| 51. |
- Pagnamenta, A. T., et al.
(författare)
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An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy
- 2021
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 144, s. 584-600
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Tidskriftsartikel (refereegranskat)abstract
- The extracellular matrix comprises a network of macromolecules such as collagens, proteoglycans and glycoproteins. VWA1 (von Willebrand factor A domain containing 1) encodes a component of the extracellular matrix that interacts with perlecan/collagen VI, appears to be involved in stabilizing extracellular matrix structures, and demonstrates high expression levels in tibial nerve. Vwa1-deficient mice manifest with abnormal peripheral nerve structure/function; however, VWA1 variants have not previously been associated with human disease. By interrogating the genome sequences of 74 180 individuals from the 100K Genomes Project in combination with international gene-matching efforts and targeted sequencing, we identified 17 individuals from 15 families with an autosomal-recessive, non-length dependent, hereditary motor neuropathy and rare biallelic variants in VWA1. A single disease-associated allele p.(G25Rfs*74), a 10-bp repeat expansion, was observed in 14/15 families and was homozygous in 10/15. Given an allele frequency in European populations approaching 1/1000, the seven unrelated homozygote individuals ascertained from the 100K Genomes Project represents a substantial enrichment above expected. Haplotype analysis identified a shared 220 kb region suggesting that this founder mutation arose 47000 years ago. A wide age-range of patients (6-83 years) helped delineate the clinical phenotype over time. The commonest disease presentation in the cohort was an early-onset (mean 2.0 +/- 1.4 years) non-length-dependent axonal hereditary motor neuropathy, confirmed on electrophysiology, which will have to be differentiated from other predominantly or pure motor neuropathies and neuronopathies. Because of slow disease progression, ambulation was largely preserved. Neurophysiology, muscle histopathology, and muscle MRI findings typically revealed clear neurogenic changes with single isolated cases displaying additional myopathic process. We speculate that a few findings of myopathic changes might be secondary to chronic denervation rather than indicating an additional myopathic disease process. Duplex reverse transcription polymerase chain reaction and immunoblotting using patient fibroblasts revealed that the founder allele results in partial nonsense mediated decay and an absence of detectable protein. CRISPR and morpholino vwa1 modelling in zebrafish demonstrated reductions in motor neuron axonal growth, synaptic formation in the skeletal muscles and locomotive behaviour. In summary, we estimate that biallelic variants in VWA1 may be responsible for up to 1% of unexplained hereditary motor neuropathy cases in Europeans. The detailed clinical characterization provided here will facilitate targeted testing on suitable patient cohorts. This novel disease gene may have previously evaded detection because of high GC content, consequential low coverage and computational difficulties associated with robustly detecting repeat-expansions. Reviewing previously unsolved exomes using lower QC filters may generate further diagnoses.
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| 52. |
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| 53. |
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| 54. |
- Pelletier, F., et al.
(författare)
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Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C
- 2021
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Ingår i: Journal of Clinical Endocrinology & Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 106:2
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Tidskriftsartikel (refereegranskat)abstract
- Context: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date. Objective: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy. Design: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated. Setting: This was a multicenter retrospective study using information collected from 3 predominant centers. Patients: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included. Main Outcome Measures: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts. Results: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients. Conclusions: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.
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| 55. |
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| 56. |
- Akrami, Y., et al.
(författare)
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Planck 2018 results IV. Diffuse component separation
- 2020
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 641
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Tidskriftsartikel (refereegranskat)abstract
- We present full-sky maps of the cosmic microwave background (CMB) and polarized synchrotron and thermal dust emission, derived from the third set of Planck frequency maps. These products have significantly lower contamination from instrumental systematic effects than previous versions. The methodologies used to derive these maps follow closely those described in earlier papers, adopting four methods (Commander, NILC, SEVEM, and SMICA) to extract the CMB component, as well as three methods (Commander, GNILC, and SMICA) to extract astrophysical components. Our revised CMB temperature maps agree with corresponding products in the Planck 2015 delivery, whereas the polarization maps exhibit significantly lower large-scale power, reflecting the improved data processing described in companion papers; however, the noise properties of the resulting data products are complicated, and the best available end-to-end simulations exhibit relative biases with respect to the data at the few percent level. Using these maps, we are for the first time able to fit the spectral index of thermal dust independently over 3 degrees regions. We derive a conservative estimate of the mean spectral index of polarized thermal dust emission of beta (d)=1.55 +/- 0.05, where the uncertainty marginalizes both over all known systematic uncertainties and different estimation techniques. For polarized synchrotron emission, we find a mean spectral index of beta (s)=-3.1 +/- 0.1, consistent with previously reported measurements. We note that the current data processing does not allow for construction of unbiased single-bolometer maps, and this limits our ability to extract CO emission and correlated components. The foreground results for intensity derived in this paper therefore do not supersede corresponding Planck 2015 products. For polarization the new results supersede the corresponding 2015 products in all respects.
