| 181. |
- Bedoni, Nicola, et al.
(författare)
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Mutations in the polyglutamylase gene TTLL5, expressed in photoreceptor cells and spermatozoa, are associated with cone-rod degeneration and reduced male fertility
- 2016
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Ingår i: Human Molecular Genetics. - 0964-6906. ; 25:20, s. 4546-4555
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Tidskriftsartikel (refereegranskat)abstract
- Hereditary retinal degenerations encompass a group of genetic diseases characterized by extreme clinical variability. Following next-generation sequencing and autozygome-based screening of patients presenting with a peculiar, recessive form of cone-dominated retinopathy, we identified five homozygous variants [p.(Asp594fs), p.(Gln117*), p.(Met712fs), p.(Ile756Phe), and p.(Glu543Lys)] in the polyglutamylase-encoding gene TTLL5, in eight patients from six families. The two male patients carrying truncating TTLL5 variants also displayed a substantial reduction in sperm motility and infertility, whereas those carrying missense changes were fertile. Defects in this polyglutamylase in humans have recently been associated with cone photoreceptor dystrophy, while mouse models carrying truncating mutations in the same gene also display reduced fertility in male animals. We examined the expression levels of TTLL5 in various human tissues and determined that this gene has multiple viable isoforms, being highly expressed in testis and retina. In addition, antibodies against TTLL5 stained the basal body of photoreceptor cells in rat and the centrosome of the spermatozoon flagellum in humans, suggesting a common mechanism of action in these two cell types. Taken together, our data indicate that mutations in TTLL5 delineate a novel, allele-specific syndrome causing defects in two as yet pathogenically unrelated functions, reproduction and vision.
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| 182. |
- Brownstein, Catherine A., et al.
(författare)
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An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge
- 2014
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Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1465-6906 .- 1474-760X. ; 15:3, s. R53-
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Tidskriftsartikel (refereegranskat)abstract
- Background: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. Results: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. Conclusions: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups.
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| 183. |
- Watts, Hannah, et al.
(författare)
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An Assessment of Geophysical Survey Techniques for Characterising the Subsurface Around Glacier Margins, and Recommendations for Future Applications
- 2022
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Ingår i: Frontiers in Earth Science. - : Frontiers Media SA. - 2296-6463. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Geophysical surveys provide an efficient and non-invasive means of studying subsurface conditions in numerous sedimentary settings. In this study, we explore the application of three geophysical methods to a proglacial environment, namely ground penetrating radar (GPR), seismic refraction and multi-channel analysis of surface waves (MASW). We apply these geophysical methods to three glacial landforms with contrasting morphologies and sedimentary characteristics, and we use the various responses to assess the applicability and limitations of each method for these proglacial targets. Our analysis shows that GPR and seismic (refraction and MASW) techniques can provide spatially extensive information on the internal architecture and composition of moraines, but careful survey designs are required to optimise data quality in these geologically complex environments. Based on our findings, we define a number of recommendations and a potential workflow to guide future geophysical investigations in analogous settings. We recommend the initial use of GPR in future studies of proglacial environments to inform (a) seismic survey design and (b) the selection of seismic interpretation techniques. We show the benefits of using multiple GPR antenna frequencies (e.g., 25 and 100 MHz) to provide decimetre scale imaging in the near surface (e.g., < 15 m) while also enabling signal penetration to targets at up to ∼40 m depth (e.g., bedrock). This strategy helps to circumvent changes in radar signal penetration resulting from variations in substrate conductivity or abundant scatterers. Our study also demonstrates the importance of combining multiple geophysical methods together with ground-truthing through sedimentological observations to reduce ambiguity in interpretations. Implementing our recommendations will improve geophysical survey practice in the field of glacial geology and allow geophysical methods to play an increasing role in the interpretation of glacial landforms and sediments.
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