Inherited Retinal Degenerations and Non-Neovascular Age-Related Macular Degeneration: Progress and Unmet Needs.

Inherited retinal degeneration (IRD) disease and age-related macular degeneration (AMD) are leading causes of irreversible vision loss and blindness. Although significant progress has advanced the field in the past 5 years, significant challenges remain. The current article reviews the accomplishments and research advances that have fueled the development of treatments for patients with IRD and AMD, including the first approved gene-augmentation treatment for RPE65-related retinal degeneration and complement inhibition therapies to slow progression of geographic atrophy (GA) in AMD.

Overcoming the Challenges to Clinical Development of X-Linked Retinitis Pigmentosa Therapies: Proceedings of an Expert Panel.

Unlabelled: X-linked retinitis pigmentosa (XLRP) is a rare inherited retinal disease manifesting as impaired night vision and peripheral vision loss that progresses to legal blindness. Although several trials of ocular gene therapy for XLRP have been conducted or are in progress, there is currently no approved treatment. In July 2022, the Foundation Fighting Blindness convened an expert panel to examine relevant research and make recommendations for overcoming the challenges and capitalizing on the opportunities in conducting clinical trials of RPGR-targeted therapy for XLRP.

Identification of a novel large multigene deletion and a frameshift indel in as the underlying cause of early-onset recessive rod-cone degeneration.

A family, with two affected identical twins with early-onset recessive inherited retinal degeneration, was analyzed to determine the underlying genetic cause of pathology. Exome sequencing revealed a rare and previously reported causative variant (c.1923_1969delinsTCTGGG; p.

Mutations in , a co-repressor of , are associated with early-onset retinal degeneration.

Many transcription factors regulating the production, survival, and function of photoreceptor cells have been identified, but little is known about transcriptional co-regulators in retinal health and disease. Here, we show that BCL6 co-repressor (BCOR), a Polycomb repressive complex 1 factor mutated in various cancers, is involved in photoreceptor degenerative diseases. Using proteomics and transcription assays, we report that BCOR interacts with the transcription factors CRX and OTX2 and reduces their ability to activate the promoters of photoreceptor-specific genes.

Tissue-specific genotype-phenotype correlations among USH2A-related disorders in the RUSH2A study.

We assessed genotype-phenotype correlations among the visual, auditory, and olfactory phenotypes of 127 participants with Usher syndrome (USH2) (n =80) or nonsyndromic autosomal recessive retinitis pigmentosa (ARRP) (n = 47) due to USH2A variants, using clinical data and molecular diagnostics from the Rate of Progression in USH2A Related Retinal Degeneration (RUSH2A) study. USH2A truncating alleles were associated with USH2 and had a dose-dependent effect on hearing loss severity with no effect on visual loss severity within the USH2 subgroup. A group of missense alleles in an interfibronectin domain appeared to be hypomorphic in ARRP.

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

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.

Mutations in the Kinesin-2 Motor KIF3B Cause an Autosomal-Dominant Ciliopathy.

Kinesin-2 enables ciliary assembly and maintenance as an anterograde intraflagellar transport (IFT) motor. Molecular motor activity is driven by a heterotrimeric complex comprised of KIF3A and KIF3B or KIF3C plus one non-motor subunit, KIFAP3. Using exome sequencing, we identified heterozygous KIF3B variants in two unrelated families with hallmark ciliopathy phenotypes.

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

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.

Detection of Large Structural Variants Causing Inherited Retinal Diseases.

Current application of next-generation sequencing (NGS) leads to detection of the underlying disease-causing gene and mutation or mutations in from 60% to 85% of patients with inherited retinal diseases (IRDs), depending on the methods used, disease type, and population tested. In a cohort of 320 families with autosomal dominant retinitis pigmentosa (adRP), we have detected the mutation in 82% of cases using a variety of methods, leaving more than 50 families with "elusive" disease genotypes. All of the remaining families have been screened for mutations in known IRD genes using retinal-targeted-capture NGS, and most have been tested by whole-exome NGS.