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| 57. |
- Burn, E., et al.
(författare)
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Deep phenotyping of 34,128 adult patients hospitalised with COVID-19 in an international network study
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Comorbid conditions appear to be common among individuals hospitalised with coronavirus disease 2019 (COVID-19) but estimates of prevalence vary and little is known about the prior medication use of patients. Here, we describe the characteristics of adults hospitalised with COVID-19 and compare them with influenza patients. We include 34,128 (US: 8362, South Korea: 7341, Spain: 18,425) COVID-19 patients, summarising between 4811 and 11,643 unique aggregate characteristics. COVID-19 patients have been majority male in the US and Spain, but predominantly female in South Korea. Age profiles vary across data sources. Compared to 84,585 individuals hospitalised with influenza in 2014-19, COVID-19 patients have more typically been male, younger, and with fewer comorbidities and lower medication use. While protecting groups vulnerable to influenza is likely a useful starting point in the response to COVID-19, strategies will likely need to be broadened to reflect the particular characteristics of individuals being hospitalised with COVID-19. Detailed knowledge of the characteristics of COVID-19 patients helps with public health planning. Here, the authors use routinely-collected data from seven databases in three countries to describe the characteristics of >30,000 patients admitted with COVID-19 and compare them with those admitted for influenza in previous years.
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| 58. |
- Coignard, J, et al.
(författare)
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A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers
- 2021
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1, s. 1078-
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.
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| 59. |
- Fabian, ID, et al.
(författare)
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Travel burden and clinical presentation of retinoblastoma: analysis of 1024 patients from 43 African countries and 518 patients from 40 European countries
- 2021
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Ingår i: The British journal of ophthalmology. - : BMJ. - 1468-2079 .- 0007-1161. ; 105:10, s. 1435-1443
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Tidskriftsartikel (refereegranskat)abstract
- The travel distance from home to a treatment centre, which may impact the stage at diagnosis, has not been investigated for retinoblastoma, the most common childhood eye cancer. We aimed to investigate the travel burden and its impact on clinical presentation in a large sample of patients with retinoblastoma from Africa and Europe.MethodsA cross-sectional analysis including 518 treatment-naïve patients with retinoblastoma residing in 40 European countries and 1024 treatment-naïve patients with retinoblastoma residing in 43 African countries.ResultsCapture rate was 42.2% of expected patients from Africa and 108.8% from Europe. African patients were older (95% CI −12.4 to −5.4, p<0.001), had fewer cases of familial retinoblastoma (95% CI 2.0 to 5.3, p<0.001) and presented with more advanced disease (95% CI 6.0 to 9.8, p<0.001); 43.4% and 15.4% of Africans had extraocular retinoblastoma and distant metastasis at the time of diagnosis, respectively, compared to 2.9% and 1.0% of the Europeans. To reach a retinoblastoma centre, European patients travelled 421.8 km compared to Africans who travelled 185.7 km (p<0.001). On regression analysis, lower-national income level, African residence and older age (p<0.001), but not travel distance (p=0.19), were risk factors for advanced disease.ConclusionsFewer than half the expected number of patients with retinoblastoma presented to African referral centres in 2017, suggesting poor awareness or other barriers to access. Despite the relatively shorter distance travelled by African patients, they presented with later-stage disease. Health education about retinoblastoma is needed for carers and health workers in Africa in order to increase capture rate and promote early referral.
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| 60. |
- Fernández, A., et al.
(författare)
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Reinterpretation of excited states in 212Po: Shell-model multiplets rather than α-cluster states
- 2021
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Ingår i: Physical Review C. - : American Physical Society. - 2469-9985 .- 2469-9993. ; 104:5
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Tidskriftsartikel (refereegranskat)abstract
- A γ-ray spectroscopic study of 212Po was performed at the Grand Accélérateur National d'Ions Lourds, using the inverse kinematics α-transfer reaction 12C(208Pb,212Po)8Be and the AGATA spectrometer. A careful analysis based on γγ coincidence relations allowed us to establish 14 new excited states in the energy range between 1.9 and 3.3 MeV. None of these states, however, can be considered as candidates for the levels with spins and parities of 1− and 2− and excitation energies below 2.1 MeV, which have been predicted by recent α-cluster model calculations. A systematic comparison of the experimentally established excitation scheme of 212Po with shell-model calculations was performed. This comparison suggests that the six states with excitation energies (spins and parities) of 1744 (4−), 1751 (8−), 1787 (6−), 1946 (4−), 1986 (8−), and 2016 (6−) keV, which previously were interpreted as α-cluster states, may in fact be of positive parity and belong to low-lying shell-model multiplets. This reinterpretation of the structure of 212Po is supported by experimental information with respect to the linear polarization of γ rays, which suggests a magnetic character of the 432-keV γ ray decaying from the state at an excitation energy of 1787 keV to the 6+ yrast state, and exclusive reaction cross sections.
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