disease. Optomap hyper fundus autofluorescence (FAF) at the fovea was noted in three patients with normal ERGs. The oldest patient showed an ovoid aggregate above the external limiting membrane at the fovea, which did not affect the PERG. CONCLUSION: ERG findings in CLN2 retinopathy show symmetrical cone-rod dysfunction, from 4y10m in this series, but a broad range of ages when ERG function is preserved.

Misaligned foveal morphology and sector retinal dysfunction in AKT1-mosaic Proteus syndrome.

PURPOSE: Proteus syndrome arises as a result of a post-zygotic mosaic activating mutation in the AKT1 oncogene, causing a disproportionate overgrowth of affected tissues. A small number of ocular complications have been reported. We present the unique findings in a patient who had molecular confirmation of AKT1 mosaicism alongside fulfilling the clinical criteria for Proteus syndrome. METHODS: Pattern electroretinography, visual evoked potentials and multifocal electroretinography testing were performed alongside detailed retinal imaging and clinical examination to detail the ophthalmic characteristics. RESULTS: Electrophysiological findings characterised unilateral macular dysfunction alongside sector retinal dysfunction of the right eye. This was demonstrated through optical coherence tomography and ultra-wide-field imaging to be associated with a misaligned foveal morphology and sector retinal dysfunction extending into the temporal retina. CONCLUSION: We propose this patient has asymmetric foveal development and concomitant sector retinal dysfunction as the result of the mosaic AKT1 mutation, either through disruption in the retinal PI3K-AKT1 signalling pathway or through mechanical distortion of ocular growth, resulting in disproportionate inner retinal development. The findings expand the ocular phenotype of Proteus syndrome and encourage early assessment to identify any incipient ocular abnormalities.

Traumatic Retinal Detachment in Patients with Self-Injurious Behavior: An International Multicenter Study.

PURPOSE: To describe the clinical characteristics, surgical outcomes, and management recommendations in patients with traumatic rhegmatogenous retinal detachment (RRD) resulting from self-injurious behavior (SIB). DESIGN: International, multicenter, retrospective, interventional case series. PARTICIPANTS: Patients with SIB from 23 centers with RRD in at least 1 eye. METHODS: Clinical histories, preoperative assessment, surgical details, postoperative management, behavioral intervention, and follow-up examination findings were reviewed. MAIN OUTCOME MEASURES: The rate of single-surgery anatomic success (SSAS) was the primary outcome. Other outcomes included new RRD in formerly attached eyes, final retinal reattachment, and final visual acuity. RESULTS: One hundred seven eyes with RRDs were included from 78 patients. Fifty-four percent of patients had bilateral RRD or phthisis bulbi in the fellow eye at final follow-up. The most common systemic diagnoses were autism spectrum disorder (35.9%) and trisomy 21 (21.8%) and the most common behavior was face hitting (74.4%). The average follow-up time was 3.3 ± 2.8 years, and surgical outcomes for operable eyes were restricted to patients with at least 3 months of follow-up (81 eyes). Primary initial surgeries were vitrectomy alone (33.3%), primary scleral buckle (SB; 26.9%), and vitrectomy with SB (39.7%), and 5 prophylactic SBs were placed. Twenty-three eyes (21.5%) with RRDs were inoperable. The SSAS was 23.1% without tamponade (37.2% if including silicone oil), and final reattachment was attained in 80% (36.3% without silicone oil tamponade). Funnel-configured RRD (P = 0.006) and the presence of grade C proliferative vitreoretinopathy (P = 0.002) correlated with re-detachment. The use of an SB predicted the final attachment rate during the initial surgery (P = 0.005) or at any surgery (P = 0.008. These associations held if restricting to 64 patients with ≥12 months followup. Anatomic reattachment correlated with better visual acuity (P < 0.001). CONCLUSIONS: RRD resulting from SIB poses therapeutic challenges because of limited patient cooperation, bilateral involvement, chronicity, and ongoing trauma in vulnerable and neglected patients. The surgical success rates were some of the lowest in the modern retinal detachment literature. The use of an SB may result in better outcomes, and visual function can be restored in some patients.