Time Course of Disease Progression of PRPF31-mediated Retinitis Pigmentosa.

Purpose: Variants in PRPF31, a splicing factor, are a common cause of autosomal dominant retinitis pigmentosa (RP). Deleterious variants are thought to cause disease by haploinsufficiency. In anticipation of upcoming replacement gene therapy trials, we present the phenotype and clinical progression of a large cohort of patients with PRPF31-mediated RP.

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

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.

Molecular Defects of the Disease-Causing Human Arrestin-1 C147F Mutant.

Purpose: The purpose of this study was to identify the molecular defect in the disease-causing human arrestin-1 C147F mutant.

Methods: The binding of wild-type (WT) human arrestin-1 and several mutants with substitutions in position 147 (including C147F, which causes dominant retinitis pigmentosa in humans) to phosphorylated and unphosphorylated light-activated rhodopsin was determined. Thermal stability of WT and mutant human arrestin-1, as well as unfolded protein response in 661W cells, were also evaluated.

Innovating patient care delivery: DSRIP's interrupted time series analysis paradigm.

Introduction: Adoption of Medicaid Section 1115 waiver is one of the many ways of innovating healthcare delivery system. The Delivery System Reform Incentive Payment (DSRIP) pool, one of the two funding pools of the waiver has four categories viz. infrastructure development, program innovation and redesign, quality improvement reporting and lastly, bringing about population health improvement.

Next-generation sequencing to solve complex inherited retinal dystrophy: A case series of multiple genes contributing to disease in extended families.

Purpose: With recent availability of next-generation sequencing (NGS), it is becoming more common to pursue disease-targeted panel testing rather than traditional sequential gene-by-gene dideoxy sequencing. In this report, we describe using NGS to identify multiple disease-causing mutations that contribute concurrently or independently to retinal dystrophy in three relatively small families.

Methods: Family members underwent comprehensive visual function evaluations, and genetic counseling including a detailed family history.

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.

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.

SeqCNV: a novel method for identification of copy number variations in targeted next-generation sequencing data.

Background: Targeted next-generation sequencing (NGS) has been widely used as a cost-effective way to identify the genetic basis of human disorders. Copy number variations (CNVs) contribute significantly to human genomic variability, some of which can lead to disease. However, effective detection of CNVs from targeted capture sequencing data remains challenging.

Diagnosis of a mild peroxisomal phenotype with next-generation sequencing.

Peroxisomal biogenesis disorders (PBD) are caused by mutations in genes, and are typically diagnosed with biochemical testing in plasma followed by confirmatory testing. Here we report the unusual diagnostic path of a child homozygous for PEX1 p.G843D.

North Carolina macular dystrophy (MCDR1) caused by a novel tandem duplication of the gene.

Purpose: To identify the underlying cause of disease in a large family with North Carolina macular dystrophy (NCMD).

Methods: A large four-generation family (RFS355) with an autosomal dominant form of NCMD was ascertained. Family members underwent comprehensive visual function evaluations.

Multimodal Imaging in Wagner Syndrome.

Wagner syndrome is a rare vitreoretinopathy described in a limited number of families. Here the authors describe four cases of suspected Wagner syndrome. All four cases had depressed rod and cone function on electroretinography, outer retinal disruption on spectral-domain optical coherence tomography, and constricted central visual fields with smaller isopter testing.

Molecular findings from 537 individuals with inherited retinal disease.

Background: Inherited retinal diseases (IRDs) are a clinically and genetically heterogeneous set of disorders, for which diagnostic second-generation sequencing (next-generation sequencing, NGS) services have been developed worldwide.

Methods: We present the molecular findings of 537 individuals referred to a 105-gene diagnostic NGS test for IRDs. We assess the diagnostic yield, the spectrum of clinical referrals, the variant analysis burden and the genetic heterogeneity of IRD.