The genetics and disease mechanisms of rhegmatogenous retinal detachment

Rhegmatogenous retinal detachment (RRD) is a sight threatening condition that warrants immediate surgical intervention. To date, 29 genes have been associated with monogenic disorders involving RRD. In addition, RRD can occur as a multifactorial disease through a combined effect of multiple genetic variants and non-genetic risk factors. In this review, we provide a comprehensive overview of the spectrum of hereditary disorders involving RRD. We discuss genotype-phenotype correlations of these monogenic disorders, and describe genetic variants associated with RRD through multifactorial inheritance. Furthermore, we evaluate our current understanding of the molecular disease mechanisms of RRD-associated genetic variants on collagen proteins, proteoglycan versican, and the TGF-β pathway. Finally, we review the role of genetics in patient management and prevention of RRD. We provide recommendations for genetic testing and prophylaxis of at-risk patients, and hypothesize on novel therapeutic approaches beyond surgical intervention.</p

The genetics and disease mechanisms of rhegmatogenous retinal detachment

Rhegmatogenous retinal detachment (RRD) is a sight threatening condition that warrants immediate surgical intervention. To date, 29 genes have been associated with monogenic disorders involving RRD. In addition, RRD can occur as a multifactorial disease through a combined effect of multiple genetic variants and non-genetic risk factors. In this review, we provide a comprehensive overview of the spectrum of hereditary disorders involving RRD. We discuss genotype-phenotype correlations of these monogenic disorders, and describe genetic variants associated with RRD through multifactorial inheritance. Furthermore, we evaluate our current understanding of the molecular disease mechanisms of RRD-associated genetic variants on collagen proteins, proteoglycan versican, and the TGF-β pathway. Finally, we review the role of genetics in patient management and prevention of RRD. We provide recommendations for genetic testing and prophylaxis of at-risk patients, and hypothesize on novel therapeutic approaches beyond surgical intervention.</p

The genetics and disease mechanisms of rhegmatogenous retinal detachment

Rhegmatogenous retinal detachment (RRD) is a sight threatening condition that warrants immediate surgical intervention. To date, 29 genes have been associated with monogenic disorders involving RRD. In addition, RRD can occur as a multifactorial disease through a combined effect of multiple genetic variants and non-genetic risk factors. In this review, we provide a comprehensive overview of the spectrum of hereditary disorders involving RRD. We discuss genotype-phenotype correlations of these monogenic disorders, and describe genetic variants associated with RRD through multifactorial inheritance. Furthermore, we evaluate our current understanding of the molecular disease mechanisms of RRD-associated genetic variants on collagen proteins, proteoglycan versican, and the TGF-β pathway. Finally, we review the role of genetics in patient management and prevention of RRD. We provide recommendations for genetic testing and prophylaxis of at-risk patients, and hypothesize on novel therapeutic approaches beyond surgical intervention.</p

The genetics and disease mechanisms of rhegmatogenous retinal detachment

Rhegmatogenous retinal detachment (RRD) is a sight threatening condition that warrants immediate surgical intervention. To date, 29 genes have been associated with monogenic disorders involving RRD. In addition, RRD can occur as a multifactorial disease through a combined effect of multiple genetic variants and non-genetic risk factors. In this review, we provide a comprehensive overview of the spectrum of hereditary disorders involving RRD. We discuss genotype-phenotype correlations of these monogenic disorders, and describe genetic variants associated with RRD through multifactorial inheritance. Furthermore, we evaluate our current understanding of the molecular disease mechanisms of RRD-associated genetic variants on collagen proteins, proteoglycan versican, and the TGF-β pathway. Finally, we review the role of genetics in patient management and prevention of RRD. We provide recommendations for genetic testing and prophylaxis of at-risk patients, and hypothesize on novel therapeutic approaches beyond surgical intervention.</p

