Strong accretion shocks are expected to illuminate the warm-hot intergalactic medium encompassed by the filaments of the cosmic web, through synchrotron radio emission. Given their high sensitivity... Show moreStrong accretion shocks are expected to illuminate the warm-hot intergalactic medium encompassed by the filaments of the cosmic web, through synchrotron radio emission. Given their high sensitivity, large low-frequency radio facilities may already be able to detect signatures of this extended radio emission from the region between two close and massive galaxy clusters. In this work we exploit the non-detection of such diffuse emission by deep observations of two pairs of relatively close (similar or equal to 10 Mpc) and massive (M-500 >= 10(14) M-circle dot) galaxy clusters using the LOw-Frequency ARray. By combining the results from the two putative inter-cluster filaments, we derive new independent constraints on the median strength of intergalactic magnetic fields: B-10Mpc < 2.5 x 10(2) nG (95% confidence level). Based on cosmological simulations and assuming a primordial origin of the B-fields, these estimates can be used to limit the amplitude of primordial seed magnetic fields: B-0 <= 10 nG. We recommend the observation of similar cluster pairs as a powerful tool to set tight constraints on the amplitude of extragalactic magnetic fields. Show less
Importance Treatment trials require sound knowledge on the natural course of disease. Objective To assess clinical features, genetic findings, and genotype-phenotype correlations in patients with... Show moreImportance Treatment trials require sound knowledge on the natural course of disease. Objective To assess clinical features, genetic findings, and genotype-phenotype correlations in patients with retinitis pigmentosa (RP) associated with biallelic sequence variations in the PDE6A gene in preparation for a gene supplementation trial. Design, Setting, and Participants This prospective, longitudinal, observational cohort study was conducted from January 2001 to December 2019 in a single center (Centre for Ophthalmology of the University of Tubingen, Germany) with patients recruited multinationally from 12 collaborating European tertiary referral centers. Patients with retinitis pigmentosa, sequence variants in PDE6A, and the ability to provide informed consent were included. Exposures Comprehensive ophthalmological examinations; validation of compound heterozygosity and biallelism by familial segregation analysis, allelic cloning, or assessment of next-generation sequencing-read data, where possible. Main Outcomes and Measures Genetic findings and clinical features describing the entire cohort and comparing patients harboring the 2 most common disease-causing variants in a homozygous state (c.304C>A;p.(R102S) and c.998 + 1G>A;p.?). Results Fifty-seven patients (32 female patients [56%]; mean [SD], 40 [14] years) from 44 families were included. All patients completed the study. Thirty patients were homozygous for disease-causing alleles. Twenty-seven patients were heterozygous for 2 different PDE6A variants each. The most frequently observed alleles were c.304C>A;p.(R102S), c.998 + 1G>A;p.?, and c.2053G>A;p.(V685M). The mean (SD) best-corrected visual acuity was 0.43 (0.48) logMAR (Snellen equivalent, 20/50). The median visual field area with object III4e was 660 square degrees (5th and 95th percentiles, 76 and 11 019 square degrees; 25th and 75th percentiles, 255 and 3923 square degrees). Dark-adapted and light-adapted full-field electroretinography showed no responses in 88 of 108 eyes (81.5%). Sixty-nine of 108 eyes (62.9%) showed additional findings on optical coherence tomography imaging (eg, cystoid macular edema or macular atrophy). The variant c.998 + 1G>A;p.? led to a more severe phenotype when compared with the variant c.304C>A;p.(R102S). Conclusions and Relevance Seventeen of the PDE6A variants found in these patients appeared to be novel. Regarding the clinical findings, disease was highly symmetrical between the right and left eyes and visual impairment was mild or moderate in 90% of patients, providing a window of opportunity for gene therapy.Question What are the clinical features and course of retinitis pigmentosa associated with biallelic sequence variations in the PDE6A gene? Findings In this longitudinal cohort study of 57 adults, 17 of the PDE6A variants appeared to be novel. Disease was highly symmetrical between right and left eyes, and visual impairment was mild or moderate in 90% of patients. Meaning These data suggest that PDE6A-retinitis pigmentosa may be amenable to gene therapy.In this cohort study, 57 patients with biallelic sequence variations in the PDE6A gene and retinitis pigmentosa were followed up to assess clinical features, genetic findings, and genotype-phenotype correlations of the disease. Show less
