800 results on '"Victorian Clinical Genetics Services"'
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2. Variants in SART3 cause a spliceosomopathy characterised by failure of testis development and neuronal defects
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Ayers, Katie, Eggers, Stefanie, Rollo, Ben, Smith, Katherine, Davidson, Nadia, Siddall, Nicole, Zhao, Liang, Bowles, Josephine, Weiss, Karin, Zanni, Ginevra, Burglen, Lydie, Ben-Shachar, Shay, Rosensaft, Jenny, Raas-Rothschild, Annick, Jørgensen, Anne, Schittenhelm, Ralf, Huang, Cheng, Robevska, Gorjana, van den Bergen, Jocelyn, Casagranda, Franca, Cyza, Justyna, Pachernegg, Svenja, Wright, David, Bahlo, Melanie, Oshlack, Alicia, O'Brien, Terrence, Kwan, Patrick, Koopman, Peter, Hime, Gary, Girard, Nadine, Hoffmann, Chen, Shilon, Yuval, Zung, Amnon, Bertini, Enrico, Milh, Mathieu, Ben Rhouma, Bochra, Belguith, Neila, Bashamboo, Anu, Mcelreavey, Ken, Banne, Ehud, Weintrob, Naomi, Benzeev, Bruria, Sinclair, Andrew, Murdoch Children's Research Institute (MCRI), University of Melbourne, Victorian Clinical Genetics Services, Monash University [Melbourne], The Walter and Eliza Hall Institute of Medical Research (WEHI), University of Queensland [Brisbane], Technion - Israel Institute of Technology [Haifa], Bambino Gesù Children’s Hospital [Rome, Italy], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Génétique des Troubles du Neurodéveloppement = Developmental Brain Disorders Laboratory (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Tel Aviv Sourasky Medical Center [Te Aviv], The Hebrew University Hadassah Medical School, Chaim Sheba Medical Center, Tel Aviv University (TAU), Rigshospitalet [Copenhagen], Copenhagen University Hospital, Monash University [Clayton], Peter Mac Callum Cancer Centre, Service de pédiatrie et neurologie pédiatrique, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Kaplan Medical Center [Rehovot, Israel], Université de Gabès, Université de Sfax - University of Sfax, Hôpital Charles Nicolle [Tunis], Génétique du Développement humain - Human developmental genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Wolfson Medical Center, This study was supported by a National Health and Medical Research Council (NHMRC) programme grant (1074258) awarded to AS, NHMRC project grant (1156942) (K.A.), a Medical Research Future Fund Stem Cells Mission grant (MRF1201781) (K.A., B.N.R. and P.Kw), an Australian Research Council Future Fellowship (FT100100764) to M.B., A NHMRC Investigator Grant (1174040) to D.W., Agence Nationale de la Recherche funding ANR-10-LABX-73 REVIVE, ANR-17-CE14-0038-01 and ANR 20 CE14 0007 to K.M., ANR-19-CE140022 and ANR-19-CE14-0012 to A.B., G.Z. and E.B. are members of the European Reference Network for Rare Neurological Diseases - Project ID No 739510., ANR-10-LABX-0073,REVIVE,Stem Cells in Regenerative Biology and Medicine(2010), ANR-20-CE14-0007,Goldilocks,Analyse intégrée du rôle du facteur de transcription SF-1 / NR5A1 et de ses gènes cibles dépendants du dosage dans la fonction gonadique et les troubles du développement sexuel (DSD)(2020), ANR-19-CE14-0022,SexDiff,Régulation de la détermination du sexe et de la différenciation ovarienne : implications dans les troubles du développement sexuel(2019), and ANR-19-CE14-0012,RNA-SEX,Fonction de l'ARN hélicase dans la détermination du sexe chez les vertébrés et les troubles du développement du sexe chez l'homme (DSD)(2019)
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MESH: Humans ,MESH: RNA-Binding Proteins ,MESH: Testis ,[SDV]Life Sciences [q-bio] ,MESH: Gonadal Dysgenesis ,MESH: Antigens, Neoplasm ,MESH: Induced Pluripotent Stem Cells ,MESH: Male ,MESH: Intellectual Disability - Abstract
International audience; Squamous cell carcinoma antigen recognized by T cells 3 ( SART3 ) is an RNA-binding protein with numerous biological functions including recycling small nuclear RNAs to the spliceosome. Here, we identify recessive variants in SART3 in nine individuals presenting with intellectual disability, global developmental delay and a subset of brain anomalies, together with gonadal dysgenesis in 46,XY individuals. Knockdown of the Drosophila orthologue of SART3 reveals a conserved role in testicular and neuronal development. Human induced pluripotent stem cells carrying patient variants in SART3 show disruption to multiple signalling pathways, upregulation of spliceosome components and demonstrate aberrant gonadal and neuronal differentiation in vitro. Collectively, these findings suggest that bi-allelic SART3 variants underlie a spliceosomopathy which we tentatively propose be termed INDYGON syndrome ( I ntellectual disability, N eurodevelopmental defects and D evelopmental delay with 46,X Y GON adal dysgenesis). Our findings will enable additional diagnoses and improved outcomes for individuals born with this condition.
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- 2023
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3. The impact of COVID-19 on oncology professionals – one year on: lessons learned from the ESMO Resilience Task Force survey series
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Lim, K. H. J., Murali, K., Thorne, E., Punie, K., Kamposioras, K., Oing, C., O'Connor, M., Elez, Elena, Amaral, T., Garrido, Pilar, Lambertini, M., Devnani, B., Westphalen, C. B., Morgan, G., Haanen, J. B. A. G., Hardy, C., Banerjee, Susana, Universidad Autònoma de Barcelona, Institut Català de la Salut, [Lim KHJ] Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester. Department of Immunology and Inflammation, Imperial College London, London. Immunobiology Laboratory, The Francis Crick Institute, London, UK. [Murali K] Victorian Clinical Genetics Services & Murdoch Children’s Research Institute, The Royal Children’s Hospital, Melbourne, Australia. [Thorne E] Division of Health Research, Faculty of Health and Medicine, Lancaster University, Lancaster, UK. [Punie K] Department of General Medical Oncology and Multidisciplinary Breast Center, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium. [Kamposioras K] Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester. [Oing C] Department of Oncology, Hematology and Bone Marrow Transplantation with Division of Pneumology, Mildred Scheel Cancer Career Centre HaTriCs4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. [Élez E] Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain, and Vall d'Hebron Barcelona Hospital Campus
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Cancer Research ,Síndrome d'esgotament professional ,Oncologia ,Health Personnel ,ENGLAND ,education ,Well-being ,Medical Oncology ,COVID-19 (Malaltia) ,enfermedades profesionales::estrés laboral::desgaste profesional [ENFERMEDADES] ,profesiones sanitarias::medicina::medicina interna::oncología médica [DISCIPLINAS Y OCUPACIONES] ,Medical ,burnout ,COVID-19 ,job performance ,oncology professionals ,resilience ,well-being ,Europe ,Female ,Humans ,Pandemics ,Societies, Medical ,Burnout, Professional ,Professional ,virosis::infecciones por virus ARN::infecciones por Nidovirales::infecciones por Coronaviridae::infecciones por Coronavirus [ENFERMEDADES] ,Burnout ,Occupational Diseases::Occupational Stress::Burnout, Professional [DISEASES] ,Health Occupations::Medicine::Internal Medicine::Medical Oncology [DISCIPLINES AND OCCUPATIONS] ,Original Research ,Science & Technology ,Job performance ,Resilience ,CANCER CENTER ,Virus Diseases::RNA Virus Infections::Nidovirales Infections::Coronaviridae Infections::Coronavirus Infections [DISEASES] ,Oncology ,Oncology professionals ,Societies ,Life Sciences & Biomedicine - Abstract
Highlights • Risk of distress/burnout amongst oncology professionals continues to worsen since COVID-19 despite improved job performance. • Female and younger (≤40 years old) colleagues continue to be at higher risk of poor well-being and feeling burnout. • Job demands have increased, with nearly half now feeling overwhelmed with workload. • Concerns regarding career development/training, job security, and international fellowship opportunities remain high. • A quarter of oncology professionals reported considering changing their career, including leaving the oncology profession. Background COVID-19 has had a significant impact on the well-being and job performance of oncology professionals globally. The European Society for Medical Oncology (ESMO) Resilience Task Force collaboration set out to investigate and monitor well-being since COVID-19 in relation to work, lifestyle and support factors in oncology professionals 1 year on since the start of the pandemic. Methods An online, anonymous survey was conducted in February/March 2021 (Survey III). Key outcome variables included risk of poor well-being or distress (expanded Well-Being Index), feeling burnout (single item from expanded Well-Being Index), and job performance since COVID-19. Longitudinal analysis of responses to the series of three surveys since COVID-19 was carried out, and responses to job demands and resources questions were interrogated. SPSS V.26.0/V.27.0 and GraphPad Prism V9.0 were used for statistical analyses. Results Responses from 1269 participants from 104 countries were analysed in Survey III: 55% (n = 699/1269) female, 54% (n = 686/1269) >40 years, and 69% (n = 852/1230) of white ethnicity. There continues to be an increased risk of poor well-being or distress (n = 464/1169, 40%) and feeling burnout (n = 660/1169, 57%) compared with Survey I (25% and 38% respectively, P < 0.0001), despite improved job performance. Compared with the initial period of the pandemic, more participants report feeling overwhelmed with workload (45% versus 29%, P < 0.0001). There remain concerns about the negative impact of the pandemic on career development/training (43%), job security (37%). and international fellowship opportunities (76%). Alarmingly, 25% (n = 266/1086) are considering changing their future career with 38% (n = 100/266) contemplating leaving the profession. Conclusion Oncology professionals continue to face increased job demands. There is now significant concern regarding potential attrition in the oncology workforce. National and international stakeholders must act immediately and work closely with oncology professionals to draw up future-proof recovery plans.
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- 2021
4. Variants in the degron of AFF3 are associated with intellectual disability, mesomelic dysplasia, horseshoe kidney, and epileptic encephalopathy
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Rhonda E. Schnur, Fabio Sirchia, Olga Levchenko, Caroline Nava, Jane Juusola, Sarah Verheyen, Marketa Vlckova, Lindsay Rhodes, Gregory M. Cooper, Darina Prchalova, Thomas Courtin, Øystein L. Holla, David Kronn, Akemi J. Tanaka, E. Martina Bebin, Tara Funari, Miroslava Hancarova, Ennio Del Giudice, Nicolas Guex, Astrid Eisenkölbl, Dawn L. Earl, Toshiki Takenouchi, Ursula Gruber-Sedlmayr, Sedlácek Z, Sofia Douzgou, Heidelis A. Seebacher, Gerarda Cappuccio, Jasmin Blatterer, Anna Mikhaleva, Dian Donnai, Wendy K. Chung, Else Merckoll, Natasha J Brown, Elizabeth A. Sellars, Stefan Mundlos, Susan M. Hiatt, Giuliana Giannuzzi, Sinje Geuer, Giuseppina Vitiello, Séverine Lorrain, Alexandre Reymond, David J. Amor, Nicolas Chatron, Julien Delafontaine, Martine Doco, Kristian Tveten, Cecilie F. Rustad, Sylvain Pradervand, Delphine Héron, Alfredo Brusco, Elena L. Dadali, Nicola Brunetti-Pierri, Boris Keren, Yuri A. Zarate, Crystle Lee, Joel Charrow, Binnaz Yalcin, Heidi Taska-Tench, Elin Tønne, Tomoko Uehara, Alexander Lavrov, Jennifer Norman, Norine Voisin, Anna C.E. Hurst, Victoria R. Sanders, Ganka Douglas, Diana Johnson, Kenjiro Kosaki, Université de Lausanne = University of Lausanne (UNIL), Cooper Medical School of Rowan University [Camden] (CMSRU), Manchester University NHS Foundation Trust (MFT), University of Manchester [Manchester], HudsonAlpha Institute for Biotechnology [Huntsville, AL], Oslo University Hospital [Oslo], Victorian Clinical Genetics Services [Melbourne, VIC, Australia] (VCGS), Murdoch Children's Research Institute (MCRI), University of Melbourne, Seattle Children’s Hospital, Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme [ CHU Pitié-Salpêtrière AP-HP] (GRC : DIA), Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Research Centre for Medical Genetics [Moscow, Russia] (RCMG), Max Planck Institute for Molecular Genetics (MPIMG), Max-Planck-Gesellschaft, Medical University of Graz, Sheffield Children's NHS Foundation Trust, University of Arkansas at Little Rock, Charles University [Prague] (CU), University Hospital Motol [Prague], University of Alabama at Birmingham [ Birmingham] (UAB), Università degli studi di Torino = University of Turin (UNITO), Azienda Ospedalerio - Universitaria Città della Salute e della Scienza di Torino = University Hospital Città della Salute e della Scienza di Torino, University of Naples Federico II = Università degli studi di Napoli Federico II, Ann & Robert H. Lurie Children's Hospital of Chicago, Swiss Institute of Bioinformatics [Lausanne] (SIB), Hémostase et Remodelage Vasculaire Post-Ischémie (HERVI - EA 3801), Université de Reims Champagne-Ardenne (URCA), GeneDx [Gaithersburg, MD, USA], Johannes Kepler University Linz [Linz] (JKU), Telemark Hospital Trust [Skien, Norway], New York Medical College (NYMC), Integris Pediatric Neurology [Oklahoma City, OK, USA] (IPN), Institute for Maternal and Child Health - IRCCS 'Burlo Garofolo' [Trieste], Keio University School of Medicine [Tokyo, Japan], Columbia University [New York], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Manchester Centre for Genomic Medicine [Manchester, UK] (MCGM), St Mary's Hospital Manchester-Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-Faculty of Biology, Medicine and Health [Manchester, UK], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Dupuis, Christine, Voisin, N., Schnur, R. E., Douzgou, S., Hiatt, S. M., Rustad, C. F., Brown, N. J., Earl, D. L., Keren, B., Levchenko, O., Geuer, S., Verheyen, S., Johnson, D., Zarate, Y. A., Hancarova, M., Amor, D. J., Bebin, E. M., Blatterer, J., Brusco, A., Cappuccio, G., Charrow, J., Chatron, N., Cooper, G. M., Courtin, T., Dadali, E., Delafontaine, J., Del Giudice, E., Doco, M., Douglas, G., Eisenkolbl, A., Funari, T., Giannuzzi, G., Gruber-Sedlmayr, U., Guex, N., Heron, D., Holla, O. L., Hurst, A. C. E., Juusola, J., Kronn, D., Lavrov, A., Lee, C., Lorrain, S., Merckoll, E., Mikhaleva, A., Norman, J., Pradervand, S., Prchalova, D., Rhodes, L., Sanders, V. R., Sedlacek, Z., Seebacher, H. A., Sellars, E. A., Sirchia, F., Takenouchi, T., Tanaka, A. J., Taska-Tench, H., Tonne, E., Tveten, K., Vitiello, G., Vlckova, M., Uehara, T., Nava, C., Yalcin, B., Kosaki, K., Donnai, D., Mundlos, S., Brunetti Pierri, N., Chung, W. K., and Reymond, A.
