James J. O'Byrne

Background/Objectives: To describe the genetic resolution rate, molecular findings, and genotype–phenotype correlations of non-ABCA4 and non-BEST1 inherited macular dystrophies (IMDs) within an Irish inherited retinal disease (IRD) registry. Methods: Retrospective review of individuals with a clinical diagnosis of macular or cone dystrophy. Comprehensive phenotyping (dilated ocular biomicroscopy, multimodal retinal imaging, visual electrophysiology) and genetic testing (panel-based next-generation sequencing, single-gene testing, whole exome/genome sequencing, WES/WGS). Variants were interpreted using ACMG AMP criteria, and genotype-phenotype match was confirmed through multidisciplinary review. Results: 232 patients with macular/cone dystrophies were identified. ABCA4 and BEST1 accounted for most molecular diagnoses (47.4%). Removing ABCA4 and BEST1, 59.0% of IMDs were genetically unresolved, higher than the rate in general IRD cohorts. Deep phenotyping enabled diagnostic reclassification in 13/72 (18.1%), namely achromatopsia, congenital stationary night blindness, and oculocutaneous albinism. Further genetic testing resolved 35/72 (48.6%) of those unresolved on first-line testing, with PRPH2 being most prevalent (n = 12), followed by GUCY2D, CRB1, PROM1, and CRX. Characteristic phenotypic signatures—such as CRB1-associated retinal thickening and retinoschisis or PROM1-associated Stargardt-like changes—supported known genotype–phenotype correlations. Conclusions: Genetic resolution rates for rare IMDs remain lower than pan-retinal IRD phenotypes. Beyond ABCA4 and BEST1, IMDs exhibit substantial genetic and phenotypic heterogeneity (24 genotypes in this cohort), with low molecular diagnostic rates despite comprehensive sequencing approaches. Detailed multimodal phenotyping (i.e., structural, functional and extra-ocular) is essential to refine diagnosis, guide genetic testing and interpret candidate variants. Genetic testing is challenging when the retinal phenotype is advanced (i.e., atrophy) or lacks pathognomonic features. Meticulous phenotyping (functional, structural and systemic) and broader genomic strategies (e.g., WES/WGS) may further increase diagnostic yield, though gene panel content is constantly improving. Consistently improving molecular diagnostic rates will ensure equitable access to emerging gene-specific therapies.

Background/Objective: Inherited retinal degenerations (IRDs) are the leading cause of blind registration in children and adults, yet 30–40% of cases remain genetically unresolved. Deep ophthalmic phenotyping may help to address this shortfall by identifying characteristic phenotypes. We describe the ophthalmic features of patients with stationary or progressive inherited retinal diseases other than outer retinal degeneration (i.e., secondary ophthalmic features, SOFs). Methods: This is a retrospective review of all patients attending an ophthalmic genetics clinic with a genetically confirmed IRD focusing on SOFs including refractive error, cataract, retinal detachment (RRD), cystoid macular lesions (CML) and epiretinal membrane (ERM). These features were assessed in the context of phenotype and genotype. Results: In a cohort of 429 genotyped patients, ≥1 SOFs were seen in 70.2% of patients, with 36.6% being affected by multiple SOFs. Refractive error (63.3%) and cataract (43.4%) were the most common secondary features, with a subset affected by CML (14.7%), ERM (10%) and RRD (4.7%). Conclusions: SOFs are common in patients with IRDs and most are amenable to therapeutic intervention even when no primary treatment (e.g., gene therapy) is available. We highlight patterns associated with genotypes and disease groups which may aid harmonisation of clinical and genetic diagnoses.

(1) Background: Inherited retinal degenertions are rare conditions which may have a dramatic impact on the daily life of those affected and how they interact with their environment. Coordination of clinical services via an ophthalmic genetics multidisciplinary team (OG-MDT) allows better efficiency of time and resources to reach diagnoses and facilitate patient needs. (2) Methods: This clinical case series was conducted by a retrospective review of patient records for patients enrolled in the Target 5000 programme and managed by the OG-MDT, at the Mater Hospital Dublin, Ireland (n = 865) (3) Results: Herein we describe clinical cases and how the use of the OG-MDT optimizes care for isolated and syndromic IRD pedigrees. (4) Conclusions: this paper demonstrates the benefits of an OG-MDT to patients with IRDs resulting in the holistic resolution of complex and syndromic cases. Furthermore, we demonstrate that this format can be adopted/developed by similar centres around the world, bringing with it the myriad benefits.

