Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease

Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in $\textit{CHM}$ in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.This work was supported by The National Institute for Health Research England (NIHR) for the NIHR BioResource – Rare Diseases project (grant number RG65966). The Moorfields Eye Hospital cohort of patients and clinical and imaging data were ascertained and collected with the support of grants from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital, National Health Service Foundation Trust, and UCL Institute of Ophthalmology, Moorfields Eye Hospital Special Trustees, Moorfields Eye Charity, the Foundation Fighting Blindness (USA), and Retinitis Pigmentosa Fighting Blindness. M.M. is a recipient of an FFB Career Development Award. E.M. is supported by UCLH/UCL NIHR Biomedical Research Centre. F.L.R. and D.G. are supported by Cambridge NIHR Biomedical Research Centre

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Conception d'un simulateur radar à synthèse d'ouverture ultra large bande pour la détection de mines

Ce travail s'inscrit dans le cadre de la validation d'un concept de détection de cibles en présence de sol par un radar à synthèse d'ouverture S.A.R., utilisant des impulsions temporelles ultra brèves couvrant un très large spectre 100MHz - 16HZ. Cette étude résulte d'une collaboration entre l'I.R.C.O.M.(Institut de Recherche en Communications Optiques et Microondes) et le C.E.L.A.R (Centre d'Electronique de l'Armement). Un démonstrateur radar SAR ULB nommé PULSAR a été construit et testé sur le site du C.E.L.A.R. L'objet de cette thèse est de décrire les outils numériques qu'il a été nécessaire d'adapter pour traiter le problème spécifique de la détection de mines, posées ou enterrées, dans des sols de caractéristiques différentes, par un radar SAR ULB. Ces résultats obtenus permettent de prédire à partir des performances du radar et de sa position par rapport au sol, les capacités de détection du système. Une bonne concordance a été obtenue entre les réponses déterminées théoriquement et celles mesurées pour des cibles positionnées en surface.LIMOGES-BU Sciences (870852109) / SudocSudocFranceF

Repérage anatomique du nerf abducens (VI) dans les abords antérieurs des tumeurs de la région du clivus

Introduction : un des buts de la chirurgie de la base du crâne est le respect des structures vasculo-nerveuses. Les voies d'abord antérieures assistées par l'endoscopie, ou exclusivement endoscopiques, se sont développées ces dernières années. On assiste concomitamment à l'essor des études anatomiques et d'imagerie ayant pour but le repérage des structures vasculo-nerveuses. Objectif : nous proposons d'établir des repères anatomiques reproductibles afin d'identifier et de préserver le nerf abducens lors des chirurgies par voie antérieure. Matériels et méthodes : ce travail anatomique a été réalisé sur têtes injectées au latex coloré et embaumées. Les dissections ont été réalisées sous microscope opératoire au laboratoire d'anatomie de Bordeaux. Le nerf abducens a été exposé par voie endocrânienne au niveau des citernes de la base et repéré par voie ventrale trans-sinusienne après fraisage du clivus jusqu'à l'apex pétreux. Les dissections ont eu pour but le repérage du segment intradural du VI, dans le foramen pétro-sphénoïdal, entre ses segments cisternal et intra-caverneux, ainsi que sa position par rapport aux éléments osseux et vasculaires de la région. Résultats : ce segment intradural du nerf abducens est stable au cours de son trajet dans le canal pétro-clival, même en cas de modifications anatomiques locales par une tumeur de la région du clivus. Le VI émerge du canal pétro-clival à 10+/-1mm de la ligne médiane et à une hauteur de 16,5+/-1,5mm par rapport au dorsum sellae. Conclusion : ce travail nous a permis de définir un trapèze au sein duquel le fraisage du clivus est sûr et épargne les deux nerfs abducens au niveau de leur émergence ventrale lors de leur traversé du canal pétro-sphénoïdal. Le nerf peut ensuite être suivi en direction crânio-caudale en intra-dural et en direction crâniale vers sa portion ventrale intracaverneuse.BORDEAUX1-Bib.electronique (335229901) / SudocSudocFranceF

Repérage anatomique du nerf abducens (VI) dans les abords antérieurs des tumeurs de la région du clivus

BORDEAUX2-BU Santé (330632101) / SudocSudocFranceF

Ultrafast Autonomous Detection and Scanning System Based on Optoelectronic Pulse Switching

International audienceA novel method allowing the ultrafast scanning of an area thanks to an Ultra Wide Band (UWB) antenna array is proposed in this paper. This method is based on the use of asynchronous optical pulses trains with di®erent repetition rates obtained in ampli¯ed regenerative cavities. By means of optoelectronic switching, providing short powerful electrical pulses trains to an UWB antenna array, it is possible to spatially scan a large area in less than 1 ms. The paper presents the principle of the transient beam steering and its potentialities to realize an ultrafast detection system

Etude et réalisation d'un démonstrateur d'un réseau d'antennes agile alimenté par des sources optoélectroniques impulsionnelles

International audienc