Antisense oligonucleotide-based splicing correction in individuals with leber congenital amaurosis due to compound heterozygosity for the c.2991+1655A>G mutation in CEP290

Leber congenital amaurosis (LCA) is a rare inherited retinal disorder affecting approximately 1:50,000 people worldwide. So far, mutations in 25 genes have been associated with LCA, with CEP290 (encoding the Centrosomal protein of 290 kDa) being the most frequently mutated gene. The most recurrent LCA-causing CEP290 mutation, c.2991+1655A>G, causes the insertion of a pseudoexon into a variable proportion of CEP290 transcripts. We previously demonstrated that antisense oligonucleotides (AONs) have a high therapeutic potential for patients homozygously harbouring this mutation, although to date, it is unclear whether rescuing one single allele is enough to restore CEP290 function. Here, we assessed the AON efficacy at RNA, protein and cellular levels in samples that are compound heterozygous for this mutation, together with a protein-truncating mutation in CEP290. We demonstrate that AONs can efficiently restore splicing and increase protein levels. However, due to a high variability in ciliation among the patient-derived cell lines, the efficacy of the AONs was more difficult to assess at the cellular level. This observation points towards the importance of the severity of the second allele and possibly other genetic variants present in each individual. Overall, AONs seem to be a promising tool to treat CEP290-associated LCA, not only in homozygous but also in compound heterozygous carriers of the c.2991+1655A>G variant

Non-syndromic retinitis pigmentosa

Retinitis pigmentosa (RP) encompasses a group of inherited retinal dystrophies characterized by the primary degeneration of rod and cone photoreceptors. RP is a leading cause of visual disability, with a worldwide prevalence of 1:4000. Although the majority of RP cases are non-syndromic, 20–30% of patients with RP also have an associated non-ocular condition. RP typically manifests with night blindness in adolescence, followed by concentric visual field loss, reflecting the principal dysfunction of rod photoreceptors; central vision loss occurs later in life due to cone dysfunction. Photoreceptor function measured with an electroretinogram is markedly reduced or even absent. Optical coherence tomography (OCT) and fundus autofluorescence (FAF) imaging show a progressive loss of outer retinal layers and altered lipofuscin distribution in a characteristic pattern. Over the past three decades, a vast number of disease-causing variants in more than 80 genes have been associated with non-syndromic RP. The wide heterogeneity of RP makes it challenging to describe the clinical findings and pathogenesis. In this review, we provide a comprehensive overview of the clinical characteristics of RP specific to genetically defined patient subsets. We supply a unique atlas with color fundus photographs of most RP subtypes, and we discuss the relevant considerations with respect to differential diagnoses. In addition, we discuss the genes involved in the pathogenesis of RP, as well as the retinal processes that are affected by pathogenic mutations in these genes. Finally, we review management strategies for patients with RP, including counseling, visual rehabilitation, and current and emerging therapeutic options

Non-syndromic retinitis pigmentosa

Retinitis pigmentosa (RP) encompasses a group of inherited retinal dystrophies characterized by the primary degeneration of rod and cone photoreceptors. RP is a leading cause of visual disability, with a worldwide prevalence of 1:4000. Although the majority of RP cases are non-syndromic, 20–30% of patients with RP also have an associated non-ocular condition. RP typically manifests with night blindness in adolescence, followed by concentric visual field loss, reflecting the principal dysfunction of rod photoreceptors; central vision loss occurs later in life due to cone dysfunction. Photoreceptor function measured with an electroretinogram is markedly reduced or even absent. Optical coherence tomography (OCT) and fundus autofluorescence (FAF) imaging show a progressive loss of outer retinal layers and altered lipofuscin distribution in a characteristic pattern. Over the past three decades, a vast number of disease-causing variants in more than 80 genes have been associated with non-syndromic RP. The wide heterogeneity of RP makes it challenging to describe the clinical findings and pathogenesis. In this review, we provide a comprehensive overview of the clinical characteristics of RP specific to genetically defined patient subsets. We supply a unique atlas with color fundus photographs of most RP subtypes, and we discuss the relevant considerations with respect to differential diagnoses. In addition, we discuss the genes involved in the pathogenesis of RP, as well as the retinal processes that are affected by pathogenic mutations in these genes. Finally, we review management strategies for patients with RP, including counseling, visual rehabilitation, and current and emerging therapeutic options