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Male ,Models, Molecular ,Hypertrichosis ,[SDV]Life Sciences [q-bio] ,Mesomelic Dysplasia ,Transcriptome ,Mice ,Gene Frequency ,Missense mutation ,Child ,Zebrafish ,Genetics (clinical) ,Genetics ,Brain Diseases ,0303 health sciences ,biology ,Protein Stability ,030305 genetics & heredity ,AFF3 ,AFF4 ,horseshoe kidney ,intellectual disability ,mesomelic dysplasia ,Nuclear Proteins ,Syndrome ,Phenotype ,Ubiquitin ligase ,[SDV] Life Sciences [q-bio] ,Child, Preschool ,Female ,Transcriptional Elongation Factors ,Adolescent ,Mutation, Missense ,Osteochondrodysplasias ,Article ,Evolution, Molecular ,Young Adult ,03 medical and health sciences ,medicine ,Animals ,Humans ,Amino Acid Sequence ,Fused Kidney ,030304 developmental biology ,Epilepsy ,Infant ,Horseshoe kidney ,biology.organism_classification ,medicine.disease ,biology.protein - Abstract
International audience; The ALF transcription factor paralogs, AFF1, AFF2, AFF3, and AFF4, are components of the transcriptional super elongation complex that regulates expression of genes involved in neurogenesis and development. We describe an autosomal dominant disorder associated with de novo missense variants in the degron of AFF3, a nine amino acid sequence important for its binding to ubiquitin ligase, or with de novo deletions of this region. The sixteen affected individuals we identified, along with two previously reported individuals, present with a recognizable pattern of anomalies, which we named KINSSHIP syndrome (KI for horseshoe kidney, NS for Nievergelt/Savarirayan type of mesomelic dysplasia, S for seizures, H for hypertrichosis, I for intellectual disability, and P for pulmonary involvement), partially overlapping the AFF4-associated CHOPS syndrome. Whereas homozygous Aff3 knockout mice display skeletal anomalies, kidney defects, brain malformations, and neurological anomalies, knockin animals modeling one of the microdeletions and the most common of the missense variants identified in affected individuals presented with lower mesomelic limb deformities like KINSSHIP-affected individuals and early lethality, respectively. Overexpression of AFF3 in zebrafish resulted in body axis anomalies, providing some support for the pathological effect of increased amount of AFF3. The only partial phenotypic overlap of AFF3-and AFF4-associated syndromes and the previously published transcriptome analyses of ALF transcription factors suggest that these factors are not redundant and each contributes uniquely to proper development.
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- 2021
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5. ACTB Loss-of-Function Mutations Result in a Pleiotropic Developmental Disorder
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Cuvertino, Sara, Stuart, Helen M., Chandler, Kate E., Roberts, Neil A., Armstrong, Ruth, Bernardini, Laura, Bhaskar, Sanjeev, Callewaert, Bert, Clayton-Smith, Jill, Davalillo, Cristina Hernando, Deshpande, Charu, Devriendt, Koenraad, Digilio, Maria C., Dixit, Abhijit, Edwards, Matthew, Friedman, Jan M., Gonzalez-Meneses, Antonio, Joss, Shelagh, Kerr, Bronwyn, Lampe, Anne Katrin, Langlois, Sylvie, Lennon, Rachel, Loget, Philippe, Ma, David Y. T., Mcgowan, Ruth, Des Medt, Maryse, O'Sullivan, James, Odent, Sylvie, Parker, Michael J., Pebrel-Richard, Céline, Petit, Florence, Stark, Zornitza, Stockler-Ipsiroglu, Sylvia, Tinschert, Sigrid, Vasudevan, Pradeep, Villa, Olaya, White, Susan M., Zahir, Farah R., Study, Ddd, Woolf, Adrian S., Banka, Siddharth, University of Manchester [Manchester], Regional Genetic Service, St Mary's Hospital, Manchester, East Anglian Medical Genetics Service, Cytogenetics Laboratory, Addenbrooke's Hospital, Mendel Laboratory, IRCCS Casa Sollievo della Sofferenza Hospital, Center for Medical Genetics [Ghent], Ghent University Hospital, Centre for Genomic Regulation [Barcelona] (CRG), Universitat Pompeu Fabra [Barcelona]-Centro Nacional de Analisis Genomico [Barcelona] (CNAG), Guy's Hospital [London], Centre for Human Genetics, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven)-University Hospitals Leuven [Leuven], IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Nottingham City Hospital, Western Sydney University (UWS), University of British Columbia (UBC), Department of Clinical Genetics (Queen Elizabeth University Hospital, Glasgow), Queen Elizabeth University Hospital (Glasgow), University of Edinburgh, Service d'anatomie et cytologie pathologiques [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Department of Clinical Genetics, Leicester Royal Infirmary, CLAD Ouest, Centre Hospitalier Universitaire [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Sheffield Children's Hospital, CHU Clermont-Ferrand, CHU de Lille, Genetic Health Services Victoria, Innsbruck Medical University [Austria] (IMU), University Hospitals of Leicester, University of Melbourne, Victorian Clinical Genetics Services, University of Northern British Columbia (UNBC), Hamad Bin Khalifa University (HBKU), The Wellcome Trust Sanger Institute [Cambridge], L002744/1, Medical Research Council UK, Central Manchester University Hospitals NHS Foundation Trust, Kidney Research UK, NIHR, Academy of Medical Sciences, 16-17/10, Newlife Foundation, 629396, Kabuki Research Fund, Wellcome Trust, HICF-1009-003, Health Innovation Challenge Fund, WT098051, Wellcome Trust Sanger Institute, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo] (IRCCS), Universitat Pompeu Fabra [Barcelona] (UPF)-Centro Nacional de Analisis Genomico [Barcelona] (CNAG), Western Sydney University, Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], CHU Pontchaillou [Rennes], University Hospitals Leicester-University Hospitals Leicester, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Sheffield Children's NHS Foundation Trust, University Hospitals Leicester, University of Northern British Columbia [Prince George] (UNBC), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Innsbruck Medical University = Medizinische Universität Innsbruck (IMU)
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DYNAMICS ,Male ,Developmental Disabilities ,CYTOSKELETON ,Haploinsufficiency ,Mice ,Medicine and Health Sciences ,RNA, Small Interfering ,Child ,Frameshift Mutation ,developmental disorder ,ARCHITECTURE ,Cell Cycle ,Coloboma ,Malformations of Cortical Development ,Codon, Nonsense ,Child, Preschool ,DELAY ,malformations ,Female ,RNA Interference ,Abnormalities ,Multiple ,Adult ,Adolescent ,Small Interfering ,Young Adult ,WINTER CEREBROFRONTOFACIAL SYNDROME ,Report ,Intellectual Disability ,Humans ,Animals ,Abnormalities, Multiple ,MALFORMATIONS ,β-actin ,Preschool ,Codon ,Aged ,Cell Proliferation ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,Infant, Newborn ,Biology and Life Sciences ,Infant ,Facies ,ACTB ,Newborn ,NUCLEAR ACTIN ,Actins ,BETA-ACTIN ,Nonsense ,DE-NOVO MUTATIONS ,MECHANICS ,chromatin ,RNA ,Gene Deletion - Abstract
ACTB encodes β-actin, an abundant cytoskeletal housekeeping protein. In humans, postulated gain-of-function missense mutations cause Baraitser-Winter syndrome (BRWS), characterized by intellectual disability, cortical malformations, coloboma, sensorineural deafness, and typical facial features. To date, the consequences of loss-of-function ACTB mutations have not been proven conclusively. We describe heterozygous ACTB deletions and nonsense and frameshift mutations in 33 individuals with developmental delay, apparent intellectual disability, increased frequency of internal organ malformations (including those of the heart and the renal tract), growth retardation, and a recognizable facial gestalt (interrupted wavy eyebrows, dense eyelashes, wide nose, wide mouth, and a prominent chin) that is distinct from characteristics of individuals with BRWS. Strikingly, this spectrum overlaps with that of several chromatin-remodeling developmental disorders. In wild-type mouse embryos, β-actin expression was prominent in the kidney, heart, and brain. ACTB mRNA expression levels in lymphoblastic lines and fibroblasts derived from affected individuals were decreased in comparison to those in control cells. Fibroblasts derived from an affected individual and ACTB siRNA knockdown in wild-type fibroblasts showed altered cell shape and migration, consistent with known roles of cytoplasmic β-actin. We also demonstrate that ACTB haploinsufficiency leads to reduced cell proliferation, altered expression of cell-cycle genes, and decreased amounts of nuclear, but not cytoplasmic, β-actin. In conclusion, we show that heterozygous loss-of-function ACTB mutations cause a distinct pleiotropic malformation syndrome with intellectual disability. Our biological studies suggest that a critically reduced amount of this protein alters cell shape, migration, proliferation, and gene expression to the detriment of brain, heart, and kidney development. ispartof: American Journal of Human Genetics vol:101 issue:6 pages:1021-1033 ispartof: location:United States status: published
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- 2017
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6. Syndrome diagnosis with single-nucleotide polymorphism (SNP) microarray
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Edwards, Matthew, Brescianini, Sally, Allgood, Catherine, Freelander, Michael, Dunstan, Richard, Patradoon-Ho, Patrick, Chin, Raymond, Morgan, Lucy, Pervez, Tasnuba, Legendre, Marie, Burgess, Trent, Amselem, Serge, Whitehall, John, Western Sydney University, Campbelltown Hospital [New South Wales, Australia] (CH), Concord Repatriation General Hospital [Sydney, Australia] (CRGH), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Victorian Clinical Genetics Services [Melbourne, VIC, Australia] (VCGS), Physiopathologie des maladies génétiques d'expression pédiatrique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), School of Medicine [Western Sydney University], UF de Génétique moléculaire [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de génétique et embryologie médicales [CHU Trousseau], and Couvet, Sandrine
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[SDV] Life Sciences [q-bio] ,Male ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,Child, Preschool ,[SDV]Life Sciences [q-bio] ,Infant, Newborn ,Humans ,[SDV.GEN] Life Sciences [q-bio]/Genetics ,Genetic Testing ,Syndrome ,Microarray Analysis ,Polymorphism, Single Nucleotide ,Ciliary Motility Disorders - Abstract
International audience; No abstract available
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- 2016
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7. Clinical reappraisal of SHORT syndrome with PIK3R1 mutations: toward recommendation for molecular testing and management
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M, Avila, D A, Dyment, J V, Sagen, J, St-Onge, U, Moog, B H Y, Chung, S, Mo, S, Mansour, A, Albanese, S, Garcia, D O, Martin, A A, Lopez, T, Claudi, R, König, S M, White, S L, Sawyer, J A, Bernstein, L, Slattery, R K, Jobling, G, Yoon, C J, Curry, M L, Merrer, B L, Luyer, D, Héron, M, Mathieu-Dramard, P, Bitoun, S, Odent, J, Amiel, P, Kuentz, J, Thevenon, M, Laville, Y, Reznik, C, Fagour, M-L, Nunes, D, Delesalle, S, Manouvrier, O, Lascols, F, Huet, C, Binquet, L, Faivre, J-B, Rivière, C, Vigouroux, P R, Njølstad, A M, Innes, C, Thauvin-Robinet, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Génétique des Anomalies du Développement (GAD), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB), Children's hospital of Eastern Ontario Research Institute, University of Bergen (UiB), Haukeland University Hospital, Human Genetics Institute, Heidelberg University, Department of Paediatrics and Adolescent Medicine [HKU], The University of Hong Kong (HKU), SW Thames Regional Genetics Service, St Georgeâ™s University of London, London, St George's Hospital, INGEMM, Instituto de Genética Médica y Molecular, IDIPAZ-Hospital Universitario La Paz, Instituto de Salud Carlos III [Madrid] (ISC), Hospital Central de la Cruz Roja San Jose y Santa Adela, University Hospital Puerta de Hierro, Madrid, Bodø University College, Humangenetik, Universitätsklinikum Frankfurt, University of Frankfurt, University of Melbourne, Victorian Clinical Genetics Services, Stanford University, The Hospital for sick children [Toronto] (SickKids), University of California [San Francisco] (UCSF), University of California, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CH Le Havre, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Trousseau [APHP], CHU Amiens-Picardie, Service de Pédiatrie [Jean Verdier], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris 13 (UP13)-Hôpital Jean Verdier [AP-HP], Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), CHU Pontchaillou [Rennes], Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Centre de Recherche en Nutrition Humaine Rhône-Alpes (CRNH-RA), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-CHU Saint-Etienne-Hospices Civils de Lyon (HCL)-CHU Grenoble, Hôpital Côte de Nacre [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), CHU Bordeaux [Bordeaux], CH Valenciennes, Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Calgary, Financial support was from the Regional Council of Burgundy and the Care4Rare Canada Consortium was funded by Genome Canada, the Canadian Institutes of Health Research, the Ontario Genomics Institute, Ontario Research Fund, Genome Quebec, and Children’sHospital of Eastern Ontario Foundation. DAD is the recipient of a CIHR Clinical Investigator award from the Institute of Genetics. PRN was supported in part by grants from the Research Council of Norway, The University of Bergen, an ERC Advanced Grant, Helse Vest and the KG Jebsen Foundation., SW Thames Regional Genetics Service, St Georgeâ™s University of London, London, Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Jean Verdier [AP-HP], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, University of Bergen (UIB), Instituto de Salud Carlos III (ISC), Stanford University [Stanford], The Hospital for Sick Children, University of Toronto, Toronto M5G 1X8, Canada, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], CHU Pitié-Salpêtrière [APHP], Service de neuropédiatrie [Trousseau], Centre hospitalier universitaire d'Amiens (CHU Amiens-Picardie), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris 13 (UP13)-Hôpital Jean Verdier [Bondy], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Recherche Clinique, Université Joseph Fourier - Grenoble 1 (UJF)-Centre de Recherche en Nutrition Humaine Rhône - Alpes, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Génétique des Anomalies du Développement ( GAD ), Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC, University of Bergen ( UIB ), The University of Hong Kong ( HKU ), Instituto de Salud Carlos III (ISCIII) - Spain RDR - CIBERER, University of California [San Francisco] ( UCSF ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Centre de Référence des Déficiences Intellectuelles de Causes Rares, Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme ( GRC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Centre hospitalier universitaire d'Amiens ( CHU Amiens-Picardie ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris 13 ( UP13 ) -Hôpital Jean Verdier, Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Cardiovasculaire, métabolisme, diabétologie et nutrition ( CarMeN ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hospices Civils de Lyon ( HCL ) -Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Institut National de la Recherche Agronomique ( INRA ), Université Joseph Fourier - Grenoble 1 ( UJF ) -Centre de Recherche en Nutrition Humaine Rhône - Alpes, Cancers et préventions, Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Universitaire de Bordeaux, Service de Génétique Clinique et Université Lille 2, Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie ( UPMC ), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition ( ICAN ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Pitié-Salpêtrière [APHP], Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques ( CIC-EC ), Université de Bourgogne ( UB ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), University of California [San Francisco] (UC San Francisco), University of California (UC), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), and Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN)
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short stature ,lipoatrophy ,intrauterine growth restriction ,[ SDV ] Life Sciences [q-bio] ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,[SDV]Life Sciences [q-bio] ,Diabetes ,PIK3R1 gene ,Insulin Resistance ,[ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics ,SHORT syndrome - Abstract
International audience; SHORT syndrome has historically been defined by its acronym: short stature (S), hyperextensibility of joints and/or inguinal hernia (H), ocular depression (O), Rieger abnormality (R) and teething delay (T). More recently several research groups have identified PIK3R1 mutations as responsible for SHORT syndrome. Knowledge of the molecular etiology of SHORT syndrome has permitted a reassessment of the clinical phenotype. The detailed phenotypes of 32 individuals with SHORT syndrome and PIK3R1 mutation, including eight newly ascertained individuals, were studied to fully define the syndrome and the indications for PIK3R1 testing. The major features described in the SHORT acronym were not universally seen and only half (52%) had 4 or more of the classic features. The commonly observed clinical features of SHORT syndrome seen in the cohort included IUGR \textless 10(th) percentile, postnatal growth restriction, lipoatrophy and the characteristic facial gestalt. Anterior chamber defects and insulin resistance or diabetes were also observed but were not as prevalent. The less specific, or minor features of SHORT syndrome include teething delay, thin wrinkled skin, speech delay, sensorineural deafness, hyperextensibility of joints and inguinal hernia. Given the high risk of diabetes mellitus, regular monitoring of glucose metabolism is warranted. An echocardiogram, ophthalmological and hearing assessments are also recommended.
