Genetic screening in sporadic ALS and FTD.

The increasing complexity of the genetic landscape in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) presents a significant resource and physician training challenge. At least 10% of those diagnosed with ALS or FTD are known to carry an autosomal dominant genetic mutation. There is no consensus on what constitutes a positive family history, and ascertainment is unreliable for many reasons. However, symptomatic individuals often wish to understand as much as possible about the cause of their disease, and to share this knowledge with their family. While the right of an individual not to know is a key aspect of patient autonomy, and despite the absence of definitive therapy, many newly diagnosed individuals are likely to elect for genetic testing if offered. It is incumbent on the practitioner to ensure that they are adequately informed, counselled and supported in this decision

Differences in 5'untranslated regions highlight the importance of translational regulation of dosage sensitive genes

Background: Untranslated regions (UTRs) are important mediators of post-transcriptional regulation. The length of UTRs and the composition of regulatory elements within them are known to vary substantially across genes, but little is known about the reasons for this variation in humans. Here, we set out to determine whether this variation, specifically in 5’UTRs, correlates with gene dosage sensitivity. Results: We investigate 5’UTR length, the number of alternative transcription start sites, the potential for alternative splicing, the number and type of upstream open reading frames (uORFs) and the propensity of 5’UTRs to form secondary structures. We explore how these elements vary by gene tolerance to loss-of-function (LoF; using the LOEUF metric), and in genes where changes in dosage are known to cause disease. We show that LOEUF correlates with 5’UTR length and complexity. Genes that are most intolerant to LoF have longer 5’UTRs, greater TSS diversity, and more upstream regulatory elements than their LoF tolerant counterparts. We show that these differences are evident in disease gene-sets, but not in recessive developmental disorder genes where LoF of a single allele is tolerated. Conclusions: Our results confirm the importance of post-transcriptional regulation through 5'UTRs in tight regulation of mRNA and protein levels, particularly for genes where changes in dosage are deleterious and lead to disease. Finally, to support gene-based investigation we release a web-based browser tool, VuTR, that supports exploration of the composition of individual 5'UTRs and the impact of genetic variation within them

Erratum to: Mitochondrial DNA point mutations and relative copy number in 1363 disease and control human brains.

Mitochondria play a key role in common neurodegenerative diseases and contain their own genome: mtDNA. Common inherited polymorphic variants of mtDNA have been associated with several neurodegenerative diseases, and somatic deletions of mtDNA have been found in affected brain regions. However, there are conflicting reports describing the role of rare inherited variants and somatic point mutations in neurodegenerative disorders, and recent evidence also implicates mtDNA levels. To address these issues we studied 1363 post mortem human brains with a histopathological diagnosis of Parkinson's disease (PD), Alzheimer's disease (AD), Frontotemporal dementia - Amyotrophic Lateral Sclerosis (FTD-ALS), Creutzfeldt Jacob disease (CJD), and healthy controls. We obtained high-depth whole mitochondrial genome sequences using off target reads from whole exome sequencing to determine the association of mtDNA variation with the development and progression of disease, and to better understand the development of mtDNA mutations and copy number in the aging brain. With this approach, we found a surprisingly high frequency of heteroplasmic mtDNA variants in 32.3% of subjects. However, we found no evidence of an association between rare inherited variants of mtDNA or mtDNA heteroplasmy and disease. In contrast, we observed a reduction in the amount of mtDNA copy in both AD and CJD. Based on these findings, single nucleotide variants of mtDNA are unlikely to play a major role in the pathogenesis of these neurodegenerative diseases, but mtDNA levels merit further investigation

Understanding the influences on successful quality improvement in emergency general surgery: learning from the RCS Chole-QuIC project

