| 1. |
- Thompson, B.A., et al.
(författare)
-
Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database
- 2014
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 46:2, s. 107-115
-
Tidskriftsartikel (refereegranskat)abstract
- The clinical classification of hereditary sequence variants identified in disease-related genes directly affects clinical management of patients and their relatives. The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) undertook a collaborative effort to develop, test and apply a standardized classification scheme to constitutional variants in the Lynch syndrome-associated genes MLH1, MSH2, MSH6 and PMS2. Unpublished data submission was encouraged to assist in variant classification and was recognized through microattribution. The scheme was refined by multidisciplinary expert committee review of the clinical and functional data available for variants, applied to 2,360 sequence alterations, and disseminated online. Assessment using validated criteria altered classifications for 66% of 12,006 database entries. Clinical recommendations based on transparent evaluation are now possible for 1,370 variants that were not obviously protein truncating from nomenclature. This large-scale endeavor will facilitate the consistent management of families suspected to have Lynch syndrome and demonstrates the value of multidisciplinary collaboration in the curation and classification of variants in public locus-specific databases. © 2014 Nature America, Inc.
|
|
| 2. |
- Cozen, W., et al.
(författare)
-
A meta-analysis of Hodgkin lymphoma reveals 19p13.3 TCF3 as a novel susceptibility locus
- 2014
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 5, s. 3856-
-
Tidskriftsartikel (refereegranskat)abstract
- Recent genome-wide association studies (GWAS) of Hodgkin lymphoma (HL) have identified associations with genetic variation at both HLA and non-HLA loci; however, much of heritable HL susceptibility remains unexplained. Here we perform a meta-analysis of three HL GWAS totaling 1,816 cases and 7,877 controls followed by replication in an independent set of 1,281 cases and 3,218 controls to find novel risk loci. We identify a novel variant at 19p13.3 associated with HL (rs1860661; odds ratio (OR) = 0.81, 95% confidence interval (95% CI) = 0.76-0.86, P-combined 3.5 x 10(-10)), located in intron 2 of TCF3 (also known as E2A), a regulator of B-and T-cell lineage commitment known to be involved in HL pathogenesis. This meta-analysis also notes associations between previously published loci at 2p16, 5q31, 6p31, 8q24 and 10p14 and HL subtypes. We conclude that our data suggest a link between the 19p13.3 locus, including TCF3, and HL risk.
|
|
| 3. |
- Flannick, Jason, et al.
(författare)
-
Loss-of-function mutations in SLC30A8 protect against type 2 diabetes.
- 2014
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 46:4, s. 357-357
-
Tidskriftsartikel (refereegranskat)abstract
- Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ∼150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10(-6)), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (-0.17 s.d., P = 4.6 × 10(-4)). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.
|
|
| 4. |
- Wunderer, C. B., et al.
(författare)
-
The PERCIVAL soft X-ray imager
- 2014
-
Ingår i: Journal of Instrumentation. - 1748-0221 .- 1748-0221. ; 9:3
-
Tidskriftsartikel (refereegranskat)abstract
- With the increased brilliance of state-of-the-art Synchrotron radiation sources and the advent of Free Electron Lasers enabling revolutionary science with EUV to X-ray photons comes an urgent need for suitable photon imaging detectors. Requirements include high frame rates, very large dynamic range, single-photon counting capability with low probability of false positives, and (multi)-megapixels. PERCIVAL (''Pixelated Energy Resolving CMOS Imager, Versatile and Large'') is currently being developed by a collaboration of DESY, RAL, Elettra and DLS to address this need for the soft X-ray regime. PERCIVAL is a monolithic active pixel sensor (MAPS), i.e. based on CMOS technology. It will be back-thinned to access its primary energy range of 250 eV to 1 keV with target efficiencies above 90%. According to its preliminary specifications, the roughly 10 × 10 cm2, 3520 × 3710 pixel monolithic sensor will operate at frame rates up to 120 Hz (commensurate with most FELs) and use multiple gains within its 27 μm pixels to measure (e.g. at 500 eV) 1 to ∼ 105 simultaneously-arriving photons. Currently, small-scale front-illuminated prototype systems (160 × 210 pixels) are undergoing detailed testing with visible-light as well as X-ray photons. © 2014 IOP Publishing Ltd and Sissa Medialab srl.
|
|
| 5. |
|
|
| 6. |
|
|
| 7. |
|
|
| 8. |
|
|
| 9. |
|
|