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- 2015
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8. Molecular and clinical characterization of 25 individuals with exonic deletions of NRXN1 and comprehensive review of the literature
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Frédéric Bilan, Armand Bottani, Damien L. Bruno, Arie van Haeringen, Stylianos E. Antonarakis, Erica H. Gerkes, Brigitte Gilbert-Dussardier, Audrey Labalme, Stefania Gimelli, Claudia A. L. Ruivenkamp, Howard R. Slater, Alain Kitzis, Trijnie Dijkhuizen, Ann-Charlotte Thuresson, Marianne Till, Devika Ganesamoorthy, Damien Sanlaville, Christele Dubourgm, Conny M. A. van Ravenswaaij-Arts, Laurent Pasquier, Britt-Marie Anderlid, Marjolein Kriek, Massimiliano Rossi, Jacqueline Schoumans, Mats Eriksson, Frédérique Béna, Maryline Gagnebin, Michel Guipponi, Zornitza Stark, Génétique médicale, Hôpitaux Universitaires de Genève (HUG), Department of Genetics, Genetic Health Services Victoria, Department of Obstetrics and Gynecology, University of Oulu-Institute of Clinical Medicine, Department of Immunology, Genetics and Pathology [Uppsala, Sueden] (IGP), Uppsala University, Service de cytogénétique constitutionnelle, Hospices Civils de Lyon (HCL)-CHU de Lyon-Centre Neuroscience et Recherche, Service de Génétique, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Poitiers - Faculté de Médecine et de Pharmacie, Université de Poitiers, Department of Human Genetics, Radboud University Medical Center [Nijmegen], Center for Medical Genetics, Victorian Clinical Genetics Services, Ethical, Legal, Social Issues in Genetics (ELSI), and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
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[SDV]Life Sciences [q-bio] ,VARIANTS ,Bioinformatics ,Cell Adhesion Molecules, Neuronal/genetics ,Cohort Studies ,neurexin ,0302 clinical medicine ,Intellectual disability ,SCHIZOPHRENIA ,Nerve Tissue Proteins/genetics ,HUMAN GENOME ,ddc:576.5 ,Copy-number variation ,exon ,deletion ,Neural Cell Adhesion Molecules ,Genetics (clinical) ,Sequence Deletion ,seizures ,Genetics ,0303 health sciences ,Exons ,Hypotonia ,3. Good health ,Psychiatry and Mental health ,Autism spectrum disorder ,SEVERE DEVELOPMENTAL DELAY ,medicine.symptom ,Haploinsufficiency ,Seizures/genetics ,Autistic Disorder/genetics ,Heterozygote ,GENES ,RARE DELETIONS ,Cell Adhesion Molecules, Neuronal ,review ,autism ,Nerve Tissue Proteins ,Biology ,Structural variation ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,NRXN1 ,medicine ,Humans ,Expressivity (genetics) ,Autistic Disorder ,030304 developmental biology ,COPY NUMBER VARIATION ,HIGH-FREQUENCY ,AUTISM SPECTRUM DISORDER ,Calcium-Binding Proteins ,medicine.disease ,Karyotyping ,Autism ,030217 neurology & neurosurgery ,MENTAL-RETARDATION - Abstract
This study aimed to elucidate the observed variable phenotypic expressivity associated with NRXN1 (Neurexin 1) haploinsufficiency by analyses of the largest cohort of patients with NRXN1 exonic deletions described to date and by comprehensively reviewing all comparable copy number variants in all disease cohorts that have been published in the peer reviewed literature (30 separate papers in all). Assessment of the clinical details in 25 previously undescribed individuals with NRXN1 exonic deletions demonstrated recurrent phenotypic features consisting of moderate to severe intellectual disability (91%), severe language delay (81%), autism spectrum disorder (65%), seizures (43%), and hypotonia (38%). These showed considerable overlap with previously reported NRXN1-deletion associated phenotypes in terms of both spectrum and frequency. However, we did not find evidence for an association between deletions involving the -isoform of neurexin-1 and increased head size, as was recently published in four cases with a deletion involving the C-terminus of NRXN1. We identified additional rare copy number variants in 20% of cases. This study supports a pathogenic role for heterozygous exonic deletions of NRXN1 in neurodevelopmental disorders. The additional rare copy number variants identified may act as possible phenotypic modifiers as suggested in a recent digenic model of neurodevelopmental disorders. (c) 2013 Wiley Periodicals, Inc.
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- 2013
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9. Periventricular heterotopia, mental retardation, and epilepsy associated with 5q14.3-q15 deletion
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Laurent Villard, Orsetta Zuffardi, Francesca Novara, Carlos Cardoso, Ingrid E. Scheffer, Brigitte Chabrol, E. Pallesi, Sabrina Khantane, Sabrina Giglio, Anne Moncla, Enrico Bertini, Cécile Mignon-Ravix, Ellena Parrini, Jacinta M McMahon, Chantal Missirian, Renzo Guerrini, Howard R. Slater, Amber Boys, Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U1249), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Victorian Clinical Genetics Services, Pediatric Neurology & Neurogenetics Unit and Laboratories, Università degli Studi di Firenze = University of Florence (UniFI)-Children's Hospital A. Meyer, Departments of Medicine and Paediatrics, University of Melbourne-Austin Health, Department of Laboratory Medicine, IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Unit of Molecular Medicine, IRCCS, Genetica Medica, Università degli Studi di Pavia = University of Pavia (UNIPV), Medical Genetics Unit, Service de pédiatrie et neurologie pédiatrique, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI)-Children's Hospital A. Meyer, Università degli Studi di Pavia, and Tyzio, Roman
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Male ,Microcephaly ,Candidate gene ,Epilepsy ,Lateral ventricles ,0302 clinical medicine ,Periventricular Nodular Heterotopia ,MESH: Mental Retardation ,MESH: Periventricular Nodular Heterotopia ,FLNA ,MESH: Syndrome ,Genetics ,MESH: Aged ,0303 health sciences ,Comparative Genomic Hybridization ,MESH: Middle Aged ,Chromosome Mapping ,Syndrome ,Middle Aged ,MESH: Young Adult ,MESH: Epilepsy ,Chromosomes, Human, Pair 5 ,Female ,Psychology ,Adult ,MESH: Chromosomes, Human, Pair 5 ,Adolescent ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,03 medical and health sciences ,Young Adult ,Fetus ,Intellectual Disability ,medicine ,Humans ,[SDV.BC] Life Sciences [q-bio]/Cellular Biology ,030304 developmental biology ,Aged ,MESH: Adolescent ,MESH: Humans ,Genetic heterogeneity ,MESH: Adult ,MESH: Fetus ,medicine.disease ,MESH: Male ,Xq28 ,MESH: Comparative Genomic Hybridization ,MESH: Gene Deletion ,Neurology (clinical) ,MESH: Chromosome Mapping ,Neuroscience ,MESH: Female ,030217 neurology & neurosurgery ,Gene Deletion ,Comparative genomic hybridization - Abstract
International audience; BACKGROUND: Periventricular heterotopia (PH) is an etiologically heterogeneous disorder characterized by nodules of neurons ectopically placed along the lateral ventricles. Most affected patients have seizures and their cognitive level varies from normal to severely impaired. At present, two genes have been identified to cause PH when mutated. Mutations in FLNA (Xq28) and ARFGEF2 (20q13) are responsible for X-linked bilateral PH and a rare autosomal recessive form of PH with microcephaly. Chromosomal rearrangements involving the 1p36, 5p15, and 7q11 regions have also been reported in association with PH but the genes implicated remain unknown. Fourteen additional distinct anatomoclinical PH syndromes have been described, but no genetic insights into their causes have been gleaned. METHODS: We report the clinical and imaging features of three unrelated patients with epilepsy, mental retardation, and bilateral PH in the walls of the temporal horns of the lateral ventricles, associated with a de novo deletion of the 5q14.3-15 region. We used microarray-based comparative genomic hybridization to define the boundaries of the deletions. RESULTS: The three patients shared a common deleted region spanning 5.8 Mb and containing 14 candidate genes. CONCLUSION: We identified a new syndrome featuring bilateral periventricular heterotopia (PH), mental retardation, and epilepsy, mapping to chromosome 5q14.3-q15. This observation reinforces the extreme clinical and genetic heterogeneity of PH. Array comparative genomic hybridization is a powerful diagnostic tool for characterizing causative chromosomal rearrangements of limited size, identifying potential candidate genes for, and improving genetic counseling in, malformations of cortical development.
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- 2009
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10. Design and evaluation of a visual genomic explainer: a mixed-methods study.
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Butler G, Andersen C, Buttery J, Gupta A, Martyn MM, Stark Z, Wilkins E, Jayasinghe K, and Quinlan C
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- Humans, Ireland, Australia, Surveys and Questionnaires, Prospective Studies, Comprehension, Attitude of Health Personnel, Audiovisual Aids, Pediatricians, Male, Genomics methods, Genetic Testing methods
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Objective: To design and assess a visual genomic explainer focusing on plain language and engaging imagery. The explainer aimed to support doctors' comprehension of complex genomic concepts and results and act as a resource promoting the integration of genomic testing into mainstream care., Design: Prospective genomic resource development and questionnaire., Setting: Regional and tertiary hospitals in Australia and Ireland, private and community-based clinicians in Australia., Participants: Recruitment of paediatricians and nephrologists in Australia and paediatricians in Ireland was multi-faceted. Emails with survey links were circulated through training bodies, advanced trainee networks, departmental heads, and professional societies., Main Outcome Measures: Comprehension, engagement and perception of the visual explainer., Results: Most clinicians surveyed (95% (53) Australian group, 100% (29) Irish group) felt that genomics would be a useful tool in their practice. 77% of Australian paediatric respondents and 73% of Irish paediatric respondents felt that genomics was underutilised. Challenges encountered with genomic testing included poor patient comprehension of the testing process and results along with difficulties perceived by clinicians in explaining complex results. 89% of Australian paediatricians and 100% of Irish paediatricians surveyed would recommend the use of the explainer to other professionals in their field., Conclusion: This genomic resource was acceptable to clinicians and could be a useful tool to support paediatricians integrating genomic testing into mainstream care., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)
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- 2025
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11. Challenges in Care Provision for Children and Adolescents With Differences of Sex Development.
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Atlas G, Hanna C, Tan TY, Tucker E, Ayers K, Sinclair A, and O'Connell MA
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Objectives: The ideal model of care for individuals with Differences of Sex Development (DSD) continues to evolve, with multiple models proposed. This study aimed to explore current care models for individuals with DSD in Australia and New Zealand (NZ) and to identify clinician perceptions of gaps and barriers in current practice., Methods: Cross-sectional anonymous online questionnaire, conducted via Research Electronic Data Capture (REDCap) software. Clinicians involved in the diagnosis and management of individuals with DSD in Australia and NZ were contacted through multimodal recruitment approaches. Themes included demographics of respondents, preferred terminology, composition of the DSD multidisciplinary team (MDT) and availability of a database., Results: Seventy-nine eligible participants from centers in all states and territories of Australia and NZ commenced the survey with 63 complete responses. Almost One-third (31%) of participants are not currently part of a DSD MDT meeting at their center. While three quarters (76%) of respondents identified changes to DSD care over the past 5 years, three quarters (75%) also identified barriers to current care provision. Only 20% of respondents reported psychology being a current part of their MDT and 70% identified psychology as a desired but missing part of their team., Conclusions: Responses to the survey identify gaps and barriers to DSD care across Australia and NZ, particularly a lack of psychosocial supports. Current models fall short of international recommendations and services need to explore the reasons for these gaps further., (© 2025 The Author(s). Clinical Endocrinology published by John Wiley & Sons Ltd.)