Abstract: Background: Acute gallstone disease is the highest volume Emergency General Surgical presentation in the UK. Recent data indicate wide variations in the quality of care provided across the country, with national guidance for care delivery not implemented in most UK hospitals. Against this backdrop, the Royal College of Surgeons of England set up a 13-hospital quality improvement collaborative (Chole-QuIC) to support clinical teams to reduce time to surgery for patients with acute gallstone disease requiring emergency cholecystectomy. Methods: Prospective, mixed-methods process evaluation to answer the following: (1) how was the collaborative delivered by the faculty and received, understood and enacted by the participants; (2) what influenced teams’ ability to improve care for patients requiring emergency cholecystectomy? We collected and analysed a range of data including field notes, ethnographic observations of meetings, and project documentation. Analysis was based on the framework approach, informed by Normalisation Process Theory, and involved the creation of comparative case studies based on hospital performance during the project. Results: Chole-QuIC was delivered as planned and was well received and understood by participants. Four hospitals were identified as highly successful, based upon a substantial increase in the number of patients having surgery in line with national guidance. Conversely, four hospitals were identified as challenged, achieving no significant improvement. The comparative analysis indicate that six inter-related influences appeared most associated with improvement: (1) achieving clarity of purpose amongst site leads and key stakeholders; (2) capacity to lead and effective project support; (3) ideas to action; (4) learning from own and others’ experience; (5) creating additional capacity to do emergency cholecystectomies; and (6) coordinating/managing the patient pathway. Conclusion: Collaborative-based quality improvement is a viable strategy for emergency surgery but success requires the deployment of effective clinical strategies in conjunction with improvement strategies. In particular, achieving clarity of purpose about proposed changes amongst key stakeholders was a vital precursor to improvement, enabling the creation of additional surgical capacity and new pathways to be implemented effectively. Protected time, testing ideas, and the ability to learn quickly from data and experience were associated with greater impact within this cohort

Exome-wide Rare Variant Analysis Identifies TUBA4A Mutations Associated with Familial ALS

Exome sequencing is an effective strategy for identifying human disease genes. However, this methodology is difficult in late-onset diseases where limited availability of DNA from informative family members prohibits comprehensive segregation analysis. To overcome this limitation, we performed an exome-wide rare variant burden analysis of 363 index cases with familial ALS (FALS). The results revealed an excess of patient variants within TUBA4A, the gene encoding the Tubulin, Alpha 4A protein. Analysis of a further 272 FALS cases and 5,510 internal controls confirmed the overrepresentation as statistically significant and replicable. Functional analyses revealed that TUBA4A mutants destabilize the microtubule network, diminishing its repolymerization capability. These results further emphasize the role of cytoskeletal defects in ALS and demonstrate the power of gene-based rare variant analyses in situations where causal genes cannot be identified through traditional segregation analysis

NEK1 variants confer susceptibility to amyotrophic lateral sclerosis

To identify genetic factors contributing to amyotrophic lateral sclerosis (ALS), we conducted whole-exome analyses of 1,022 index familial ALS (FALS) cases and 7,315 controls. In a new screening strategy, we performed gene-burden analyses trained with established ALS genes and identified a significant association between loss-of-function (LOF) NEK1 variants and FALS risk. Independently, autozygosity mapping for an isolated community in the Netherlands identified a NEK1 p.Arg261His variant as a candidate risk factor. Replication analyses of sporadic ALS (SALS) cases and independent control cohorts confirmed significant disease association for both p.Arg261His (10,589 samples analyzed) and NEK1 LOF variants (3,362 samples analyzed). In total, we observed NEK1 risk variants in nearly 3% of ALS cases. NEK1 has been linked to several cellular functions, including cilia formation, DNA-damage response, microtubule stability, neuronal morphology and axonal polarity. Our results provide new and important insights into ALS etiopathogenesis and genetic etiology

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe

Constraints on the structure and seasonal variations of Triton's atmosphere from the 5 October 2017 stellar occultation and previous observations

