Familial exudative vitreoretinopathy (FEVR) is an inherited blinding disorder characterized by the abnormal development of the retinal vasculature. The majority of mutations identified in FEVR are found within four genes that encode the receptor complex (FZD4, LRP5, and TSPAN12) and ligand (NDP) of a molecular pathway that controls angiogenesis, the Norrin-b-catenin signaling pathway. However, half of all FEVR-affected case subjects do not harbor mutations in these genes, indicating that further mutated genes remain to be identified. Here we report the identification of mutations in CTNNB1, the gene encoding b-catenin, as a cause of FEVR. We describe heterozygous mutations (c.2142_2157dup [p.His720*] and c.2128C>T [p.Arg710Cys]) in two dominant FEVR-affected families and a de novo mutation (c.1434_1435insC [p.Glu479Argfs*18]) in a simplex case subject. Previous studies have reported heterozygous de novo CTNNB1 mutations as a cause of syndromic intellectual disability (ID) and autism spectrum disorder, and somatic mutations are linked to many cancers. However, in this study we show that Mendelian inherited CTNNB1 mutations can cause non-syndromic FEVR and that FEVR can be a part of the syndromic ID phenotype, further establishing the role that b-catenin signaling plays in the development of the retinal vasculature.

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The Genetics of Exfoliation Syndrome Partnership IMPORTANCE Exfoliation syndrome is a systemic disorder characterized by progressive accumulation of abnormal fibrillar protein aggregates manifesting clinically in the anterior chamber of the eye. This disorder is the most commonly known cause of glaucoma and a major cause of irreversible blindness.OBJECTIVE To determine if exfoliation syndrome is associated with rare, protein-changing variants predicted to impair protein function. DESIGN, SETTING, AND PARTICIPANTSA 2-stage, case-control, whole-exome sequencing association study with a discovery cohort and 2 independently ascertained validation cohorts. Study participants from 14 countries were enrolled between February 1999 and December 2019. The date of last clinical follow-up was December 2019. Affected individuals had exfoliation material on anterior segment structures of at least 1 eye as visualized by slit lamp examination. Unaffected individuals had no signs of exfoliation syndrome.EXPOSURES Rare, coding-sequence genetic variants predicted to be damaging by bioinformatic algorithms trained to recognize alterations that impair protein function. MAIN OUTCOMES AND MEASURESThe primary outcome was the presence of exfoliation syndrome. Exome-wide significance for detected variants was defined as P < 2.5 × 10 −6 . The secondary outcomes included biochemical enzymatic assays and gene expression analyses. RESULTSThe discovery cohort included 4028 participants with exfoliation syndrome (median age, 78 years [interquartile range, 73-83 years]; 2377 [59.0%] women) and 5638 participants without exfoliation syndrome (median age, 72 years [interquartile range, 65-78 years]; 3159 [56.0%] women). In the discovery cohort, persons with exfoliation syndrome, compared with those without exfoliation syndrome, were significantly more likely to carry damaging CYP39A1 variants (1.3% vs 0.30%, respectively; odds ratio, 3.55 [95% CI, 2.07-6.10]; P = 6.1 × 10 −7 ). This outcome was validated in 2 independent cohorts. The first validation cohort included 2337 individuals with exfoliation syndrome (median age, 74 years; 1132 women; n = 1934 with demographic data) and 2813 individuals without exfoliation syndrome (median age, 72 years; 1287 women; n = 2421 with demographic data). The second validation cohort included 1663 individuals with exfoliation syndrome (median age, 75 years; 587 women; n = 1064 with demographic data) and 3962 individuals without exfoliation syndrome (median age, 74 years; 951 women; n = 1555 with demographic data). Of the individuals from both validation cohorts, 5.2% with exfoliation syndrome carried CYP39A1 damaging alleles vs 3.1% without exfoliation syndrome (odds ratio, 1.82 [95% CI, 1.47-2.26]; P < .001). Biochemical assays classified 34 of 42 damaging CYP39A1 alleles as functionally deficient (median reduction in enzymatic activity compared with wild-type CYP39A1, 94.4% [interquartile range, 78.7%-98.2%] for the 34 deficient variants). CYP39A1 transcript expression was 47% lower (95% CI, 30%-64% lower; P < ....

Emerging anti-vascular endothelial growth factor (anti-VEGF) therapies for neovascular agerelated macular degeneration (nAMD) have revolutionised medical retina practice and the management and eventual outcome of nAMD. Recent research has focused on evaluating and comparing the efficacy of the two most widely employed anti-VEGF agents, bevacizumab and ranibizumab; however, a subgroup of patients with nAMD demonstrates a suboptimal response to standard therapy. We have therefore conducted a review of pertinent studies published until August 2018 which have documented the clinical efficacy when switching to a different anti-VEGF. Evidence on baseline disease characteristics, injection frequency and disease outcome has been obtained for patients treated with ranibizumab 0.5 mg and/or bevacizumab 1.25 mg and were switched to aflibercept 2 mg. Our review identified 45 studies investigating switching to aflibercept. Our review showed a clear anatomical benefit after the switch in terms of central retinal thickness and pigment epithelium detachment characteristics, whereas the functional outcomes were variable. Remarkable heterogeneity was documented among the relevant studies with regard to several factors including the baseline characteristics of the cohorts, the non-response definition and previous treatment protocols. Larger prospective trials with appropriate control arms are therefore required to elucidate the potential benefit when switching between anti-VEGF agents in refractory nAMD.

Introduction: Full-thickness macular hole (FTMH) formation is rarely seen in patients with retinitis pigmentosa (RP) and can have an adverse impact on their residual visual function. The underlying mechanisms are unknown, and clinical experience is limited regarding surgical outcomes. Here, we describe the surgical management of FTMH in a young patient with genetically confirmed Usher syndrome, the most common form of syndromic RP. Case Report: A 28-year-old woman presented with blurred vision in her right eye (RE). She had a history of RP and bilateral hearing impairment since childhood. Fundoscopy and spectral-domain optical coherence tomography revealed a FTMH in the RE along with typical RP features bilaterally. After pars plana vitrectomy (PPV) with internal limiting membrane peel and gas tamponade, the FTMH closed. Six months after PPV the patient underwent cataract surgery in the affected eye, and the visual acuity remained stable compared to baseline. The clinical diagnosis of Usher syndrome was genetically confirmed by whole exome sequencing (WES), which revealed the presence of two pathogenic nucleotide variants in trans (compound heterozygosity) in the gene USH2A. Conclusion: We report a rare case of successful closure of a FTMH in a patient with Usher Digital Features To view digital features for this article go to