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- 2025
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12. Failure to repair damaged NAD(P)H blocks de novo serine synthesis in human cells.
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Walvekar AS, Warmoes M, Cheung D, Sikora T, Seyedkatouli N, Gomez-Giro G, Perrone S, Dengler L, Unger F, Santos BFR, Gavotto F, Dong X, Becker-Kettern J, Kwon YJ, Jäger C, Schwamborn JC, Van Bergen NJ, Christodoulou J, and Linster CL
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- Humans, NAD metabolism, Mitochondria metabolism, Mitochondria drug effects, Cell Line, Cell Survival drug effects, Racemases and Epimerases, Serine metabolism, NADP metabolism
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Background: Metabolism is error prone. For instance, the reduced forms of the central metabolic cofactors nicotinamide adenine dinucleotide (NADH) and nicotinamide adenine dinucleotide phosphate (NADPH), can be converted into redox-inactive products, NADHX and NADPHX, through enzymatically catalyzed or spontaneous hydration. The metabolite repair enzymes NAXD and NAXE convert these damaged compounds back to the functional NAD(P)H cofactors. Pathogenic loss-of-function variants in NAXE and NAXD lead to development of the neurometabolic disorders progressive, early-onset encephalopathy with brain edema and/or leukoencephalopathy (PEBEL)1 and PEBEL2, respectively., Methods: To gain insights into the molecular disease mechanisms, we investigated the metabolic impact of NAXD deficiency in human cell models. Control and NAXD-deficient cells were cultivated under different conditions, followed by cell viability and mitochondrial function assays as well as metabolomic analyses without or with stable isotope labeling. Enzymatic assays with purified recombinant proteins were performed to confirm molecular mechanisms suggested by the cell culture experiments., Results: HAP1 NAXD knockout (NAXDko) cells showed growth impairment specifically in a basal medium containing galactose instead of glucose. Surprisingly, the galactose-grown NAXDko cells displayed only subtle signs of mitochondrial impairment, whereas metabolomic analyses revealed a strong inhibition of the cytosolic, de novo serine synthesis pathway in those cells as well as in NAXD patient-derived fibroblasts. We identified inhibition of 3-phosphoglycerate dehydrogenase as the root cause for this metabolic perturbation. The NAD precursor nicotinamide riboside (NR) and inosine exerted beneficial effects on HAP1 cell viability under galactose stress, with more pronounced effects in NAXDko cells. Metabolomic profiling in supplemented cells indicated that NR and inosine act via different mechanisms that at least partially involve the serine synthesis pathway., Conclusions: Taken together, our study identifies a metabolic vulnerability in NAXD-deficient cells that can be targeted by small molecules such as NR or inosine, opening perspectives in the search for mechanism-based therapeutic interventions in PEBEL disorders., Competing Interests: Declarations. Ethics approval and consent to participate: All patient cell lines used in this study were obtained following ethical approval and consent as described in our previous study, which provides detailed clinical and genetic information [11]. Case 1 was recruited as part of a gene discovery program in children with undiagnosed neurological disease from the Sydney Children’s Hospital Network (10/CHW/113), and case 3 was recruited from Kasturba Hospital, Manipal, India (IEC 570/2015). Cases 2 and 4 consented for NHS diagnostic tests for clinical purposes, which included collection of skin biopsies for use in research and consent for publication. These clinical diagnostic services were provided by University of Exeter Medical School, Exeter, UK and Birmingham Children’s Hospital, Birmingham, UK between 2016 and 2017. All institutes acted on the Helsinki Declaration of 1975, as revised in 2000. Written informed consent was obtained from the carers or parents on behalf of the patients. Consent for publication: Not applicable. Competing interests: The authors declare that they have no conflicts of interest with the contents of this article., (© 2025. The Author(s).)
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- 2025
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13. Formation of I 2 +III 2 supercomplex rescues respiratory chain defects.
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Liang C, Padavannil A, Zhang S, Beh S, Robinson DRL, Meisterknecht J, Cabrera-Orefice A, Koves TR, Watanabe C, Watanabe M, Illescas M, Lim R, Johnson JM, Ren S, Wu YJ, Kappei D, Ghelli AM, Funai K, Osaka H, Muoio D, Ugalde C, Wittig I, Stroud DA, Letts JA, and Ho L
- Abstract
Mitochondrial electron transport chain (ETC) complexes partition between free complexes and quaternary assemblies known as supercomplexes (SCs). However, the physiological requirement for SCs and the mechanisms regulating their formation remain controversial. Here, we show that genetic perturbations in mammalian ETC complex III (CIII) biogenesis stimulate the formation of a specialized extra-large SC (SC-XL) with a structure of I
2 +III2 , resolved at 3.7 Å by cryoelectron microscopy (cryo-EM). SC-XL formation increases mitochondrial cristae density, reduces CIII reactive oxygen species (ROS), and sustains normal respiration despite a 70% reduction in CIII activity, effectively rescuing CIII deficiency. Consequently, inhibiting SC-XL formation in CIII mutants using the Uqcrc1DEL:E258-D260 contact site mutation leads to respiratory decompensation. Lastly, SC-XL formation promotes fatty acid oxidation (FAO) and protects against ischemic heart failure in mice. Our study uncovers an unexpected plasticity in the mammalian ETC, where structural adaptations mitigate intrinsic perturbations, and suggests that manipulating SC-XL formation is a potential therapeutic strategy for mitochondrial dysfunction., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)- Published
- 2025
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14. Experiences of perinatal genetic screening for people from migrant and refugee backgrounds: a scoping review.
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Kanga-Parabia A, Archibald AD, Biggs LJ, Lewis S, Tutty E, and Dawson-McClaren B
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People from refugee and migrant backgrounds often face poor experiences and outcomes in healthcare, and genetic healthcare is no exception. Understanding whether and how these health inequities manifest is an important step towards equitable perinatal genetic screening for genetic or chromosomal conditions (offered preconception, prenatally, or during the newborn period). A scoping review was conducted to review international evidence of perceptions and experiences of perinatal genetic screening for people from migrant and refugee backgrounds. Search strategies were applied to Medline, Embase, and CINAHL databases to identify articles meeting eligibility criteria. Evidence was synthesised using descriptive and content analysis, with theoretical frameworks of proportionate universality and relational autonomy used to interpret findings. Of 11,046 unique articles identified, twenty-six met inclusion criteria and underwent full-text review. Most studies were set in Western countries, and participants were primarily born in Asia, South America, or Africa. Studies indicated varying awareness, knowledge, attitudes, and uptake of screening. Several studies highlighted a lack of adequate in-language resources, the use of concepts that were unrecognised in particular communities, and poor interactions with healthcare providers. Strategies to address the above issues included person-centred counselling, increased consultation time, access to interpreters, and training for relevant providers. Other recommendations included addressing structural, financial, and geographical barriers to improve access to screening and associated care. Whilst additional research is required, we propose evidence and theory-informed strategies to improve perinatal genetic screening services for people from migrant and refugee backgrounds., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)
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- 2025
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15. Critically unwell infants and children with mitochondrial disorders diagnosed by ultrarapid genomic sequencing.
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Ball M, Bouffler SE, Barnett CB, Freckmann ML, Hunter MF, Kamien B, Kassahn KS, Lunke S, Patel CV, Pinner J, Roscioli T, Sandaradura SA, Scott HS, Tan TY, Wallis M, Compton AG, Thorburn DR, Stark Z, and Christodoulou J
- Subjects
- Humans, Infant, Male, Female, Child, Child, Preschool, High-Throughput Nucleotide Sequencing, Genetic Testing methods, Infant, Newborn, DNA, Mitochondrial genetics, Retrospective Studies, Exome Sequencing, Genomics methods, Mutation genetics, Mitochondrial Diseases genetics, Mitochondrial Diseases diagnosis, Critical Illness
- Abstract
Purpose: To characterize the diagnostic and clinical outcomes of a cohort of critically ill infants and children with suspected mitochondrial disorders (MD) undergoing ultrarapid genomic testing as part of a national program., Methods: Ultrarapid genomic sequencing was performed in 454 families (genome sequencing: n = 290, exome sequencing +/- mitochondrial DNA sequencing: n = 164). In 91 individuals, MD was considered, prompting analysis using an MD virtual gene panel. These individuals were reviewed retrospectively and scored according to modified Nijmegen Mitochondrial Disease Criteria., Results: A diagnosis was achieved in 47% (43/91) of individuals, 40% (17/43) of whom had an MD. Seven additional individuals in whom an MD was not suspected were diagnosed with an MD after broader analysis. Gene-agnostic analysis led to the discovery of 2 novel disease genes, with pathogenicity validated through targeted functional studies (CRLS1 and MRPL39). Functional studies enabled diagnosis in another 4 individuals. Of the 24 individuals ultimately diagnosed with an MD, 79% had a change in management, which included 53% whose care was redirected to palliation., Conclusion: Ultrarapid genetic diagnosis of MD in acutely unwell infants and children is critical for guiding decisions about the need for additional investigations and clinical management., Competing Interests: Conflict of Interest John Christodoulou is an approved pathology provider for the Victorian Clinical Genetics Service. All other authors declare no conflicts of interest., (Copyright © 2024 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)
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- 2025
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16. The Australian Genomics Mitochondrial Flagship: A national program delivering mitochondrial diagnoses.
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Rius R, Compton AG, Baker NL, Balasubramaniam S, Best S, Bhattacharya K, Boggs K, Boughtwood T, Braithwaite J, Bratkovic D, Bray A, Brion MJ, Burke J, Casauria S, Chong B, Coman D, Cowie S, Cowley M, de Silva MG, Delatycki MB, Edwards S, Ellaway C, Fahey MC, Finlay K, Fletcher J, Frajman LE, Frazier AE, Gayevskiy V, Ghaoui R, Goel H, Goranitis I, Haas M, Hock DH, Howting D, Jackson MR, Kava MP, Kemp M, King-Smith S, Lake NJ, Lamont PJ, Lee J, Long JC, MacShane M, Madelli EO, Martin EM, Marum JE, Mattiske T, McGill J, Metke A, Murray S, Panetta J, Phillips LK, Quinn MCJ, Ryan MT, Schenscher S, Simons C, Smith N, Stroud DA, Tchan MC, Tom M, Wallis M, Ware TL, Welch AE, Wools C, Wu Y, Christodoulou J, and Thorburn DR
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- Humans, Child, Male, Australia, Female, Adult, Adolescent, Child, Preschool, Middle Aged, Prospective Studies, Young Adult, Genetic Testing methods, Mitochondria genetics, Infant, Genome, Mitochondrial genetics, Exome genetics, Mitochondrial Diseases genetics, Mitochondrial Diseases diagnosis, DNA, Mitochondrial genetics, Genomics methods
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Purpose: Families living with mitochondrial diseases (MD) often endure prolonged diagnostic journeys and invasive testing, yet many remain without a molecular diagnosis. The Australian Genomics Mitochondrial Flagship, comprising clinicians, diagnostic, and research scientists, conducted a prospective national study to identify the diagnostic utility of singleton genomic sequencing using blood samples., Methods: A total of 140 children and adults living with suspected MD were recruited using modified Nijmegen criteria (MNC) and randomized to either exome + mitochondrial DNA (mtDNA) sequencing or genome sequencing., Results: Diagnostic yield was 55% (n = 77) with variants in nuclear (n = 37) and mtDNA (n = 18) MD genes, as well as phenocopy genes (n = 22). A nuclear gene etiology was identified in 77% of diagnoses, irrespective of disease onset. Diagnostic rates were higher in pediatric-onset (71%) than adult-onset (31%) cases and comparable in children with non-European (78%) vs European (67%) ancestry. For children, higher MNC scores correlated with increased diagnostic yield and fewer diagnoses in phenocopy genes. Additionally, 3 adult patients had a mtDNA deletion discovered in skeletal muscle that was not initially identified in blood., Conclusion: Genomic sequencing from blood can simplify the diagnostic pathway for individuals living with suspected MD, especially those with childhood onset diseases and high MNC scores., Competing Interests: Conflict of Interest John Christodoulou is an approved pathology provider for Victorian Clinical Genetics Services., (Copyright © 2024 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)
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- 2025
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17. Mitochondrial DNA variant detection in over 6,500 rare disease families by the systematic analysis of exome and genome sequencing data resolves undiagnosed cases.
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Stenton SL, Laricchia K, Lake NJ, Chaluvadi S, Ganesh V, DiTroia S, Osei-Owusu I, Pais L, O'Heir E, Austin-Tse C, O'Leary M, Abu Shanap M, Barrows C, Berger S, Bönnemann CG, Bujakowska KM, Campagna DR, Compton AG, Donkervoort S, Fleming MD, Gallacher L, Gleeson JG, Haliloglu G, Pierce EA, Place EM, Sankaran VG, Shimamura A, Stark Z, Tan TY, Thorburn DR, White SM, Vilain E, Lek M, Rehm HL, and O'Donnell-Luria A
- Abstract
Background: Variants in the mitochondrial genome (mtDNA) cause a diverse collection of mitochondrial diseases and have extensive phenotypic overlap with Mendelian diseases encoded on the nuclear genome. The mtDNA is often not specifically evaluated in patients with suspected Mendelian disease, resulting in overlooked diagnostic variants., Methods: Using dedicated pipelines to address the technical challenges posed by the mtDNA - circular genome, variant heteroplasmy, and nuclear misalignment - single nucleotide variants, small indels, and large mtDNA deletions were called from exome and genome sequencing data, in addition to RNA-sequencing when available. A cohort of 6,660 rare disease families were analyzed (5,625 genetically undiagnosed, 84%) from the Genomics Research to Elucidate the Genetics of Rare diseases (GREGoR) Consortium as well as other rare disease cohorts., Results: Diagnostic mtDNA variants were identified in 10 previously genetically undiagnosed families (one large deletion, eight reported pathogenic variants, one novel pathogenic variant). In one additional undiagnosed proband, the detection of >900 heteroplasmic variants provided functional evidence of pathogenicity to a novel de novo variant in the nuclear gene POLG (DNA polymerase gamma), responsible for mtDNA replication and repair., Conclusion: mtDNA variant calling from data generated by exome and genome sequencing for nuclear variant analysis resulted in a genetic diagnosis or detection of a candidate variant for 0.4% of undiagnosed families affected by a broad range of rare diseases., Competing Interests: A.O’D-L was a paid consultant to Tome Biosciences, Ono Pharma USA, Addition Therapeutics, Congenica, receives research funding from Pacific Biosciences, and is on the American Journal of Human Genetics Editorial Board (unpaid). H.L.R has received rare-disease research funding from Microsoft. V.G.S. serves as an advisor to Ensoma. All other authors declare no competing interests.