Context. A stellar occultation by Neptune's main satellite, Triton, was observed on 5 October 2017 from Europe, North Africa, and the USA. We derived 90 light curves from this event, 42 of which yielded a central flash detection. Aims. We aimed at constraining Triton's atmospheric structure and the seasonal variations of its atmospheric pressure since the Voyager 2 epoch (1989). We also derived the shape of the lower atmosphere from central flash analysis. Methods. We used Abel inversions and direct ray-tracing code to provide the density, pressure, and temperature profiles in the altitude range similar to 8 km to similar to 190 km, corresponding to pressure levels from 9 mu bar down to a few nanobars. Results. (i) A pressure of 1.18 +/- 0.03 mu bar is found at a reference radius of 1400 km (47 km altitude). (ii) A new analysis of the Voyager 2 radio science occultation shows that this is consistent with an extrapolation of pressure down to the surface pressure obtained in 1989. (iii) A survey of occultations obtained between 1989 and 2017 suggests that an enhancement in surface pressure as reported during the 1990s might be real, but debatable, due to very few high S/N light curves and data accessible for reanalysis. The volatile transport model analysed supports a moderate increase in surface pressure, with a maximum value around 2005-2015 no higher than 23 mu bar. The pressures observed in 1995-1997 and 2017 appear mutually inconsistent with the volatile transport model presented here. (iv) The central flash structure does not show evidence of an atmospheric distortion. We find an upper limit of 0.0011 for the apparent oblateness of the atmosphere near the 8 km altitude.J.M.O. acknowledges financial support from the Portuguese Foundation for Science and Technology (FCT) and the European Social Fund (ESF) through the PhD grant SFRH/BD/131700/2017. The work leading to these results has received funding from the European Research Council under the European Community's H2020 2014-2021 ERC grant Agreement nffi 669416 "Lucky Star". We thank S. Para who supported some travels to observe the 5 October 2017 occultation. T.B. was supported for this research by an appointment to the National Aeronautics and Space Administration (NASA) Post-Doctoral Program at the Ames Research Center administered by Universities Space Research Association (USRA) through a contract with NASA. We acknowledge useful exchanges with Mark Gurwell on the ALMA CO observations. This work has made use of data from the European Space Agency (ESA) mission Gaia (https://www.cosmos.esa.int/gaia), processed by the Gaia Data Processing and Analysis Consortium (DPAC, https://www.cosmos.esa.int/web/gaia/dpac/consortium).Funding for the DPAC has been provided by national institutions, in particular the institutions participating in the Gaia Multilateral Agreement. J.L.O., P.S.-S., N.M. and R.D. acknowledge financial support from the State Agency for Research of the Spanish MCIU through the "Center of Excellence Severo Ochoa" award to the Instituto de Astrofisica de Andalucia (SEV-2017-0709), they also acknowledge the financial support by the Spanish grant AYA-2017-84637-R and the Proyecto de Excelencia de la Junta de Andalucia J.A. 2012-FQM1776. The research leading to these results has received funding from the European Union's Horizon 2020 Research and Innovation Programme, under Grant Agreement no. 687378, as part of the project "Small Bodies Near and Far" (SBNAF). P.S.-S. acknowledges financial support by the Spanish grant AYA-RTI2018-098657-J-I00 "LEO-SBNAF". The work was partially based on observations made at the Laboratorio Nacional de Astrofisica (LNA), Itajuba-MG, Brazil. The following authors acknowledge the respective CNPq grants: F.B.-R. 309578/2017-5; R.V.-M. 304544/2017-5, 401903/2016-8; J.I.B.C. 308150/2016-3 and 305917/2019-6; M.A. 427700/20183, 310683/2017-3, 473002/2013-2. This study was financed in part by the Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior -Brasil (CAPES) -Finance Code 001 and the National Institute of Science and Technology of the e-Universe project (INCT do e-Universo, CNPq grant 465376/2014-2). G.B.R. acknowledges CAPES-FAPERJ/PAPDRJ grant E26/203.173/2016 and CAPES-PRINT/UNESP grant 88887.571156/2020-00, M.A. FAPERJ grant E26/111.488/2013 and A.R.G.Jr. FAPESP grant 2018/11239-8. B.E.M. thanks CNPq 150612/2020-6 and CAPES/Cofecub-394/2016-05 grants. Part of the photometric data used in this study were collected in the frame of the photometric observations with the robotic and remotely controlled telescope at the University of Athens Observatory (UOAO; Gazeas 2016). The 2.3 m Aristarchos telescope is operated on Helmos Observatory by the Institute for Astronomy, Astrophysics, Space Applications and Remote Sensing of the National Observatory of Athens. Observations with the 2.3 m Aristarchos telescope were carried out under OPTICON programme. This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 730890. This material reflects only the authors views and the Commission is not liable for any use that may be made of the information contained therein. The 1. 2m Kryoneri telescope is operated by the Institute for Astronomy, Astrophysics, Space Applications and Remote Sensing of the National Observatory of Athens. The Astronomical Observatory of the Autonomous Region of the Aosta Valley (OAVdA) is managed by the Fondazione Clement Fillietroz-ONLUS, which is supported by the Regional Government of the Aosta Valley, the Town Municipality of Nus and the "Unite des Communes valdotaines Mont-Emilius". The 0.81 m Main Telescope at the OAVdA was upgraded thanks to a Shoemaker NEO Grant 2013 from The Planetary Society. D.C. and J.M.C. acknowledge funds from a 2017 'Research and Education' grant from Fondazione CRT-Cassa di Risparmio di Torino. P.M. acknowledges support from the Portuguese Fundacao para a Ciencia e a Tecnologia ref. PTDC/FISAST/29942/2017 through national funds and by FEDER through COMPETE 2020 (ref. POCI010145 FEDER007672). F.J. acknowledges Jean Luc Plouvier for his help. S.J.F. and C.A. would like to thank the UCL student support observers: Helen Dai, Elise Darragh-Ford, Ross Dobson, Max Hipperson, Edward Kerr-Dineen, Isaac Langley, Emese Meder, Roman Gerasimov, Javier Sanjuan, and Manasvee Saraf. We are grateful to the CAHA, OSN and La Hita Observatory staffs. This research is partially based on observations collected at Centro Astronomico HispanoAleman (CAHA) at Calar Alto, operated jointly by Junta de Andalucia and Consejo Superior de Investigaciones Cientificas (IAA-CSIC). This research was also partially based on observation carried out at the Observatorio de Sierra Nevada (OSN) operated by Instituto de Astrofisica de Andalucia (CSIC). This article is also based on observations made with the Liverpool Telescope operated on the island of La Palma by Liverpool John Moores University in the Spanish Observatorio del Roque de los Muchachos of the Instituto de Astrofisica de Canarias with financial support from the UK Science and Technology Facilities Council. Partially based on observations made with the Tx40 and Excalibur telescopes at the Observatorio Astrofisico de Javalambre in Teruel, a Spanish Infraestructura Cientifico-Tecnica Singular (ICTS) owned, managed and operated by the Centro de Estudios de Fisica del Cosmos de Aragon (CEFCA). Tx40 and Excalibur are funded with the Fondos de Inversiones de Teruel (FITE). A.R.R. would like to thank Gustavo Roman for the mechanical adaptation of the camera to the telescope to allow for the observation to be recorded. R.H., J.F.R., S.P.H. and A.S.L. have been supported by the Spanish projects AYA2015-65041P and PID2019-109467GB-100 (MINECO/FEDER, UE) and Grupos Gobierno Vasco IT1366-19. Our great thanks to Omar Hila and their collaborators in Atlas Golf Marrakech Observatory for providing access to the T60cm telescope. TRAPPIST is a project funded by the Belgian Fonds (National) de la Recherche Scientifique (F.R.S.-FNRS) under grant PDR T.0120.21. TRAPPIST-North is a project funded by the University of Liege, and performed in collaboration with Cadi Ayyad University of Marrakesh. E.J. is a FNRS Senior Research Associate

Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.Objective: To identify the genetic variants associated with juvenile ALS.Design, Setting, and Participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism.Main Outcomes and Measures: De novo variants present only in the index case and not in unaffected family members.Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway.Conclusions and Relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.</p

The 16th Data Release of the Sloan Digital Sky Surveys: First Release from the APOGEE-2 Southern Survey and Full Release of eBOSS Spectra

This paper documents the 16th data release (DR16) from the Sloan Digital Sky Surveys (SDSS), the fourth and penultimate from the fourth phase (SDSS-IV). This is the first release of data from the Southern Hemisphere survey of the Apache Point Observatory Galactic Evolution Experiment 2 (APOGEE-2); new data from APOGEE-2 North are also included. DR16 is also notable as the final data release for the main cosmological program of the Extended Baryon Oscillation Spectroscopic Survey (eBOSS), and all raw and reduced spectra from that project are released here. DR16 also includes all the data from the Time Domain Spectroscopic Survey and new data from the SPectroscopic IDentification of ERosita Survey programs, both of which were co-observed on eBOSS plates. DR16 has no new data from the Mapping Nearby Galaxies at Apache Point Observatory (MaNGA) survey (or the MaNGA Stellar Library "MaStar"). We also preview future SDSS-V operations (due to start in 2020), and summarize plans for the final SDSS-IV data release (DR17)