Asymmetric Inter-Eye Progression in Stargardt Disease

PURPOSE. Asymmetry in disease progression between left and right eyes can occur in Stargardt disease (STGD1), and this needs to be considered in novel therapeutic trials with a fellow-eye paired controlled design. This study investigated the inter-eye discordance of best-corrected visual acuity (BCVA) and progression of RPE atrophy in STGD1. METHODS. We performed a retrospective cohort study collecting 68 STGD1 patients (136 eyes) with ‡1 ABCA4 variants and ‡0.5-year follow-up on BCVA and fundus autofluorescence. We compared inter-eye correlations of RPE atrophy progression between early-onset ( 10 years), intermediate-onset , and late-onset ( ‡45) STGD1 and ABCA4 variant combinations by v 2 tests. We identified associations of discordant baseline BCVA and RPE atrophy with discordant RPE atrophy progression by odds ratios (OR). We defined discordance by differences &gt;1.5 interquartile ranges 6 first/third interquartiles. RESULTS. Progression of RPE atrophy correlated moderately between eyes (q ¼ 0.766), which decreased with later onset (P ¼ 9.8 3 10 À7 ) and lower pathogenicity of ABCA4 combinations (P ¼ 0.007). Twelve patients (17.6%) had discordant inter-eye RPE atrophy progression, associated with baseline discordance of RPE atrophy (OR,.34]), but not BCVA (OR, ]). CONCLUSIONS. Lower inter-eye correlations are more likely found in late-onset STGD1 and patients carrying low pathogenic ABCA4 combinations. To achieve the highest power in a therapeutic trial, early-phase studies should minimize inter-eye discordance by selecting earlyonset STGD1 patients carrying severe ABCA4 variants without evidence of asymmetry at baseline

Clinical characteristics of rod and cone photoreceptor dystrophies in patients with mutations

METHODS. Eight patients-four diagnosed with retinitis pigmentosa (RP) and four with conerod dystrophy (CRD), carrying causal C8orf37 mutations-were clinically evaluated, including extensive medical history taking, slit-lamp biomicroscopy, ophthalmoscopy, kinetic perimetry, electroretinography (ERG), spectral-domain optical coherence tomography (SD-OCT), autofluorescence (AF) imaging, and fundus photography. RESULTS. In families A and D, respectively, one and three patients showed a classic RP phenotype with night blindness followed by concentric loss of visual field. Severe visual loss to light perception occurred early in the course of the disease. The symptoms initiated during infancy (family A) or adolescence (family D). Ophthalmoscopy revealed macular atrophy, bone spicules, attenuated vessels, and waxy pale optic discs. SD-OCT showed profound photoreceptor degeneration and AF demonstrated atrophy of the retinal pigment epithelium (RPE). ERG responses were nonrecordable in these patients. In families B and C, the patients were diagnosed with CRD. Initial symptoms were photophobia or loss of visual acuity and occurred during infancy (family B) or adolescence (family C). Ophthalmoscopy and AF revealed profound macular RPE atrophy and SD-OCT demonstrated macular photoreceptor degeneration. ERG responses were severely reduced in a cone-rod pattern or were nonrecordable. Interestingly, both patients in family B demonstrated polydactyly. CONCLUSIONS. Mutations in C8orf37 give rise to an early or adolescent-onset autosomal recessive CRD or RP phenotype with early macular atrophy. The occurrence of postaxial polydactyly in one family suggests a syndromic phenotype, which may indicate C8orf37 has a ciliary function