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- 2024
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18. A Standardized Measurement and Valuation Scale of Genomic Utility for Policy Decisions: The GUV Scale.
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Goranitis I, Sheen D, Fehlberg Z, Mallett AJ, Best S, and Stark Z
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Objectives: The multifaceted ways in which genomics can be valuable to clinicians, patients, families, and society are important for informing prioritization decisions by policy makers. This study aims to develop a standardized, cumulative, and preference-weighted genomic utility valuation (GUV) on a scale of 0% to 100%., Methods: A multicriteria decision analysis was conducted with experts involved in policy, clinical, research, and consumer advocacy leadership in Australia for the valuation of policy priority indicators of genomic utility. The use of the GUV scale to support policy decisions is illustrated through a stylized example, and benchmark scoring thresholds of genomic utility were identified by mapping evidence from real-world health technology assessments leading to the public reimbursement of genomic testing in Australia onto the GUV scale., Results: In total, 33 (73%) invited experts participated in the study. Clinical utility had the highest priority, followed by societal, diagnostic, economic, and family utilities. Improving health outcomes had the highest preference value (29.5%), followed by improving equity (22.6%), Having high diagnostic yield (22.2%), improving symptom management (15.5%), being cost saving (14.3%), having average diagnostic yield (13.1%), enabling access to clinical trials (12.3%), and enabling reproductive family planning (11.5%). Genomic testing scores from real-world health technology assessments ranged from 46% for syndromic and nonsyndromic intellectual disability to about 60% for mitochondrial conditions and genetic kidney diseases., Conclusions: Comparisons of genomic utility across different clinical contexts may seem difficult because of the multiple criteria required to be weighted to support policy decisions. This comparison is now facilitated in a standardized manner with the GUV scale., Competing Interests: Author Disclosures Author disclosure forms can be accessed below in the Supplemental Material section., (Copyright © 2025. Published by Elsevier Inc.)
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- 2024
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19. A case of dermatopathia pigmentosa reticularis masquerading as dyskeratosis congenita: the importance of nailing the correct diagnosis.
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Le Q, Le Fevre A, Tan TY, and Robertson S
- Abstract
Competing Interests: Conflicts of interest The authors declare no conflicts of interest.
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- 2024
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20. Blurring the lines: an empirical examination of the interrelationships among acceptability, appropriateness, and feasibility.
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Fehlberg Z, Stark Z, Klaic M, and Best S
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Background: Acceptability, appropriateness, and feasibility are established implementation outcomes used to understand stakeholders' perceptions of an intervention. Further, they are thought to provide insight into behaviors, such as adoption. To date, measurement instruments for the three outcomes have focused on their individual assessment whilst nodding to the idea that they may interrelate. Despite this acknowledgment, there is little empirical evidence of the association among these constructs. Using the example of genetic health professionals providing additional genomic results to patients, this study aimed to examine the interrelationships among acceptability, appropriateness, and feasibility., Methods: A sequential explanatory mixed methods approach was employed. All genetic counsellors and clinical geneticists involved in a large research program were invited to complete pre/post surveys using existing measures of acceptability, appropriateness, and feasibility. Follow-up interviews, informed by the survey results, explored clinicians' perspectives of the three outcomes in relation to providing additional genomic results to patients. To categorize interrelationships and generate feedback loops, survey data were analyzed using descriptive and correlation statistics and interpreted alongside interview data analyzed using content analysis., Results: The survey results (pre n = 53 and post n = 40) for each outcome showed a similar midpoint mean, wide ranges, and little change post implementation (Acceptability: pre M = 3.55, range 2-5 post M = 3.56, range 1.5-5; Appropriateness: pre M = 3.35, range 1-5, post M = 3.48, range 1-5; Feasibility: pre M = 3.30, post M = 3.32; range 1.25-5). The strength of correlation among outcomes ranged from 0.54 to 0.78. Five interrelationships were categorized from analysis of interview data (n = 14) and explain how clinicians' perceptions of the intervention, positive or negative, were determined by interrelating factors of acceptability, appropriateness, and feasibility and that in different scenarios, the function and emphasis of importance among outcomes switched., Conclusions: Rather than existing separately, our study promotes the need to consider interrelationships among acceptability, appropriateness, and feasibility to better characterize clinicians' perceptions of complex health care interventions and aid in the development of implementation strategies that have real world impact. Further, in the interest of reducing research waste, more research is needed to determine if the outcomes could serve as proxies for each other., Competing Interests: Declarations. Ethics approval and consent to participate: The study was approved by the Royal Children’s Hospital Melbourne, Human Research Ethics Committee (HREC/71973/RCHM-2023). After the opportunity to view study information, survey participants could click to consent and proceed, and interview participants provided verbal consent prior to the interview commencing. Consent for publication: Not applicable. Competing interests: The authors declare that they have no competing interests., (© 2024. The Author(s).)
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- 2024
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21. Perceptions of severity and their influence on reproductive decision-making following reproductive genetic carrier screening.
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Swainson E, Tutty E, Freeman L, Dive L, McClaren BD, and Archibald AD
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The concept of severity in healthcare is multidimensional and subjective. It is a primary consideration in reproductive genetic carrier screening design where the focus is providing reproductive couples with information about the chance of severe genetic conditions in their offspring. When offering this screening, it is important to understand how condition severity is perceived and incorporated into reproductive decision-making. We analysed data from 41 semi-structured interviews with people who received a screening result indicating an increased chance for having children with a genetic condition. Thematic analysis revealed a desire for comprehensive information about the condition including clinical features, prognosis, impact on quality of life and treatment/management options. Participants integrated this information with their personal circumstances, beliefs/values and lived experience to form a perception of the severity of the condition. For rare and reduced-penetrance conditions where clinical information was limited or ambiguous, decision-making was more complex and greater anxiety was experienced. For conditions with a severity spectrum, reproductive decisions were based on the 'worst-case' clinical presentation. Where the impact of the condition was perceived as significant, the imperative to avoid that condition in future children appeared to be the greatest. Participants reported feeling that knowing their increased reproductive chance of the condition conferred a responsibility to avoid the condition, to prevent suffering and/or reduced quality of life for their children and future generations. These findings offer critical insight into how severity is perceived and the role it plays in reproductive decision-making and justifies a carefully considered approach to screening panel design., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: Ethics approval was granted by the Royal Children’s Hospital Human Research Ethics Committee (2019.097) and ratified by the University of Technology Sydney Human Research Ethics Committee (ETH22-7554) for this sub-study. Interview participants provided informed verbal consent after reviewing the participant information content., (© 2024. The Author(s), under exclusive licence to European Society of Human Genetics.)
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- 2024
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22. A multi-exon RFC1 deletion in a case of CANVAS: expanding the genetic mechanism of disease.
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Davies KC, Fearnley LG, Snell P, Bourke D, Mossman S, Kyne K, McKeown C, Delatycki MB, Bahlo M, and Lockhart PJ
- Abstract
Competing Interests: Declarations. Conflicts of interest: On behalf of all authors, the corresponding author states that there is no conflict of interest. Ethical approval: The Royal Children’s Hospital Human Research Ethics Committee (HREC #28097) and the Walter and Eliza Hall Institute of Medical Research Human Research Ethics Committee (HREC #18/06) approved the study, and all procedures were conducted according to the guidelines of the Declaration of Helsinki. Informed consent was obtained from the participant and clinical details were collected from review of medical records.
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- 2024
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23. Genomic testing for differences of sex development: Practices and perceptions of clinicians.
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Atlas G, Hanna C, Tan TY, Nisselle A, Tucker E, Ayers K, Sinclair A, and O'Connell MA
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- Humans, Surveys and Questionnaires, Male, Female, Australia, New Zealand, Adult, Attitude of Health Personnel, Genomics methods, Middle Aged, Genetic Testing, Disorders of Sex Development genetics, Disorders of Sex Development diagnosis
- Abstract
Objectives: To investigate the approach taken by clinicians involved in the diagnosis and management of individuals with Differences of Sex Development (DSD), particularly with regard to genomic testing, and identify perceived gaps/strengths/barriers in current practice., Design and Methods: An anonymous online survey was developed, with questions exploring demographics, perceptions of genomic testing, availability of genetics services and opinions on the role and utility of genomic testing in DSD. All responses were anonymous. Clinicians involved in the diagnosis and management of individuals with DSD were recruited from relevant societies and departments across Australia and New Zealand., Results: 79 eligible clinicians commenced the survey, with 63 completing it and 16 providing a partial response. The perceived benefit of having a genetic diagnosis for DSD was almost unanimous (97%). Almost half (48%) of respondents reported barriers in genomic testing. 81% of respondents reported they order genomic tests currently. Approaches to genomic testing when faced with four different clinical scenarios varied across respondents. Clinicians perceived genomic testing to be underutilised (median 36 on sliding scale from 0 to 100)., Conclusions: Despite 97% of respondents reporting benefit of a genetic diagnosis for individuals with DSD, this was not reflected throughout the survey with regard to clinical implementation. When faced with clinical scenarios, the recommendations for genomic testing from respondents was much lower, indicating the discrepancy between perception and clinical practice. Genomic testing in the context of DSD is seen as both beneficial and desired, yet there are multiple barriers impacting its integration into standard clinical care., (© 2024 The Author(s). Clinical Endocrinology published by John Wiley & Sons Ltd.)
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- 2024
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24. Offering reproductive genetic carrier screening for cystic fibrosis, spinal muscular atrophy and fragile X syndrome: Views of Victorian general practitioners.
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Leibowitz R, Lewis S, Delatycki M, Massie J, Emery J, and Archibald A
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- Humans, Female, Victoria, Adult, Qualitative Research, Interviews as Topic methods, Male, Genetic Testing methods, Genetic Testing statistics & numerical data, Pregnancy, Middle Aged, Cystic Fibrosis genetics, Cystic Fibrosis diagnosis, Cystic Fibrosis psychology, Fragile X Syndrome psychology, Fragile X Syndrome diagnosis, Fragile X Syndrome genetics, Fragile X Syndrome physiopathology, Genetic Carrier Screening methods, Muscular Atrophy, Spinal genetics, Muscular Atrophy, Spinal diagnosis, Muscular Atrophy, Spinal psychology, Muscular Atrophy, Spinal physiopathology, General Practitioners psychology, General Practitioners statistics & numerical data
- Abstract
Background and Objectives: The Royal Australian College of General Practice recommends that all women contemplating pregnancy or in early pregnancy should be offered reproductive genetic carrier screening (RGCS). In November 2023, a new Medicare item number was introduced for RGCS to detect cystic fibrosis (CF), spinal muscular atrophy (SMA) and fragile X syndrome (FXS) carrier status. The role of general practice in offering RGCS is recognised as being of crucial importance, but only a minority of general practitioners (GPs) are offering such screening. This study investigates the facilitators and barriers to offering RGCS in general practice., Method: Fifteen Victorian GPs who had offered RGCS for CF, SMA and FXS participated in semi-structured telephone interviews. A behavioural change framework was used for this study., Results: Barriers to offering screening (eg out-of-pocket costs, low frequency of preconception care and lack of GP education) mapped predominantly onto the 'opportunity' domain of the behaviour change framework., Discussion: Reducing out-of-pocket costs and increasing the provision of preconception care and GP education will provide more people with the opportunity to make informed choices about participation in RGCS.
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- 2024
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25. A micro-costing study of mass-spectrometry based quantitative proteomics testing applied to the diagnostic pipeline of mitochondrial and other rare disorders.
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Santos Gonzalez F, Hock DH, Thorburn DR, Mordaunt D, Williamson NA, Ang CS, Stroud DA, Christodoulou J, and Goranitis I
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- Humans, Mass Spectrometry methods, Mass Spectrometry economics, Tandem Mass Spectrometry methods, Chromatography, Liquid methods, Proteomics methods, Mitochondrial Diseases diagnosis, Mitochondrial Diseases economics, Rare Diseases
- Abstract
Background: Mass spectrometry-based quantitative proteomics has a demonstrated utility in increasing the diagnostic yield of mitochondrial disorders (MDs) and other rare diseases. However, for this technology to be widely adopted in routine clinical practice, it is crucial to accurately estimate delivery costs. Resource use and unit costs required to undertake a proteomics test were measured and categorized into consumables, equipment, and labor. Unit costs were aggregated to obtain a total cost per patient, reported in 2023 Australian dollars (AUD). Probabilistic and deterministic sensitivity analysis were conducted to evaluate parameter uncertainty and identify key cost drivers., Results: The mean cost of a proteomics test was $897 (US$ 607) per patient (95% CI: $734-$1,111). Labor comprised 53% of the total costs. At $342 (US$ 228) per patient, liquid chromatography coupled tandem mass spectrometry (LC-MS/MS) was the most expensive non-salary component. An integrated analysis pipeline where all the standard analysis are performed automatically, as well as discounts or subsidized LC-MS/MS equipment or consumables can lower the cost per test., Conclusions: Proteomics testing provide a lower-cost option and wider application compared to respiratory chain enzymology for mitochondrial disorders and potentially other functional assays in Australia. Our analysis suggests that streamlining and automating workflows can reduce labor costs. Using PBMC samples may be a cheaper and more efficient alternative to generating fibroblasts, although their use has not been extensively tested yet. Use of fibroblasts could potentially lower costs when fibroblasts are already available by avoiding the expense of isolating PBMCs. A joint evaluation of the health and economic implications of proteomics is now needed to support its introduction to routine clinical care., Competing Interests: Declarations. Ethics approval and consent to participate: The study was part of the Australian Undiagnosed Diseases Network (UDN-Aus): An internationally networked national approach for transforming diagnosis for individuals living with rare diseases project and received was approved by a Human Research Ethics Committee (RCH-79712). Consent for publication: Not applicable. The study does not contain data from any individual person. Competing interests: The authors declare that they have no competing interests., (© 2024. The Author(s).)
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- 2024
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26. Assessing the unmet needs of genomic testing in Australia: a geospatial exploration.