New variants and in silico analyses in GRK1 associated Oguchi disease.

Biallelic mutations in G-Protein coupled receptor kinase 1 (GRK1) cause Oguchi disease, a rare subtype of congenital stationary night blindness (CSNB). The purpose of this study was to identify disease causing GRK1 variants and use in-depth bioinformatic analyses to evaluate how their impact on protein structure could lead to pathogenicity. Patients' genomic DNA was sequenced by whole genome, whole exome or focused exome sequencing. Disease associated variants, published and novel, were compared to nondisease associated missense variants. The impact of GRK1 missense variants at the protein level were then predicted using a series of computational tools. We identified twelve previously unpublished cases with biallelic disease associated GRK1 variants, including eight novel variants, and reviewed all GRK1 disease associated variants. Further structure-based scoring revealed a hotspot for missense variants in the kinase domain. In addition, to aid future clinical interpretation, we identified the bioinformatics tools best able to differentiate disease associated from nondisease associated variants. We identified GRK1 variants in Oguchi disease patients and investigated how disease-causing variants may impede protein function in-silico.

Diffuse bear-track retina: profound, bilateral, grouped congenital pigmentation of the retinal pigment epithelium in an infant.

Grouped congenital hypertrophy of the retinal pigment epithelium is a conspicuous ocular anomaly wherein highly pigmented, demarcated but flat retinal lesions arise from the retinal pigment epithelium. These lesions ("bear tracks") typically increase in size as they approach the retinal periphery. The discovery of pigmentary lesions in a young infant with a poor red reflex warrants urgent ophthalmological and electrodiagnostic review to exclude serious diagnoses, including an early-onset severe retinal dystrophy. We present the case of a 2-month-old boy with marked bear-tracks over the entirety of each retina, but with normal electrodiagnostic findings, genetics, and visual behavior.

Impact of sight and hearing loss in patients with Norrie disease: advantages of Dual Sensory clinics in patient care.

Norrie disease (ND) is a rare, X-linked condition of visual and auditory impairment, often presenting with additional neurological features and developmental delays of varying severity. While all affected patients are born blind, or lose their vision in infancy, progressive sensorineural hearing loss develops in the majority of cases and is typically detected in the second decade of life. A range of additional symptoms of ND, such as seizure disorders, typically appear from a young age, but it is difficult to predict the range of symptoms ND patients will experience. After growing up without vision, hearing loss represents the greatest worry for many patients with ND, as they may lose the ability to participate in previously enjoyed activities or to communicate with others. Dual sensory loss has a physical, psychosocial and financial impact on both patients with ND and their families. Routine monitoring of the condition is required in order to identify, treat and provide support for emerging health problems, leading to a large burden of medical appointments. Many patients need to travel long distances to meet with specialists, representing a further burden on time and finances. Additionally, the rare nature of dual sensory impairment in children means that few clinical environments are designed to meet their needs. Dual Sensory clinics are multidisciplinary environments designed for sensory-impaired children and have been suggested to alleviate the impact of diseases involving sensory loss such as ND. Here, we discuss the diagnosis, monitoring and management of ND and the impact it has on paediatric patients and their caregivers. We describe the potential for dual sensory clinics to reduce disease burden through providing an appropriate clinical environment, access to multiple clinical experts in one visit, and ease of monitoring for patients with ND.

Expanding the phenotypic spectrum consequent upon de novo WDR37 missense variants.

