Pathogenic variants in IMPG1 cause autosomal dominant and autosomal recessive retinitis pigmentosa.

BACKGROUND: Inherited retinal disorders are a clinically and genetically heterogeneous group of conditions and a major cause of visual impairment. Common disease subtypes include vitelliform macular dystrophy (VMD) and retinitis pigmentosa (RP). Despite the identification of over 90 genes associated with RP, conventional genetic testing fails to detect a molecular diagnosis in about one third of patients with RP. METHODS: Exome sequencing was carried out for identifying the disease-causing gene in a family with autosomal dominant RP. Gene panel testing and exome sequencing were performed in 596 RP and VMD families to identified additional IMPG1 variants. In vivo analysis in the medaka fish system by knockdown assays was performed to screen IMPG1 possible pathogenic role. RESULTS: Exome sequencing of a family with RP revealed a splice variant in IMPG1. Subsequently, the same variant was identified in individuals from two families with either RP or VMD. A retrospective study of patients with RP or VMD revealed eight additional families with different missense or nonsense variants in IMPG1. In addition, the clinical diagnosis of the IMPG1 retinopathy-associated variant, originally described as benign concentric annular macular dystrophy, was also revised to RP with early macular involvement. Using morpholino-mediated ablation of Impg1 and its paralog Impg2 in medaka fish, we confirmed a phenotype consistent with that observed in the families, including a decreased length of rod and cone photoreceptor outer segments. CONCLUSION: This study discusses a previously unreported association between monoallelic or biallelic IMPG1 variants and RP. Notably, similar observations have been reported for IMPG2.

Low vision rehabilitation for better quality of life in visually impaired adults.

BACKGROUND: Low vision rehabilitation aims to optimise the use of residual vision after severe vision loss, but also aims to teach skills in order to improve visual functioning in daily life. Other aims include helping people to adapt to permanent vision loss and improving psychosocial functioning. These skills promote independence and active participation in society. Low vision rehabilitation should ultimately improve quality of life (QOL) for people who have visual impairment. OBJECTIVES: To assess the effectiveness of low vision rehabilitation interventions on health-related QOL (HRQOL), vision-related QOL (VRQOL) or visual functioning and other closely related patient-reported outcomes in visually impaired adults. SEARCH METHODS: We searched relevant electronic databases and trials registers up to 18 September 2019. SELECTION CRITERIA: We included randomised controlled trials (RCTs) investigating HRQOL, VRQOL and related outcomes of adults, with an irreversible visual impairment (World Health Organization criteria). We included studies that compared rehabilitation interventions with active or inactive control. DATA COLLECTION AND ANALYSIS: We used standard methods expected by Cochrane. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included 44 studies (73 reports) conducted in North America, Australia, Europe and Asia. Considering the clinical diversity of low vision rehabilitation interventions, the studies were categorised into four groups of related intervention types (and by comparator): (1) psychological therapies and/or group programmes, (2) methods of enhancing vision, (3) multidisciplinary rehabilitation programmes, (4) other programmes. Comparators were no care or waiting list as an inactive control group, usual care or other active control group. Participants included in the reported studies were mainly older adults with visual impairment or blindness, often as a result of age-related macular degeneration (AMD). Study settings were often hospitals or low vision rehabilitation services. Effects were measured at the short-term (six months or less) in most studies. Not all studies reported on funding, but those who did were supported by public or non-profit funders (N = 31), except for two studies. Compared to inactive comparators, we found very low-certainty evidence of no beneficial effects on HRQOL that was imprecisely estimated for psychological therapies and/or group programmes (SMD 0.26, 95% CI -0.28 to 0.80; participants = 183; studies = 1) and an imprecise estimate suggesting little or no effect of multidisciplinary rehabilitation programmes (SMD -0.08, 95% CI -0.37 to 0.21; participants = 183; studies = 2; I2 = 0%); no data were available for methods of enhancing vision or other programmes. Regarding VRQOL, we found low- or very low-certainty evidence of imprecisely estimated benefit with psychological therapies and/or group programmes (SMD -0.23, 95% CI -0.53 to 0.08; studies = 2; I2 = 24%) and methods of enhancing vision (SMD -0.19, 95% CI -0.54 to 0.15; participants = 262; studies = 5; I2 = 34%). Two studies using multidisciplinary rehabilitation programmes showed beneficial but inconsistent results, of which one study, which was at low risk of bias and used intensive rehabilitation, recorded a very large and significant effect (SMD: -1.64, 95% CI -2.05 to -1.24), and the other a small and uncertain effect (SMD -0.42, 95%: -0.90 to 0.07). Compared to active comparators, we found very low-certainty evidence of small or no beneficial effects on HRQOL that were imprecisely estimated with psychological therapies and/or group programmes including no difference (SMD -0.09, 95% CI -0.39 to 0.20; participants = 600; studies = 4; I2 = 67%). We also found very low-certainty evidence of small or no beneficial effects with methods of enhancing vision, that were imprecisely estimated (SMD -0.09, 95% CI -0.28 to 0.09; participants = 443; studies = 2; I2 = 0%) and multidisciplinary rehabilitation programmes (SMD -0.10, 95% CI -0.31 to 0.12; participants = 375; studies = 2; I2 = 0%). Concerning VRQOL, low-certainty evidence of small or no beneficial effects that were imprecisely estimated, was found with psychological therapies and/or group programmes (SMD -0.11, 95% CI -0.24 to 0.01; participants = 1245; studies = 7; I2 = 19%) and moderate-certainty evidence of small effects with methods of enhancing vision (SMD -0.24, 95% CI -0.40 to -0.08; participants = 660; studies = 7; I2 = 16%). No additional benefit was found with multidisciplinary rehabilitation programmes (SMD 0.01, 95% CI -0.18 to 0.20; participants = 464; studies = 3; I2 = 0%; low-certainty evidence). Among secondary outcomes, very low-certainty evidence of a significant and large, but imprecisely estimated benefit on self-efficacy or self-esteem was found for psychological therapies and/or group programmes versus waiting list or no care (SMD -0.85, 95% CI -1.48 to -0.22; participants = 456; studies = 5; I2 = 91%). In addition, very low-certainty evidence of a significant and large estimated benefit on depression was found for psychological therapies and/or group programmes versus waiting list or no care (SMD -1.23, 95% CI -2.18 to -0.28; participants = 456; studies = 5; I2 = 94%), and moderate-certainty evidence of a small benefit versus usual care (SMD -0.14, 95% CI -0.25 to -0.04; participants = 1334; studies = 9; I2 = 0%). ln the few studies in which (serious) adverse events were reported, these seemed unrelated to low vision rehabilitation. AUTHORS' CONCLUSIONS: In this Cochrane Review, no evidence of benefit was found of diverse types of low vision rehabilitation interventions on HRQOL. We found low- and moderate-certainty evidence, respectively, of a small benefit on VRQOL in studies comparing psychological therapies or methods for enhancing vision with active comparators. The type of rehabilitation varied among studies, even within intervention groups, but benefits were detected even if compared to active control groups. Studies were conducted on adults with visual impairment mainly of older age, living in high-income countries and often having AMD. Most of the included studies on low vision rehabilitation had a short follow-up, Despite these limitations, the consistent direction of the effects in this review towards benefit justifies further research activities of better methodological quality including longer maintenance effects and costs of several types of low vision rehabilitation. Research on the working mechanisms of components of rehabilitation interventions in different settings, including low-income countries, is also needed.