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Casauria S, Collins F, White SM, Konings P, Wallis M, Pachter N, McGaughran J, Barnett C, and Best S
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The role of genomic testing in rare disease clinical management is growing. However, geographical and socioeconomic factors contribute to inequitable uptake of testing. Geographical investigations of genomic testing across Australia have not been undertaken. Therefore, we aimed to investigate the geospatial distribution of genomic testing nationally between remoteness areas, and areas of varying socioeconomic advantage and disadvantage. We requested patient postcodes, age, and test type from genomic testing records from seven Australian laboratories for a 6-month period between August 2019 and June 2022. Postcode data were aggregated to Local Government Areas (LGAs) and visualised geospatially. Data were further aggregated to Remoteness Areas and Socio-Economic Index for Areas (SEIFA) quintiles for exploratory analysis. 11,706 records were eligible for analysis. Most tests recorded were paediatric (n = 8358, 71.4%). Microarray was the most common test captured (n = 8186, 69.9%). The median number of tests per LGA was 5.4 (IQR 1.0-21.0). Fifty-seven (10.4%) LGAs had zero tests recorded. Remoteness level was negatively correlated with number of tests across LGAs (rho = -0.781, p < 0.001). However, remote areas recorded the highest rate of testing per 100,000 populations. SEIFA score positively correlated with number of tests across LGAs (rho = 0.386, p < 0.001). The third SEIFA quintile showed the highest rate of testing per 100,000 populations. Our study establishes a foundation for ongoing assessment of genomic testing accessibility and equity and highlights the need to improve access to genomic testing for patients who are disadvantaged geographically or socioeconomically. Future research should include additional laboratories to achieve a larger representation of genomic testing rates nationally., Competing Interests: Competing interests: The authors declare no competing interests. Ethical approval: Ethical approval was granted from the Melbourne Health Human Research Ethics Committee (HREC/16/MH/251)., (© 2024. The Author(s), under exclusive licence to European Society of Human Genetics.)
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- 2024
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27. Nationwide, Couple-Based Genetic Carrier Screening.
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Kirk EP, Delatycki MB, Archibald AD, Tutty E, Caruana J, Halliday JL, Lewis S, McClaren BJ, Newson AJ, Dive L, Best S, Long JC, Braithwaite J, Downes MJ, Scuffham PA, Massie J, Barlow-Stewart K, Kulkarni A, Ruscigno A, Kanga-Parabia A, Rodrigues B, Bennetts BH, Ebzery C, Hunt C, Cliffe CC, Lee C, Azmanov D, King EA, Madelli EO, Zhang F, Ho G, Danos I, Liebelt J, Fletcher J, Kennedy J, Beilby J, Emery JD, McGaughran J, Marum JE, Scarff K, Fisk K, Harrison K, Boggs K, Giameos L, Fitzgerald L, Thomas L, Burnett L, Freeman L, Harris M, Berbic M, Davis MR, Cifuentes Ochoa M, Wallis M, Wall M, Chow MTM, Ferrie MM, Pachter N, Quayum N, Lang N, Kasi Pandy P, Casella R, Allcock RJN, Ong R, Edwards S, Sundercombe S, Jelenich S, Righetti S, Lunke S, Kaur S, Stock-Myer S, Eggers S, Walker SP, Theodorou T, Catchpool T, Clinch T, Roscioli T, Hardy T, Zhu Y, Fehlberg Z, Boughtwood TF, and Laing NG
- Subjects
- Adult, Female, Humans, Male, Pregnancy, Australia, Feasibility Studies, Patient Acceptance of Health Care statistics & numerical data, Decision Making, Heterozygote, Family Characteristics, Reproductive Behavior, Genetic Carrier Screening methods, Genetic Carrier Screening statistics & numerical data, Genetic Diseases, Inborn genetics, Genetic Diseases, Inborn prevention & control, Genetic Diseases, Inborn psychology
- Abstract
Background: Genomic sequencing technology allows for identification of reproductive couples with an increased chance, as compared with that in the general population, of having a child with an autosomal recessive or X-linked genetic condition., Methods: We investigated the feasibility, acceptability, and outcomes of a nationwide, couple-based genetic carrier screening program in Australia as part of the Mackenzie's Mission project. Health care providers offered screening to persons before pregnancy or early in pregnancy. The results obtained from testing at least 1281 genes were provided to the reproductive couples. We aimed to ascertain the psychosocial effects on participants, the acceptability of screening to all participants, and the reproductive choices of persons identified as having an increased chance of having a child with a condition for which we screened., Results: Among 10,038 reproductive couples enrolled in the study, 9107 (90.7%) completed screening, and 175 (1.9%) were newly identified as having an increased chance of having a child with a genetic condition for which we screened. These conditions involved pathogenic variants in 90 different genes; 74.3% of the conditions were autosomal recessive. Three months after receiving the results, 76.6% of the couples with a newly identified increased chance had used or planned to use reproductive interventions to avoid having an affected child. Those newly identified as having an increased chance had greater anxiety than those with a low chance. The median level of decisional regret was low in all result groups, and 98.9% of participants perceived screening to be acceptable., Conclusions: Couple-based reproductive genetic carrier screening was largely acceptable to participants and was used to inform reproductive decision making. The delivery of screening to a diverse and geographically dispersed population was feasible. (Funded by the Medical Research Future Fund of the Australian government; ClinicalTrials.gov number, NCT04157595.)., (Copyright © 2024 Massachusetts Medical Society.)
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- 2024
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28. The ClinGen Syndromic Disorders Gene Curation Expert Panel: Assessing the Clinical Validity of 111 Gene-Disease Relationships.
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Broeren E, Gitau V, Byrne A, Ajuyah P, Balzotti M, Berg J, Bluske K, Bowen BM, Brown MP, Buchanan A, Burns B, Burns NJ, Chandrasekhar A, Chawla A, Chong J, Chopra M, Clause A, DiStefano M, DiTroia S, Elnagheeb M, Girod A, Goel H, Golden-Grant K, Ha T, Hamosh A, Huang J, Hughes M, Jamuar S, Kam S, Kesari A, Koh AL, Lassiter R, Leigh S, Lemire G, Lim JY, Malhotra A, McCurry H, Milewski B, Moosa S, Murray S, Owens E, Palmer E, Palus B, Patel M, Rajkumar R, Ratliff J, Raymond FL, Assis BDRR, Sajan S, Schlachetzki Z, Schmidt S, Stark Z, Strom S, Taylor J, Thaxton C, Thrush D, Toro S, Tshering K, Vasilevsky N, Wayburn B, Webb R, O'Donnell-Luria A, and Coffey AJ
- Abstract
Purpose: The Clinical Genome Resource (ClinGen) Gene Curation Expert Panels (GCEPs) have historically focused on specific organ systems or phenotypes; thus, the ClinGen Syndromic Disorders GCEP (SD-GCEP) was formed to address an unmet need., Methods: The SD-GCEP applied ClinGen's framework to evaluate the clinical validity of genes associated with rare syndromic disorders. 111 Gene-Disease Relationships (GDRs) associated with 100 genes spanning the clinical spectrum of syndromic disorders were curated., Results: From April 2020 through March 2024, 38 precurations were performed on genes with multiple disease relationships and were reviewed to determine if the disorders were part of a spectrum or distinct entities. 14 genes were lumped into a single disease entity and 24 were split into separate entities, of which 11 were curated by the SD-GCEP. A full review of 111 GDRs for 100 genes followed, with 78 classified as Definitive, 9 as Strong, 15 as Moderate, and 9 as Limited highlighting where further data are needed. All diseases involved two or more organ systems, while the majority (88/111 GDRs, 79.2%) had five or more organ systems affected., Conclusion: The SD-GCEP addresses a critical gap in gene curation efforts, enabling inclusion of genes for syndromic disorders in clinical testing and contributing to keeping pace with the rapid discovery of new genetic syndromes., Competing Interests: Conflict of Interest K.B., M.P.B., B.T.B., N.J.B., An.C., Ad.C., A.R.C, K.L.G., A.K., A.M., R.R., Z.Sc., J.P.T., A.J.C. are current or former employees and shareholders of Illumina Inc. K.B., J.M.H., D.L.T., B.W. are employees of Ambry Genetics. K.L.G. is an employee of Rady Children’s Institute for Genomic Medicine. SSJ is the co-founder of Global Gene Corporation Pte Ltd. J.P.T is an employee of Blueprint Genetics (a Quest company). AODL was a paid consultant for Tome Biosciences, Ono Pharma USA, and Addition Therapeutics and receives research funding from Pacific Biosciences. All other authors declare no conflicts of interest.
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- 2024
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29. Omaveloxolone for the Treatment of Friedreich Ataxia: Efficacy, Safety, and Future Perspectives.
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Naghipour S, Corben LA, Hulme AJ, Dottori M, Delatycki MB, Lees JG, and Lim SY
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- 2024
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30. Analysis of public perceptions on the use of artificial intelligence in genomic medicine.
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Harrison JE, Lynch F, Stark Z, and Vears DF
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- Humans, Male, Female, Adult, Middle Aged, Australia, Public Opinion, Focus Groups, High-Throughput Nucleotide Sequencing, Aged, Artificial Intelligence, Genomics
- Abstract
Purpose: Next generation sequencing has led to the creation of large pools of genomic data with analysis rather than data generation now the limiting factor. Artificial intelligence (AI) may be required to optimize the benefits of these data, but little is known about how the public feels about the use of AI in genomics., Methods: We conducted focus groups with members of the Australian public. Participants were recruited via social media advertisements. We explored potential uses of AI in genomic medicine, the benefits, risks, and the possible social implications of its use., Results: Participants (n = 34) largely felt comfortable with AI analysing their own genomic data and generally agreed about its benefits. Concerns were raised over data security, the potential for misdiagnosis, and bias AI may perpetuate. Many participants wanted checking mechanisms for when results were generated using AI., Conclusions: The insights gained from these discussions help to understand public concerns around the use of AI in genomic medicine. Our findings can help to inform both policies around genomic AI and how to educate the public on its use., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)
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- 2024
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31. Offering complex genomic screening in acute pediatric settings: Family decision-making and outcomes.
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Martyn M, Lee L, Jan A, Tytherleigh R, Lynch F, Mighton C, Bouffler SE, Lynch E, Macciocca I, Curnow L, McCorkell G, Lunke S, Chong B, Delatycki MB, Downie L, Vears D, Best S, Clausen M, Bombard Y, Stark Z, and Gaff C
- Abstract
Purpose: Families of children in pediatric acute care who are offered ultrarapid genomic sequencing are making complex decisions during a high-stress period. To reduce complexity for families and clinicians, we offered genomic screening for the child and parents after the completion of diagnostic testing. We evaluated uptake, understanding, and service delivery preferences., Methods: A cohort of 235 families who had completed ultrarapid diagnostic genomic sequencing at 17 Australian hospitals were offered up to 3 screens on their genomic data: pediatric-onset, adult-onset, and expanded couple carrier screening. We investigated decision making, understanding, and service delivery preferences using surveys at 3 time points (pre counseling, post counseling, and post result) and performed inductive content analysis of pretest genetic counseling transcripts., Results: A total of 119 families (51%) attended genetic counseling with 115 (49%) accepting genomic screening. Survey respondents were more likely to find decisions about couple carrier screening easy (87%) compared with adult (68%; P = .002) or pediatric (71%; P = .01) screening decisions. All respondents with newly detected pathogenic variants accurately recalled this 1 month later. A delayed offer of screening was acceptable to most respondents (78%)., Conclusion: Separating genomic screening from the stressful diagnostic period is supported by families who demonstrate good knowledge and recall. Our results suggest delaying genomic screening should be trialed more widely., Competing Interests: Conflict of Interest Yvonne Bombard and Marc Clausen report ownership in Genetics Adviser, Inc. All other authors declare no potential conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2024
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32. HMGCS1 variants cause rigid spine syndrome amenable to mevalonic acid treatment in an animal model.
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Dofash LNH, Miles LB, Saito Y, Rivas E, Calcinotto V, Oveissi S, Serrano RJ, Templin R, Ramm G, Rodger A, Haywood J, Ingley E, Clayton JS, Taylor RL, Folland CL, Groth D, Hock DH, Stroud DA, Gorokhova S, Donkervoort S, Bönnemann CG, Sud M, VanNoy GE, Mangilog BE, Pais L, O'Donnell-Luria A, Madruga-Garrido M, Scala M, Fiorillo C, Baratto S, Traverso M, Malfatti E, Bruno C, Zara F, Paradas C, Ogata K, Nishino I, Laing NG, Bryson-Richardson RJ, Cabrera-Serrano M, and Ravenscroft G
- Abstract
Rigid spine syndrome is a rare childhood-onset myopathy characterised by slowly progressive or non-progressive scoliosis, neck and spine contractures, hypotonia, and respiratory insufficiency. Biallelic variants in SELENON account for most cases of rigid spine syndrome, however, the underlying genetic cause in some patients remains unexplained. We used exome and genome sequencing to investigate the genetic basis of rigid spine syndrome in patients without a genetic diagnosis. In five patients from four unrelated families, we identified biallelic variants in HMGCS1 (3-hydroxy-3-methylglutaryl-coenzyme A synthase). These included six missense variants and one frameshift variant distributed throughout HMGCS1. All patients presented with spinal rigidity primarily affecting the cervical and dorsolumbar regions, scoliosis, and respiratory insufficiency. Creatine kinase levels were variably elevated. The clinical course worsened with intercurrent disease or certain drugs in some patients; one patient died from respiratory failure following infection. Muscle biopsies revealed irregularities in oxidative enzyme staining with occasional internal nuclei and rimmed vacuoles. HMGCS1 encodes a critical enzyme of the mevalonate pathway and has not yet been associated with disease. Notably, biallelic hypomorphic variants in downstream enzymes including HMGCR and GGPS1 are associated with muscular dystrophy resembling our cohort's presentation. Analyses of recombinant human HMGCS1 protein and four variants (p.S447P, p.Q29L, p.M70T, p.C268S) showed that all mutants maintained their dimerization state. Three of the four mutants exhibited reduced thermal stability, and two mutants showed subtle changes in enzymatic activity compared to the wildtype. Hmgcs1 mutant zebrafish displayed severe early defects, including immobility at 2 days and death by day 3 post-fertilisation and were rescued by HMGCS1 mRNA. We demonstrate that the four variants tested (S447P, Q29L M70T, and C268S) have reduced function compared to wildtype HMGCS1 in zebrafish rescue assays. Additionally, we demonstrate the potential for mevalonic acid supplementation to reduce phenotypic severity in mutant zebrafish. Overall, our analyses suggest that these missense variants in HMGCS1 act through a hypomorphic mechanism. Here, we report an additional component of the mevalonate pathway associated with disease and suggest biallelic variants in HMGCS1 should be considered in patients presenting with an unresolved rigid spine myopathy phenotype. Additionally, we highlight mevalonoic acid supplementation as a potential treatment for patients with HMGCS1-related disease., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
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- 2024
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33. Goal-Directed Rehabilitation Versus Standard Care for Individuals with Hereditary Cerebellar Ataxia: A Multicenter, Single-Blind, Randomized Controlled Superiority Trial.