Structural eye disorders are increasingly recognised as having a genetic basis, although current genetic testing is limited in its success. De novo missense variants in WDR37 are a recently described cause of a multisystemic syndromic disorder featuring ocular coloboma. This study characterises the phenotypic spectrum of this disorder and reports 2 de novo heterozygous variants (p.Thr115Ile, p.Ser119Tyr) in three unrelated Caucasian individuals. All had a clinical phenotype consisting of bilateral iris and retinal coloboma, developmental delay and additional, variable multisystem features. The variants fall within a highly conserved region upstream of the WD-repeat domains, within an apparent mutation cluster. Consistent with the literature, intellectual disability, structural eye disorders, epilepsy, congenital heart disease, genitorenal anomalies and dysmorphic facial features were observed. In addition, a broader developmental profile is reported with a more specific musculoskeletal phenotype described in association with the novel variant (p.Thr115Ile). We further expand the phenotypic spectrum of WDR37-related disorders to include those with milder developmental delay and strengthen the association of ocular coloboma and musculoskeletal features. We promote the inclusion of WDR37 on gene panels for intellectual disability, epilepsy and structural eye disorders.

Clinical and Molecular Characterization of Familial Exudative Vitreoretinopathy Associated With Microcephaly.

PURPOSE: Familial exudative vitreoretinopathy (FEVR) is a rare finding in patients with genetic forms of microcephaly. This study documents the detailed phenotype and expands the range of genetic heterogeneity. DESIGN: Retrospective case series. METHODS: Twelve patients (10 families) with a diagnosis of FEVR and microcephaly were ascertained from pediatric genetic eye clinics and underwent full clinical assessment including retinal imaging. Molecular investigations included candidate gene Sanger sequencing, whole-exome sequencing (WES), and whole-genome sequencing (WGS). RESULTS: All patients had reduced vision and nystagmus. Six were legally blind. Two probands carried bi-allelic LRP5 variants, both presenting with bilateral retinal folds. A novel homozygous splice variant, and 2 missense variants were identified. Subsequent bone density measurement identified osteoporosis in one proband. Four families had heterozygous KIF11 variants. Two probands had a retinal fold in one eye and chorioretinal atrophy in the other; the other 2 had bilateral retinal folds. Four heterozygous variants were found, including 2 large deletions not identified on Sanger sequencing or WES. Finally, a family of 2 children with learning difficulties, abnormal peripheral retinal vasculogenesis, and rod-cone dystrophy were investigated. They were found to have bi-allelic splicing variants in TUBGCP6. Three families remain unsolved following WES and WGS. CONCLUSIONS: Molecular diagnosis has been achieved in 7 of 10 families investigated, including a previously unrecognized association with LRP5. WGS enabled molecular diagnosis in 3 families after prior negative Sanger sequencing of the causative gene. This has enabled patient-specific care with targeted investigations and accurate family counseling.

Accuracy of scleral transillumination techniques to identify infant ciliary body for sclerostomy and intravitreal injections.

IMPORTANCE: There is variation in the literature for sclerotomy and intravitreal injection placement in young children, ranging from 0.5 to 3.0 mm from the limbus. We assess the accuracy of scleral transillumination to identify the ciliary body in infants for safe sclerotomy and intravitreal injections in young children. BACKGROUND: The study compares the perilimbal "dark band" seen on scleral transillumination (STI) with the ultrasound biomicroscopy (UBM), and compares these measurements with the current guidelines for sclerotomy in infants. DESIGN: Prospective case series in a tertiary paediatric hospital. PARTICIPANTS: Children aged ≤36 months undergoing general anaesthesia for eye procedures. METHODS: Scleral transillumination was performed to measure the perilimbal dark band. UBM of the ciliary body region was then performed, and correlated with transillumination findings. MAIN OUTCOME MEASURES: The midpoints of STI and UBM were compared to current cadaver-based guidelines to assess the safe point for sclerotomy. RESULTS: Twenty children were recruited, 36 STI and 35 UBM measurements were obtained. The posterior edge of the dark band had good correlation with the posterior border of the ciliary body. Transillumination and UBM correlated well for midpoint measurements. The midpoint of the dark band on transillumination was confirmed to be in the ciliary body by UBM in all cases. CONCLUSIONS AND RELEVANCE: The STI technique is a useful and fast technique to demonstrate the ciliary body. The midpoint of the dark band on STI correlates well with the UBM, and has a potential use for confirming safe-entry into the posterior segment if using current guidelines. The current cadaver-based paediatric guidelines safely avoid retinal injury.

