Cost-effective sequence analysis of 113 genes in 1,192 probands with retinitis pigmentosa and Leber congenital amaurosis

Introduction: Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are two groups of inherited retinal diseases (IRDs) where the rod photoreceptors degenerate followed by the cone photoreceptors of the retina. A genetic diagnosis for IRDs is challenging since >280 genes are associated with these conditions. While whole exome sequencing (WES) is commonly used by diagnostic facilities, the costs and required infrastructure prevent its global applicability. Previous studies have shown the cost-effectiveness of sequence analysis using single molecule Molecular Inversion Probes (smMIPs) in a cohort of patients diagnosed with Stargardt disease and other maculopathies. Methods: Here, we introduce a smMIPs panel that targets the exons and splice sites of all currently known genes associated with RP and LCA, the entire RPE65 gene, known causative deep-intronic variants leading to pseudo-exons, and part of the RP17 region associated with autosomal dominant RP, by using a total of 16,812 smMIPs. The RP-LCA smMIPs panel was used to screen 1,192 probands from an international cohort of predominantly RP and LCA cases. Results and discussion: After genetic analysis, a diagnostic yield of 56% was obtained which is on par with results from WES analysis. The effectiveness and the reduced costs compared to WES renders the RP-LCA smMIPs panel a competitive approach to provide IRD patients with a genetic diagnosis, especially in countries with restricted access to genetic testing

Herpes simplex virus-type 1 induced amyloid precursor protein production as a risk factor for Alzheimer’s disease

De begeleider en/of auteur heeft geen toestemming gegeven tot het openbaar maken van de scriptie. The supervisor and/or the author did not authorize public publication of the thesis.

Usher syndrome type IV: clinically and molecularly confirmed by novel ARSG variants

Usher syndrome (USH) is an autosomal recessively inherited disease characterized by sensorineural hearing loss (SNHL) and retinitis pigmentosa (RP) with or without vestibular dysfunction. It is highly heterogeneous both clinically and genetically. Recently, variants in the arylsulfatase G (ARSG) gene have been reported to underlie USH type IV. This distinct type of USH is characterized by late-onset RP with predominantly pericentral and macular changes, and late onset SNHL without vestibular dysfunction. In this study, we describe the USH type IV phenotype in three unrelated subjects. We identified three novel pathogenic variants, two novel likely pathogenic variants, and one previously described pathogenic variant in ARSG. Functional experiments indicated a loss of sulfatase activity of the mutant proteins. Our findings confirm that ARSG variants cause the newly defined USH type IV and support the proposed extension of the phenotypic USH classification

Impact of the quality of life of inseminators on the results of artificial insemination programs in beef cattle Impacto da qualidade de vida dos inseminadores nos resultados de programas de inseminação artificial em bovinos de corte

The objective of the present study was to evaluate the effect of factors of personal life and work conditions on the results obtained by inseminators in conventional and fixed-timed artificial insemination programs in beef cattle. Inseminators from three farms (21 in the total) were interviewed and evaluated according to the general obtained pregnancy rates. The differences among the pregnancy rates obtained in the farms, motivation and its association with the obtained pregnancy rate and the effect of each variable of the groups of needs on the pregnancy rate at first insemination were evaluated. The open questions were grouped by similarity and then analyzed by frequency of the answers. Pregnancy rates obtained by the inseminators ranged from 12 to 57%, with a mean service index of 3.10 ± 1.62 doses/pregnancy. It was also observed that the satisfaction of biological, financial, and training needs was more intimately related to the pregnancy rate than the satisfaction of the other needs, although none had shown an antagonistic relationship with it. Factors concerned to life quality and to the work can be important in determining the performance of these professionals.<br>Objetivou-se avaliar o efeito de fatores ligados à vida pessoal e ao trabalho sobre os resultados obtidos por inseminadores em programas de inseminação artificial convencional e em tempo fixo em bovinos de corte. Inseminadores de três propriedades rurais (21 no total) foram entrevistados e avaliados quanto à taxa de gestação geral obtida. Foram avaliadas as diferenças entre as taxas de gestação obtidas nas fazendas, a motivação e sua associação com a taxa de gestação obtida e o efeito de cada variável dos grupos de necessidades sobre a taxa de gestação à primeira inseminação. As questões abertas, depois de agrupadas por similaridade, foram analisadas por frequência de respostas. A taxa de gestação obtida pelos inseminadores variou entre 12 e 57%, com índice de serviço de 3,10 ± 1,62 doses/prenhez. A satisfação das necessidades biológicas, financeiras e de treinamento foi mais intimamente relacionada à taxa de gestação que a satisfação das demais necessidades, embora nenhuma delas tenha apresentado relação antagônica com a taxa de gestação. Fatores ligados à qualidade de vida e ao trabalho podem ser importantes na determinação do desempenho dos inseminadores

Optical genome mapping and revisiting short-read genome sequencing data reveal previously overlooked structural variants disrupting retinal disease-associated genes.

PURPOSE: Structural variants (SVs) play an important role in inherited retinal diseases (IRD). Although the identification of SVs significantly improved upon the availability of genome sequencing, it is expected that involvement of SVs in IRDs is higher than anticipated. We revisited short-read genome sequencing data to enhance the identification of gene-disruptive SVs. METHODS: Optical genome mapping was performed to improve SV detection in short-read genome sequencing-negative cases. In addition, reanalysis of short-read genome sequencing data was performed to improve the interpretation of SVs and to re-establish SV prioritization criteria. RESULTS: In a monoallelic USH2A case, optical genome mapping identified a pericentric inversion (173 megabase), with 1 breakpoint disrupting USH2A. Retrospectively, the variant could be observed in genome sequencing data but was previously deemed false positive. Reanalysis of short-read genome sequencing data (427 IRD cases) was performed which yielded 30 pathogenic SVs affecting, among other genes, USH2A (n = 15), PRPF31 (n = 3), and EYS (n = 2). Eight of these (>25%) were overlooked during previous analyses. CONCLUSION: Critical evaluation of our findings allowed us to re-establish and improve our SV prioritization and interpretation guidelines, which will prevent missing pathogenic events in future analyses. Our data suggest that more attention should be paid to SV interpretation and the current contribution of SVs in IRDs is still underestimated