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Milne SC, Roberts M, Williams S, Chua J, Grootendorst AC, Agostinelli G, Grobler AC, Ross HL, Robinson A, Grove K, Modderman G, Price A, Thomson M, Massey L, Liang C, Kumar KR, Dalziel K, Burns J, Sue CM, Pathirana PN, Horne M, Gelfard N, Curd H, Szmulewicz D, Corben LA, and Delatycki MB
- Abstract
Objective: Rehabilitation is thought to reduce ataxia severity in individuals with hereditary cerebellar ataxia (HCA). This multicenter, randomized controlled superiority trial aimed to examine the efficacy of a 30-week goal-directed rehabilitation program compared with 30 weeks of standard care on function, ataxia, health-related quality of life, and balance in individuals with an HCA., Methods: Individuals with an autosomal dominant or recessive ataxia (aged ≥15 years) were enrolled at 5 sites in Australia. Participants were randomized (1:1) to receive rehabilitation (6 weeks of outpatient physiotherapy followed by a 24-week home exercise program) (n = 39) or continued their usual activity (n = 37). The primary outcome measure was the motor domain of the Functional Independence Measure (mFIM) at 7 weeks. Secondary outcomes included the Scale for the Assessment and Rating of Ataxia (SARA) and the SF-36v2, assessed at 7, 18, and 30 weeks. Outcome assessors were blinded to treatment allocation., Results: Seventy-one participants (rehabilitation, 37; standard-care, 34) were included in the intention-to-treat analysis. At 7 weeks, mFIM (mean difference 2.26, 95% confidence interval [CI]: 0.26 to 4.26, p = 0.028) and SARA (-1.21, 95% CI: -2.32 to -0.11, p = 0.032) scores improved after rehabilitation compared with standard care. Compared with standard care, rehabilitation improved SARA scores at 30 weeks (mean difference -1.51, 95% CI: -2.76 to -0.27, p = 0.017), but not mFIM scores (1.74, 95% CI: -0.32 to 3.81, p = 0.098). Frequent adverse events in both groups were fatigue, pain, and falls., Interpretation: Goal-directed rehabilitation improved function at 7 weeks, with improvement in ataxia and health-related quality of life maintained at 30 weeks in individuals with HCA, beyond that of standard care. ANN NEUROL 2024., (© 2024 American Neurological Association.)
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- 2024
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34. Benchmarking nanopore sequencing and rapid genomics feasibility: validation at a quaternary hospital in New Zealand.
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Nyaga DM, Tsai P, Gebbie C, Phua HH, Yap P, Le Quesne Stabej P, Farrow S, Rong J, Toldi G, Thorstensen E, Stark Z, Lunke S, Gamet K, Van Dyk J, Greenslade M, and O'Sullivan JM
- Abstract
Approximately 200 critically ill infants and children in New Zealand are in high-dependency care, many suspected of having genetic conditions, requiring scalable genomic testing. We adopted an acute care genomics protocol from an accredited laboratory and established a clinical pipeline using Oxford Nanopore Technologies PromethION 2 solo system and Fabric GEM™ software. Benchmarking of the pipeline was performed using Global Alliance for Genomics and Health benchmarking tools and Genome in a Bottle samples (HG002-HG007). Evaluation of single nucleotide variants resulted in a precision and recall of 0.997 and 0.992, respectively. Small indel identification approached a precision of 0.922 and recall of 0.838. Large genomic variations from Coriell Copy Number Variation Reference Panel 1 were reliably detected with ~2 M long reads. Finally, we present results obtained from fourteen trio samples, ten of which were processed in parallel with a clinically accredited short-read rapid genomic testing pipeline (Newborn Genomics Programme; NCT06081075; 2023-10-12)., (© 2024. The Author(s).)
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- 2024
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35. Microcosting genomics: Challenges and opportunities.
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Santos Gonzalez F, Ungar WJ, Buchanan J, Christodoulou J, Stark Z, and Goranitis I
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Competing Interests: Conflict of Interest The authors declare no conflicts of interest.
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- 2024
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36. 'I Could Trust It': Experiences of Reciprocal Translocation Carriers and Their Partners With Prenatal Cell-Free DNA Screening for Unbalanced Translocations.
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Cifuentes Ochoa M, Archibald AD, Flowers NJ, and Pertile MD
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Objective: To explore the experiences of people having cfDNA screening to detect unbalanced translocations, and to understand motivations for choosing this option., Methods: We used a qualitative approach with in-depth semi-structured interviews with reciprocal translocation carriers and their partners. People who underwent cfDNA screening with translocation analysis through Victorian Clinical Genetics Services between 2015 and 2019 were invited to take part. Purposive sampling based on the participant's geographic location, requesting practitioner specialty and cfDNA screening result was used to capture a range of experiences. Interview transcripts were analysed using thematic analysis., Results: Participants (n = 13) had complex reproductive journeys associated with the translocation and opted for cfDNA screening rather than prenatal diagnosis to avoid risk to their pregnancy. Participants benefited from having a result early in pregnancy and had sufficient confidence in the result to decline a diagnostic testing procedure., Conclusion: Participants' experiences with cfDNA screening were intertwined with the experience of being a carrier of a reciprocal translocation. cfDNA screening with translocation analysis was perceived as an acceptable alternative to prenatal diagnosis and should be made more accessible to balanced translocation carriers. Access to specialist genetic counselling services is needed to ensure couples are provided with information about all prenatal testing options, including the benefits and limitations associated with cfDNA screening with translocation analysis., (© 2024 John Wiley & Sons Ltd.)
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- 2024
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37. An integrated multi-omics approach allowed ultra-rapid diagnosis of a deep intronic pathogenic variant in PDHX and precision treatment in a neonate critically ill with lactic acidosis.
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Starosta RT, Larson AA, Meeks NJL, Gracie S, Friederich MW, Gaughan SM, Baker PR 2nd, Knupp KG, Michel CR, Reisdorph R, Hock DH, Stroud DA, Wood T, and Van Hove JLK
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- Humans, Infant, Newborn, Proteomics methods, Critical Illness, Introns genetics, Pyruvate Dehydrogenase (Lipoamide) genetics, Male, Multiomics, Acidosis, Lactic genetics, Acidosis, Lactic diagnosis, Dichloroacetic Acid therapeutic use
- Abstract
The diagnosis of mitochondrial disorders is complex. Rapid whole genome sequencing is a first line test for critically ill neonates and infants allowing rapid diagnosis and treatment. Standard genomic technology and bioinformatic pipelines still have an incomplete diagnostic yield requiring complementary approaches. There are currently limited options for rapid additional tests to continue a diagnostic work-up after a negative rapid whole-genome sequencing result, reflecting a gap in clinical practice. Multi-modal integrative diagnostic approaches derived from systems biology including proteomics and transcriptomics show promise in suspected mitochondrial disorders. In this article, we report the case of a neonate who presented with severe lactic acidosis on the second day of life, for whom an initial report of ultra-rapid genome sequencing was negative. The patient was started on dichloroacetate as an emergency investigational new drug (eIND), with a sharp decline in lactic acid levels and clinical stabilization. A proteomics-based approach identified a complete absence of PDHX protein, leading to a re-review of the genome data for the PDHX gene in which a homozygous deep intronic pathogenic variant was identified. Subsequent testing in the following months confirmed the diagnosis with deficient pyruvate dehydrogenase enzyme activity, reduced protein levels of E3-binding protein, and confirmed by mRNA sequencing to lead to the inclusion of a cryptic exon and a premature stop codon. This case highlights the power of rapid proteomics in guiding genomic analysis. It also shows a promising role for dichloroacetate treatment in controlling lactic acidosis related to PDHX-related pyruvate dehydrogenase complex deficiency., (Copyright © 2024 Elsevier B.V. and Mitochondria Research Society. All rights reserved.)
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- 2024
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38. Quantifying constraint in the human mitochondrial genome.
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Lake NJ, Ma K, Liu W, Battle SL, Laricchia KM, Tiao G, Puiu D, Ng KK, Cohen J, Compton AG, Cowie S, Christodoulou J, Thorburn DR, Zhao H, Arking DE, Sunyaev SR, and Lek M
- Subjects
- Humans, Genome, Human genetics, Heteroplasmy genetics, Mitochondrial Proteins genetics, Mutation, RNA, Ribosomal genetics, RNA, Transfer genetics, Selection, Genetic, Databases, Genetic, Datasets as Topic, Mitochondria genetics, Mitochondria pathology, Phenotype, Female, DNA, Mitochondrial genetics, Genetic Variation, Genome, Mitochondrial genetics, Models, Genetic
- Abstract
Mitochondrial DNA (mtDNA) has an important yet often overlooked role in health and disease. Constraint models quantify the removal of deleterious variation from the population by selection and represent powerful tools for identifying genetic variation that underlies human phenotypes
1-4 . However, nuclear constraint models are not applicable to mtDNA, owing to its distinct features. Here we describe the development of a mitochondrial genome constraint model and its application to the Genome Aggregation Database (gnomAD), a large-scale population dataset that reports mtDNA variation across 56,434 human participants5 . Specifically, we analyse constraint by comparing the observed variation in gnomAD to that expected under neutrality, which was calculated using a mtDNA mutational model and observed maximum heteroplasmy-level data. Our results highlight strong depletion of expected variation, which suggests that many deleterious mtDNA variants remain undetected. To aid their discovery, we compute constraint metrics for every mitochondrial protein, tRNA and rRNA gene, which revealed a range of intolerance to variation. We further characterize the most constrained regions within genes through regional constraint and identify the most constrained sites within the entire mitochondrial genome through local constraint, which showed enrichment of pathogenic variation. Constraint also clustered in three-dimensional structures, which provided insight into functionally important domains and their disease relevance. Notably, we identify constraint at often overlooked sites, including in rRNA and noncoding regions. Last, we demonstrate that these metrics can improve the discovery of deleterious variation that underlies rare and common phenotypes., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2024
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39. Reanalysis of genomic data in rare disease: current practice and attitudes among Australian clinical and laboratory genetics services.
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Best S, Fehlberg Z, Richards C, Quinn MCJ, Lunke S, Spurdle AB, Kassahn KS, Patel C, Vears DF, Goranitis I, Lynch F, Robertson A, Tudini E, Christodoulou J, Scott H, McGaughran J, and Stark Z
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- Humans, Australia, Attitude of Health Personnel, Laboratories, Clinical, Genomics methods, Genomics standards, Rare Diseases genetics, Rare Diseases diagnosis, Genetic Testing standards, Genetic Testing methods
- Abstract
Reanalyzing stored genomic data over time is highly effective in increasing diagnostic yield in rare disease. Automation holds the promise of delivering the benefits of reanalysis at scale. Our study aimed to understand current reanalysis practices among Australian clinical and laboratory genetics services and explore attitudes towards large-scale automated re-analysis. We collected audit data regarding testing and reanalysis volumes, policies and procedures from all Australian diagnostic laboratories providing rare disease genomic testing. A genetic health professionals' survey explored current practices, barriers to reanalysis, preferences and attitudes towards automation. Between 2018 and 2021, Australian diagnostic laboratories performed over 25,000 new genomic tests and 950 reanalyses, predominantly in response to clinician requests. Laboratory and clinical genetic health professionals (N = 134) identified workforce capacity as the principal barrier to reanalysis. No specific laboratory or clinical guidelines for genomic data reanalysis or policies were identified nationally. Perceptions of acceptability and feasibility of automating reanalysis were positive, with professionals emphasizing clinical and workflow benefits. In conclusion, there is a large and rapidly growing unmet need for reanalysis of existing genomic data. Beyond developing scalable automated reanalysis pipelines, leadership and policy are needed to successfully transform service delivery models and maximize clinical benefit., Competing Interests: Competing interests The authors declare no competing interests. Ethical approval The Royal Children’s Hospital Melbourne research office approved the workforce survey as a negligible risk project (QA/81406/RCHM-2021)., (© 2024. The Author(s).)
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- 2024
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40. Structural Variants at the LMNB1 Locus: Deciphering Pathomechanisms in Autosomal Dominant Adult-Onset Demyelinating Leukodystrophy.
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Dimartino P, Zadorozhna M, Yumiceba V, Basile A, Cani I, Melo US, Henck J, Breur M, Tonon C, Lodi R, Brusco A, Pippucci T, Koufi FD, Boschetti E, Ramazzotti G, Manzoli L, Ratti S, Pinto E Vairo F, Delatycki MB, Vaula G, Cortelli P, Bugiani M, Spielmann M, and Giorgio E
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- Humans, Male, Adult, Female, Middle Aged, Pelizaeus-Merzbacher Disease genetics, Genomic Structural Variation genetics, Lamin Type B genetics, Hereditary Central Nervous System Demyelinating Diseases genetics
- Abstract
Objective: We aimed to elucidate the pathogenic mechanisms underlying autosomal dominant adult-onset demyelinating leukodystrophy (ADLD), and to understand the genotype/phenotype correlation of structural variants (SVs) in the LMNB1 locus., Background: Since the discovery of 3D genome architectures and topologically associating domains (TADs), new pathomechanisms have been postulated for SVs, regardless of gene dosage changes. ADLD is a rare genetic disease associated with duplications (classical ADLD) or noncoding deletions (atypical ADLD) in the LMNB1 locus., Methods: High-throughput chromosome conformation capture, RNA sequencing, histopathological analyses of postmortem brain tissues, and clinical and neuroradiological investigations were performed., Results: We collected data from >20 families worldwide carrying SVs in the LMNB1 locus and reported strong clinical variability, even among patients carrying duplications of the entire LMNB1 gene, ranging from classical and atypical ADLD to asymptomatic carriers. We showed that patients with classic ADLD always carried intra-TAD duplications, resulting in a simple gene dose gain. Atypical ADLD was caused by LMNB1 forebrain-specific misexpression due to inter-TAD deletions or duplications. The inter-TAD duplication, which extends centromerically and crosses the 2 TAD boundaries, did not cause ADLD. Our results provide evidence that astrocytes are key players in ADLD pathology., Interpretation: Our study sheds light on the 3D genome and TAD structural changes associated with SVs in the LMNB1 locus, and shows that a duplication encompassing LMNB1 is not sufficient per se to diagnose ADLD, thereby strongly affecting genetic counseling. Our study supports breaking TADs as an emerging pathogenic mechanism that should be considered when studying brain diseases. ANN NEUROL 2024;96:855-870., (© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)
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- 2024
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41. A call to action to scale up research and clinical genomic data sharing.