Missense variants in the X-linked gene PRPS1 cause retinal degeneration in females.

Retinal dystrophies are a heterogeneous group of disorders of visual function leading to partial or complete blindness. We report the genetic basis of an unusual retinal dystrophy in five families with affected females and no affected males. Heterozygous missense variants were identified in the X-linked phosphoribosyl pyrophosphate synthetase 1 (PRPS1) gene: c.47C > T, p.(Ser16Phe); c.586C > T, p.(Arg196Trp); c.641G > C, p.(Arg214Pro); and c.640C > T, p.(Arg214Trp). Missense variants in PRPS1 are usually associated with disease in male patients, including Arts syndrome, Charcot-Marie-Tooth, and nonsyndromic sensorineural deafness. In our study families, affected females manifested a retinal dystrophy with interocular asymmetry. Three unrelated females from these families had hearing loss leading to a diagnosis of Usher syndrome. Other neurological manifestations were also observed in three individuals. Our data highlight the unexpected X-linked inheritance of retinal degeneration in females caused by variants in PRPS1 and suggest that tissue-specific skewed X-inactivation or variable levels of pyrophosphate synthetase-1 deficiency are the underlying mechanism(s). We speculate that the absence of affected males in the study families suggests that some variants may be male embryonic lethal when inherited in the hemizygous state. The unbiased nature of next-generation sequencing enables all possible modes of inheritance to be considered for association of gene variants with novel phenotypic presentation.

Clinical Characterization of CNGB1-Related Autosomal Recessive Retinitis Pigmentosa.

IMPORTANCE: There are limited published data on the phenotype of retinitis pigmentosa (RP) related to CNGB1 variants. These data are needed both for prognostic counseling of patients and for understanding potential treatment windows. OBJECTIVE: To describe the detailed clinical and molecular genetic findings in a series of patients with RP with likely pathogenic variants in CNGB1. DESIGN, SETTING, AND PARTICIPANTS: In this case series, 10 patients from 9 families underwent full ophthalmologic examination. Molecular investigations included whole-exome analysis in 6 patients. The study was conducted from April 17, 2013, to March 3, 2016, with final follow-up completed on March 2, 2016, and data were analyzed from October 27, 2014, to March 29, 2016. MAIN OUTCOMES AND MEASURES: Results of ophthalmologic examination and molecular genetic analysis of CNGB1. RESULTS: In this case series, 7 women and 3 men from 9 families with a mean (SD) age of 47.4 (13.2) years identified as having CNGB1 variants were included in this study; there was a mean (SD) follow-up length of 3.7 (2.8) years. The first clinical presentation was with nyctalopia in childhood with visual field loss documented later at a mean (SD) age of 33.2 (8.0) years. All patients had preserved best-corrected visual acuity into adulthood, with a mean of 0.1 logMAR (Snellen equivalent, 20/25) in each eye (logMAR range, 0.0 to 0.3 [Snellen 20/20 to 20/40] in the right eye and -0.1 to 0.3 [Snellen 20/16 to 20/40] in the left eye). Fundus examination revealed midperipheral retinal pigment epithelial atrophy and intraretinal pigment migration. Optical coherence tomography of the macula demonstrated complete preservation of the inner segment ellipsoid band in 1 patient, with variable lateral extent in the other patients corresponding to the diameter of a paracentral ring of increased fundus autofluorescence. Electrophysiologic testing in 6 patients confirmed a rod-cone dystrophy phenotype. Molecular investigations identified a previously reported missense variant (p.[N986I]) and 7 variants not previously reported in disease including 4 nonsense (p.[(Q88*], p.[Q222*], p.[Q318*], and p.[R729*]), 2 frameshift (p.[A1048fs*13], p.[L849Afs*3]), and a splice site variant (c.761 + 2T>A). CONCLUSIONS AND RELEVANCE: The data from this study suggest that visual acuity and foveal structure in patients with RP are preserved into adult life such that a lengthy window of opportunity should exist for intervention with novel therapies.

Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease.

Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in CHM in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.