Whole-genome copy-number analysis identifies new leads for chromosomal aberrations involved in the oncogenesis and metastastic behavior of uveal melanomas.

To further elucidate the genetic underpinnings of uveal melanoma (UM) and identify new markers that correlate with disease outcome, archival formalin-fixed, paraffin-embedded enucleation specimens from 25 patients with UM and a mean follow-up of 14 years were analyzed for whole-genome copy-number alterations using OncoScan analysis. Copy-number alterations of chromosomes 1, 3, 6, and 8 were also analyzed in these tumors using multiplex ligation-dependent probe-amplification, and mutations in GNAQ, GNA11, and BAP1 were searched for by Sanger sequencing. Our study confirms the previously reported GNAQ and GNA11 mutation frequencies in UMs as well as the presence of monosomy 3 as a factor strongly indicating poor prognosis. Two cases with metastatic disease, but without monosomy of chromosome 3, showed loss of a small region in the distal part of chromosome 2p. Also, UMs leading to metastatic disease had more chromosomal aberrations than those without metastases. Three UMs lacking a GNAQ or a GNA11 mutation showed a gain of chromosome 8q; one of these cases showed extensive chromothripsis. Another case (with suspect lung metastasis) showed focal chromothripsis. Our whole-genome copy-number analysis shows that focal loss of chromosome 2p may be involved in the metastatic spread of UMs without monosomy 3; metastatic UMs carry more chromosomal aberrations than those without metastases; and chromothripsis may play a role in the oncogenesis of UMs, but does not necessarily indicate a poor prognosis. The clinical and particularly diagnostic utility of these findings needs to be corroborated in a larger set of patients with UM.

Clinical evaluation of 3 families with basal laminar drusen caused by novel mutations in the complement factor H gene.

OBJECTIVES: To identify novel complement factor H (CFH) gene mutations and to specify the clinical characteristics in patients with basal laminar drusen (BLD), a clinical subtype of age-related macular degeneration. METHODS: Twenty-one probands with BLD were included in this study. The ophthalmic examination included nonstereoscopic 30° color fundus photography, fluorescein angiography, and high-resolution spectral-domain optical coherence tomography. Renal function was tested by measurement of serum creatinine and urea nitrogen levels. Venous blood samples were drawn for genomic DNA, and all coding exons and splice junctions of the CFH gene were analyzed by direct sequencing. RESULTS: In 3 families, we identified novel heterozygous mutations in theCFHgene: p.Ile184fsX, p.Lys204fsX, and c.1697-17_-8del. Ten of 13 mutation carriers displayed the BLD phenotype with a wide variety in clinical presentation, ranging from limited macular drusen to extensive drusen in the posterior pole as well as the peripheral retina. Two patients with BLD developed endstage kidney disease as a result of membranoproliferative glomerulonephritis type II. CONCLUSIONS: The early-onset BLD phenotype can be caused by heterozygous mutations in the CFH gene. Because some patients with BLD are at risk to develop membranoproliferative glomerulonephritis type II, we recommend that patients with extensive BLD undergo screening for renal dysfunction. CLINICAL RELEVANCE: Elucidation of the clinical BLD phenotype will facilitate identification of individuals predisposed to developing disease-related comorbidity, such as membranoproliferative glomerulonephritis type II. Moreover, with upcoming treatment modalities targeting specific components of the complement system, early identification of patients with BLD and detection of the genetic defect become increasingly important.