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- Fresard, Laure, et al.
(author)
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Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts
- 2019
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In: Nature Medicine. - : NATURE PUBLISHING GROUP. - 1078-8956 .- 1546-170X. ; 25:6, s. 911-919
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Journal article (peer-reviewed)abstract
- It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene(1). The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches(2-5). For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases(6-8). This includes muscle biopsies from patients with undiagnosed rare muscle disorders(6,9), and cultured fibroblasts from patients with mitochondrial disorders(7). However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution.
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2. |
- Rusz, Jan, et al.
(author)
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Probing the electronic structure of pure and doped CeMIn5 (M=Co,Rh,Ir) crystals with nuclear quadrupolar resonance
- 2008
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In: Physical Review B. Condensed Matter and Materials Physics. - 1098-0121 .- 1550-235X. ; 77:24, s. 245124-
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Journal article (peer-reviewed)abstract
- We report calculations of the electric-field gradients (EFGs) in pure and doped CeMIn5 (M=Co, Rh, and Ir) compounds and compare with experiment. The degree to which the Ce 4f electron is localized is treated within various models: the local-density approximation, generalized gradient approximation (GGA), GGA+U, and 4f-core approaches. We find that there is a correlation between the observed EFG and whether the 4f electron participates in the band formation or not. We also find that the EFG evolves linearly with Sn doping in CeRhIn5, suggesting the electronic structure is modified by doping. In contrast, the observed EFG in CeCoIn5 doped with Cd changes little with doping. These results indicate that nuclear quadrupolar resonance is a sensitive probe of electronic structure.
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