Inherited retinal degenerations (IRDs) account for over one third of the underlying causes of blindness in the paediatric population. Patients with IRDs often experience long delays prior to reaching a definitive diagnosis. Children attending a tertiary care paediatric ophthalmology department with phenotypic (i.e., clinical and/or electrophysiologic) evidence suggestive of IRD were contacted for genetic testing during the SARS-CoV-2-19 pandemic using a “telegenetics” approach. Genetic testing approach was panel-based next generation sequencing (351 genes) via a commercial laboratory (Blueprint Genetics, Helsinki, Finland). Of 70 patient samples from 57 pedigrees undergoing genetic testing, a causative genetic variant(s) was detected for 60 patients (85.7%) from 47 (82.5%) pedigrees. Of the 60 genetically resolved IRD patients, 5% (n = 3) are eligible for approved therapies (RPE65) and 38.3% (n = 23) are eligible for clinical trial-based gene therapies including CEP290 (n = 2), CNGA3 (n = 3), CNGB3 (n = 6), RPGR (n = 5) and RS1 (n = 7). The early introduction of genetic testing in the diagnostic/care pathway for children with IRDs is critical for genetic counselling of these families prior to upcoming gene therapy trials. Herein, we describe the pathway used, the clinical and genetic findings, and the therapeutic implications of the first systematic coordinated round of genetic testing of a paediatric IRD cohort in Ireland.

Although rare, inherited retinal degenerations (IRDs) are the most common reason for blind registration in the working age population. They are highly genetically heterogeneous (>300 known genetic loci), and confirmation of a molecular diagnosis is a prerequisite for many therapeutic clinical trials and approved treatments. First-tier genetic testing of IRDs with panel-based next-generation sequencing (pNGS) has a diagnostic yield of ≈70–80%, leaving the remaining more challenging cases to be resolved by second-tier testing methods. This study describes the phenotypic reassessment of patients with a negative result from first-tier pNGS and the rationale, outcomes, and cost of second-tier genetic testing approaches. Removing non-IRD cases from consideration and utilizing case-appropriate second-tier genetic testing techniques, we genetically resolved 56% of previously unresolved pedigrees, bringing the overall resolve rate to 92% (388/423). At present, pNGS remains the most cost-effective first-tier approach for the molecular assessment of diverse IRD populations Second-tier genetic testing should be guided by clinical (i.e., reassessment, multimodal imaging, electrophysiology), and genetic (i.e., single alleles in autosomal recessive disease) indications to achieve a genetic diagnosis in the most cost-effective manner.

The Irish national registry for inherited retinal degenerations (Target 5000) is a clinical and scientific program to identify individuals in Ireland with inherited retinal disorders and to attempt to ascertain the genetic cause underlying the disease pathology. Potential participants first undergo a clinical assessment, which includes clinical history and analysis with multimodal retinal imaging, electrophysiology, and visual field testing. If suitable for recruitment, a sample is taken and used for genetic analysis. Genetic analysis is conducted by use of a retinal gene panel target capture sequencing approach. With over 1000 participants from 710 pedigrees now screened, there is a positive candidate variant detection rate of approximately 70% (495/710). Where an autosomal recessive inheritance pattern is observed, an additional 9% (64/710) of probands have tested positive for a single candidate variant. Many novel variants have also been detected as part of this endeavor. The target capture approach is an economic and effective means of screening patients with inherited retinal disorders. Despite the advances in sequencing technology and the ever-decreasing associated processing costs, target capture remains an attractive option as the data produced is easily processed, analyzed, and stored compared to more comprehensive methods. However, with decreasing costs of whole genome and whole exome sequencing, the focus will likely move towards these methods for more comprehensive data generation.