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Stark Z, Glazer D, Hofmann O, Rendon A, Marshall CR, Ginsburg GS, Lunt C, Allen N, Effingham M, Hastings Ward J, Hill SL, Ali R, Goodhand P, Page A, Rehm HL, North KN, and Scott RH
- Subjects
- Humans, Precision Medicine methods, Information Dissemination methods, Genomics methods
- Abstract
Genomic data from millions of individuals have been generated worldwide to drive discovery and clinical impact in precision medicine. Lowering the barriers to using these data collectively is needed to equitably realize the benefits of the diversity and scale of population data. We examine the current landscape of global genomic data sharing, including the evolution of data sharing models from data aggregation through to data visiting, and for certain use cases, cross-cohort analysis using federated approaches across multiple environments. We highlight emerging examples of best practice relating to participant, patient and community engagement; evolution of technical standards, tools and infrastructure; and impact of research and health-care policy. We outline 12 actions we can all take together to scale up efforts to enable safe global data sharing and move beyond projects demonstrating feasibility to routinely cross-analysing research and clinical data sets, optimizing benefit., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. Springer Nature Limited.)
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- 2025
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42. Embedding Specialised Educators in Modalities for Continuing Medical Education. A Study of Effectiveness, and Health Care Practitioner and Educator Preferences.
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Fehlberg Z, Long JC, Kanga-Parabia A, Archibald AD, Braithwaite J, and Best S
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- Adult, Female, Humans, Male, Middle Aged, Education, Distance organization & administration, Education, Distance methods, Health Personnel education, Random Allocation, Education, Medical, Continuing methods
- Abstract
Introduction: As the delivery of continuing medical education moves towards digital modes, determining how to embed and capitalise on the skills of specialised educators in digital modalities is critical. Drawing on social theories of adult learning and behaviour change, this study trialled multiple delivery modes of education about reproductive genetic 'carrier screening' with varying levels of specialised educator (genetic counsellors) input to examine clinical effectiveness, and health care practitioners and educator preferences., Methods: A subset of health care practitioners (n = 209) interested in offering carrier screening through a large study were randomly allocated to receive education via face-to-face, a pre-recorded video or an online module, with active or passive educator input. The modes were evaluated using four levels of behaviour-linked outcomes., Findings: The results of our study show that although face-to-face and a video modality with active educator input had the highest completion rates and impact on clinical practice, there was little difference across modes on self-reported behaviour change outcomes. The educators observed that there was no one-size-fits-all approach to education delivery and reported benefits and drawbacks to each. Going forward, 56% of health care practitioners considered an online mode of education delivery, such as videos, written material or both, to be viable approaches with options for ongoing educator support., Conclusion: Embedding highly specialised educators with ongoing support and incorporating aspects of social learning within functional digital platforms should be considered in the development of continuing medical education, especially for health care practitioners who may work in smaller and isolated clinics., (© 2024 Association for the Study of Medical Education and John Wiley & Sons Ltd.)
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- 2025
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43. A guide to gene-disease relationships in nephrology.
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Stark Z, Byrne AB, Sampson MG, Lennon R, and Mallett AJ
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- Humans, Genetic Predisposition to Disease, Phenotype, Kidney Diseases genetics, Nephrology
- Abstract
The use of next-generation sequencing technologies such as exome and genome sequencing in research and clinical care has transformed our understanding of the molecular architecture of genetic kidney diseases. Although the capability to identify and rigorously assess genetic variants and their relationship to disease has advanced considerably in the past decade, the curation of clinically relevant relationships between genes and specific phenotypes has received less attention, despite it underpinning accurate interpretation of genomic tests. Here, we discuss the need to accurately define gene-disease relationships in nephrology and provide a framework for appraising genetic and experimental evidence critically. We describe existing international programmes that provide expert curation of gene-disease relationships and discuss sources of discrepancy as well as efforts at harmonization. Further, we highlight the need for alignment of disease and phenotype terminology to ensure robust and reproducible curation of knowledge. These collective efforts to support evidence-based translation of genomic sequencing into practice across clinical, diagnostic and research settings are crucial for delivering the promise of precision medicine in nephrology, providing more patients with timely diagnoses, accurate prognostic information and access to targeted treatments., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. Springer Nature Limited.)
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- 2025
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44. Case report: Partial regression of metastatic squamous cell carcinoma with altered azathioprine dosage after long-term use in renal transplant patient.
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Ormston T, Da Gama Duarte J, Quigley LT, Jackett L, Whitlam J, Behren A, and Gyorki DE
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- Humans, Male, Aged, Lymphatic Metastasis, Lymph Nodes pathology, Lymph Nodes immunology, Lymph Nodes drug effects, Azathioprine administration & dosage, Azathioprine therapeutic use, Kidney Transplantation adverse effects, Immunosuppressive Agents administration & dosage, Immunosuppressive Agents therapeutic use, Carcinoma, Squamous Cell secondary, Carcinoma, Squamous Cell drug therapy
- Abstract
Introduction: We report the partial regression of metastatic squamous cell carcinoma (SCC) after reduction of long-term azathioprine therapy while awaiting surgery. The patient was a 69-year-old man with a history of kidney transplantation. Moderately differentiated SCC arising in the anterior neck was initially diagnosed, followed later by poorly differentiated SCC metastases to cervical lymph nodes. Lymph node clearance was performed 28 days after a reduction in azathioprine dosage. The palpable lymph node lesion had noticeably decreased in size at the time of surgery, and subsequent histology only detected 7mm and 0.2mm deposits of poorly differentiated SCC in 2 of 5 level I nodes, and a further 10 reactive nodes from levels II and III. One positive level I and another benign level II/III node, demonstrated necrosis, histiocytic infiltration and fibrosis, interpreted as features of regression. Hence, we investigated the role of immune cells in the partial regression of metastatic SCC after reduction of long-term azathioprine therapy while awaiting surgery., Methods: Multispectral immunohistochemistry using custom markers was performed on regions of interest of excised cervical lymph nodes, encompassing the entire SCC deposit and the surrounding adjacent stroma to quantify to number and types of immune cells present., Results: Multispectral immunohistochemistry revealed the heavy infiltration of activated T cells in the tumour, as well as PD-L1+ antigen-presenting cells in the surrounding adjacent stroma, suggesting an immunologically mediated partial regression., Discussion: We hypothesize that this reaction was triggered by azathioprine dose reduction. Dose modification of long-term immunosuppressive medications in patients with a transplantation history who later develop SCCs warrants further investigation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Ormston, Da Gama Duarte, Quigley, Jackett, Whitlam, Behren and Gyorki.)
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- 2024
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45. Multi-cancer early detection: searching for evidence.
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Lippi G, Lackner KJ, Melichar B, Schlattmann P, Greaves R, Gillery P, and Plebani M
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- 2024
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46. Biallelic variants in MRPL49 cause variable clinical presentations, including sensorineural hearing loss, leukodystrophy, and ovarian insufficiency.
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Thomas HB, Demain LAM, Cabrera-Orefice A, Schrauwen I, Shamseldin HE, Rea A, Bharadwaj T, Smith TB, Oláhová M, Thompson K, He L, Kaur N, Shukla A, Abukhalid M, Ansar M, Rehman S, Riazuddin S, Abdulwahab F, Smith JM, Stark Z, Carrera S, Yue WW, Munro KJ, Alkuraya FS, Jamieson P, Ahmed ZM, Leal SM, Taylor RW, Wittig I, O'Keefe RT, and Newman WG
- Abstract
Combined oxidative phosphorylation deficiency (COXPD) is a rare multisystem disorder which is clinically and genetically heterogeneous. Genome sequencing identified biallelic MRPL49 variants in individuals from five unrelated families with presentations ranging from Perrault syndrome (primary ovarian insufficiency and sensorineural hearing loss) to severe childhood onset of leukodystrophy, learning disability, microcephaly and retinal dystrophy. Complexome profiling of fibroblasts from affected individuals revealed reduced levels of the small and, a more pronounced reduction of, the large mitochondrial ribosomal subunits. There was no evidence of altered mitoribosomal assembly. The reductions in levels of OXPHOS enzyme complexes I and IV are consistent with a form of COXPD associated with biallelic MRPL49 variants, expanding the understanding of how disruption of the mitochondrial ribosomal large subunit results in multi-system phenotypes., Competing Interests: Declaration of interest: The authors declare no competing interests.
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- 2024
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47. ESMO Resilience Task Force recommendations to manage psychosocial risks, optimise well-being, and reduce burnout in oncology.
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Lim KHJ, Kamposioras K, Élez E, Haanen JBAG, Hardy C, Murali K, O'Connor M, Oing C, Punie K, de Azambuja E, Blay JY, and Banerjee S
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- Humans, Advisory Committees, Health Personnel psychology, Resilience, Psychological, Europe, Burnout, Professional prevention & control, Medical Oncology standards
- Abstract
Background: Burnout in health care professionals (HCPs) results from exposure to psychosocial risks at work. Left unaddressed, burnout can lead to chronic health problems, increased staff turnover, reduced work hours, absenteeism, and early retirement from clinical practice, thus impacting patient care. The European Society for Medical Oncology (ESMO) Resilience Task Force (RTF) was established in December 2019 to support the well-being of oncology HCPs globally. This ESMO RTF position paper aims to provide a set of recommendations to optimise well-being and mitigate burnout in oncology, and to help individuals and institutions maintain the delivery of optimal cancer care., Design: Recommendations were developed by a diverse multinational panel of interprofessional experts based on the key findings from three previously reported ESMO RTF surveys., Results: Several recurrent work-related psychosocial risks in oncology were identified; in particular, concerns about workload and professional development. The need for flexible work patterns, continued use of virtual resources, well-being resources, and targeted support for at-risk groups were highlighted as key considerations to safeguard HCPs' health and prevent burnout. In total, 11 recommendations relating to three priority themes were developed: (i) information and training; (ii) resources; (iii) activism and advocacy., Conclusion: Optimising the well-being of oncology HCPs is essential for the provision of high-quality, sustainable care for patients globally. The ESMO RTF will continue its mission and is rolling out several initiatives and activities to support the implementation of these recommendations., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
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- 2024
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48. A national education program for rapid genomics in pediatric acute care: Building workforce confidence, competence, and capability.
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McCorkell G, Nisselle A, Halton D, Bouffler SE, Patel C, Christodoulou J, Maher F, McClaren B, Brett GR, Sandaradura S, Boggs K, de Silva MG, Lynch F, Macciocca I, Lynch E, Martyn M, Best S, Stark Z, and Gaff CL
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- Humans, Clinical Competence, Genetic Testing methods, Male, Female, Curriculum, Child, Genomics education, Genomics methods, Pediatrics education
- Abstract
Purpose: To develop and evaluate a scalable national program to build confidence, competence and capability in the use of rapid genomic testing (rGT) in the acute pediatric setting., Methods: We used theory-informed approaches to design a modular, adaptive program of blended learning aimed at diverse professional groups involved in acute pediatric care. The program comprised 4 online learning modules and an online workshop and was centered on case-based learning. We evaluated the program using the Kirkpatrick 4-level model of training evaluation and report our findings using the Reporting Item Standards for Education and its Evaluation (RISE2) guidelines for genomics education and evaluation., Results: Two hundred and two participants engaged with at least 1 component of the program. Participants self-reported increased confidence in using rGT, (P < .001), and quiz responses objectively demonstrated increased competence (eg, correct responses to a question on pretest counseling increased from 30% to 64%; P < .001). Additionally, their capability in applying genomic principles to simulated clinical cases increased (P < .001), as did their desire to take on more responsibility for performing rGT. The clinical interpretation of more complex test results (such as negative results or variants of uncertain significance) appeared to be more challenging, indicating a need for targeted education in this area., Conclusion: The program format was effective in delivering multidisciplinary and wide-scale genomics education in the acute care context. The modular approach we have developed now lends itself to application in other medical specialties or areas of health care., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2024
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49. Managing Newborn Screening Repeat Collections for Sick and Preterm Neonates.
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Greaves RF, Northfield JA, Cross L, Mawad N, Nguyen T, Tan M, O'Connell MA, and Pitt J
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Some preterm and sick neonates have altered biochemical profiles and follow-up newborn screening (NBS) collections are recommended. The Victorian NBS program historically recommended repeat collections for babies with birth weight < 1500 g (managed by the maternity service provider) and 3 weeks post-transfusion (managed by the laboratory). We aimed to determine adherence to current guidelines and review the guidelines to improve NBS performance. To do this, we audited data from 348,584 babies between January 2018 and June 2022. Babies with a recorded birth weight of <1500 g were filtered for inclusion. For the overall review and visualization of the protocol, we sourced information from the literature, our professional society and tertiary hospital services. A total of 2647 babies had a birth weight recorded between 200 and 1499 g. Of these, 2036 (77%) had a second sample collected, indicating that >1 in 5 babies were not receiving a follow-up collection. Our timing of repeat collections for transfused babies, requiring a 3-week follow-up collection, was longer than in other Australasian jurisdictions. A new combined "sick-prem protocol" was launched to support repeat collections and after a 1-year review achieved 95% compliance. We recommend NBS laboratories audit preterm and sick neonate repeat collections to ensure appropriate follow-up. This should be supported with a visual process map to aid education and compliance.
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- 2024
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50. Correction: Novel CDKL5 targets identified in human iPSC-derived neurons.
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Massey S, Ang CS, Davidson NM, Quigley A, Rollo B, Harris AR, Kapsa RMI, Christodoulou J, and Van Bergen NJ
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- 2024
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