Importance Treatment trials require sound knowledge on the natural course of disease. Objective To assess clinical features, genetic findings, and genotype-phenotype correlations in patients with... Show moreImportance Treatment trials require sound knowledge on the natural course of disease. Objective To assess clinical features, genetic findings, and genotype-phenotype correlations in patients with retinitis pigmentosa (RP) associated with biallelic sequence variations in thePDE6Agene in preparation for a gene supplementation trial. Design, Setting, and Participants This prospective, longitudinal, observational cohort study was conducted from January 2001 to December 2019 in a single center (Centre for Ophthalmology of the University of Tubingen, Germany) with patients recruited multinationally from 12 collaborating European tertiary referral centers. Patients with retinitis pigmentosa, sequence variants inPDE6A, and the ability to provide informed consent were included. Exposures Comprehensive ophthalmological examinations; validation of compound heterozygosity and biallelism by familial segregation analysis, allelic cloning, or assessment of next-generation sequencing-read data, where possible. Main Outcomes and Measures Genetic findings and clinical features describing the entire cohort and comparing patients harboring the 2 most common disease-causing variants in a homozygous state (c.304C>A;p.(R102S) and c.998 + 1G>A;p.?). Results Fifty-seven patients (32 female patients [56%]; mean [SD], 40 [14] years) from 44 families were included. All patients completed the study. Thirty patients were homozygous for disease-causing alleles. Twenty-seven patients were heterozygous for 2 differentPDE6Avariants each. The most frequently observed alleles were c.304C>A;p.(R102S), c.998 + 1G>A;p.?, and c.2053G>A;p.(V685M). The mean (SD) best-corrected visual acuity was 0.43 (0.48) logMAR (Snellen equivalent, 20/50). The median visual field area with object III4e was 660 square degrees (5th and 95th percentiles, 76 and 11019 square degrees; 25th and 75th percentiles, 255 and 3923 square degrees). Dark-adapted and light-adapted full-field electroretinography showed no responses in 88 of 108 eyes (81.5%). Sixty-nine of 108 eyes (62.9%) showed additional findings on optical coherence tomography imaging (eg, cystoid macular edema or macular atrophy). The variant c.998 + 1G>A;p.? led to a more severe phenotype when compared with the variant c.304C>A;p.(R102S). Conclusions and Relevance Seventeen of thePDE6Avariants found in these patients appeared to be novel. Regarding the clinical findings, disease was highly symmetrical between the right and left eyes and visual impairment was mild or moderate in 90% of patients, providing a window of opportunity for gene therapy.Question What are the clinical features and course of retinitis pigmentosa associated with biallelic sequence variations in thePDE6Agene? Findings In this longitudinal cohort study of 57 adults, 17 of thePDE6Avariants appeared to be novel. Disease was highly symmetrical between right and left eyes, and visual impairment was mild or moderate in 90% of patients. Meaning These data suggest thatPDE6A-retinitis pigmentosa may be amenable to gene therapy.In this cohort study, 57 patients with biallelic sequence variations in thePDE6Agene and retinitis pigmentosa were followed up to assess clinical features, genetic findings, and genotype-phenotype correlations of the disease. Show less
Khan, M.; Cornelis, S.S.; Pozo-Valero, M.D. del; Whelan, L.; Runhart, E.H.; Mishra, K.; ... ; Cremers, F.P.M. 2020
Purpose Missing heritability in human diseases represents a major challenge, and this is particularly true for ABCA4-associated Stargardt disease (STGD1). We aimed to elucidate the genomic and... Show morePurpose Missing heritability in human diseases represents a major challenge, and this is particularly true for ABCA4-associated Stargardt disease (STGD1). We aimed to elucidate the genomic and transcriptomic variation in 1054 unsolved STGD and STGD-like probands. Methods Sequencing of the complete 128-kb ABCA4 gene was performed using single-molecule molecular inversion probes (smMIPs), based on a semiautomated and cost-effective method. Structural variants (SVs) were identified using relative read coverage analyses and putative splice defects were studied using in vitro assays. Results In 448 biallelic probands 14 known and 13 novel deep-intronic variants were found, resulting in pseudoexon (PE) insertions or exon elongations in 105 alleles. Intriguingly, intron 13 variants c.1938-621G>A and c.1938-514G>A resulted in dual PE insertions consisting of the same upstream, but different downstream PEs. The intron 44 variant c.6148-84A>T resulted in two PE insertions and flanking exon deletions. Eleven distinct large deletions were found, two of which contained small inverted segments. Uniparental isodisomy of chromosome 1 was identified in one proband. Conclusion Deep sequencing of ABCA4 and midigene-based splice assays allowed the identification of SVs and causal deep-intronic variants in 25% of biallelic STGD1 cases, which represents a model study that can be applied to other inherited diseases. Show less