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1. Mutations in PIGS, Encoding a GPI Transamidase, Cause a Neurological Syndrome Ranging from Fetal Akinesia to Epileptic Encephalopathy

Author

Nguyen, Thi Tuyet Mai, Murakami, Yoshiko, Wigby, Kristen M, Baratang, Nissan V, Rousseau, Justine, St-Denis, Anik, Rosenfeld, Jill A, Laniewski, Stephanie C, Jones, Julie, Iglesias, Alejandro D, Jones, Marilyn C, Masser-Frye, Diane, Scheuerle, Angela E, Perry, Denise L, Taft, Ryan J, Le Deist, Françoise, Thompson, Miles, Kinoshita, Taroh, and Campeau, Philippe M

Subjects
Neurodegenerative, Congenital Structural Anomalies, Pediatric, Brain Disorders, Rare Diseases, Genetics, Human Genome, Neurosciences, 2.1 Biological and endogenous factors, Aetiology, Abnormalities, Multiple, Acyltransferases, Arthrogryposis, Cell Line, Cerebellar Ataxia, Child, Child, Preschool, Developmental Disabilities, Epilepsy, Generalized, Female, HEK293 Cells, Humans, Intellectual Disability, Male, Muscle Hypotonia, Mutation, Nervous System Malformations, Pedigree, Seizures, Syndrome, Whole Exome Sequencing, Exome Sequencing, PIGS, epilepsy, glycosylphosphatidylinositol, glycosylphosphatidylinositol biosynthesis defect, inherited GPI deficiency, seizures, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Inherited GPI deficiencies (IGDs) are a subset of congenital disorders of glycosylation that are increasingly recognized as a result of advances in whole-exome sequencing (WES) and whole-genome sequencing (WGS). IGDs cause a series of overlapping phenotypes consisting of seizures, dysmorphic features, multiple congenital malformations, and severe intellectual disability. We present a study of six individuals from three unrelated families in which WES or WGS identified bi-allelic phosphatidylinositol glycan class S (PIGS) biosynthesis mutations. Phenotypes included severe global developmental delay, seizures (partly responding to pyridoxine), hypotonia, weakness, ataxia, and dysmorphic facial features. Two of them had compound-heterozygous variants c.108G>A (p.Trp36∗) and c.101T>C (p.Leu34Pro), and two siblings of another family were homozygous for a deletion and insertion leading to p.Thr439_Lys451delinsArgLeuLeu. The third family had two fetuses with multiple joint contractures consistent with fetal akinesia. They were compound heterozygous for c.923A>G (p.Glu308Gly) and c.468+1G>C, a splicing mutation. Flow-cytometry analyses demonstrated that the individuals with PIGS mutations show a GPI-AP deficiency profile. Expression of the p.Trp36∗ variant in PIGS-deficient HEK293 cells revealed only partial restoration of cell-surface GPI-APs. In terms of both biochemistry and phenotype, loss of function of PIGS shares features with PIGT deficiency and other IGDs. This study contributes to the understanding of the GPI-AP biosynthesis pathway by describing the consequences of PIGS disruption in humans and extending the family of IGDs.

Published
2018

2. Comparative Population Genomics Analysis of the Mammalian Fungal Pathogen Pneumocystis

Author

Cissé, Ousmane H, Ma, Liang, Wei Huang, Da, Khil, Pavel P, Dekker, John P, Kutty, Geetha, Bishop, Lisa, Liu, Yueqin, Deng, Xilong, Hauser, Philippe M, Pagni, Marco, Hirsch, Vanessa, Lempicki, Richard A, Stajich, Jason E, Cuomo, Christina A, and Kovacs, Joseph A

Subjects
Microbiology, Biological Sciences, Genetics, Lung, Pneumonia, Infectious Diseases, Pneumonia & Influenza, Human Genome, Aetiology, 2.2 Factors relating to the physical environment, Infection, Animals, Genetic Variation, Genomics, Humans, Mice, Phylogeny, Pneumocystis, Pneumonia, Pneumocystis, Rats, Rats, Sprague-Dawley, Recombination, Genetic, Rodent Diseases, evolutionary biology, genetic diversity, genetic recombination, pneumonia, population structure, Biochemistry and cell biology, Medical microbiology
Abstract

Pneumocystis species are opportunistic mammalian pathogens that cause severe pneumonia in immunocompromised individuals. These fungi are highly host specific and uncultivable in vitro Human Pneumocystis infections present major challenges because of a limited therapeutic arsenal and the rise of drug resistance. To investigate the diversity and demographic history of natural populations of Pneumocystis infecting humans, rats, and mice, we performed whole-genome and large-scale multilocus sequencing of infected tissues collected in various geographic locations. Here, we detected reduced levels of recombination and variations in historical demography, which shape the global population structures. We report estimates of evolutionary rates, levels of genetic diversity, and population sizes. Molecular clock estimates indicate that Pneumocystis species diverged before their hosts, while the asynchronous timing of population declines suggests host shifts. Our results have uncovered complex patterns of genetic variation influenced by multiple factors that shaped the adaptation of Pneumocystis populations during their spread across mammals.IMPORTANCE Understanding how natural pathogen populations evolve and identifying the determinants of genetic variation are central issues in evolutionary biology. Pneumocystis, a fungal pathogen which infects mammals exclusively, provides opportunities to explore these issues. In humans, Pneumocystis can cause a life-threatening pneumonia in immunosuppressed individuals. In analysis of different Pneumocystis species infecting humans, rats, and mice, we found that there are high infection rates and that natural populations maintain a high level of genetic variation despite low levels of recombination. We found no evidence of population structuring by geography. Our comparisons of the times of divergence of these species to their respective hosts suggest that Pneumocystis may have undergone recent host shifts. The results demonstrate that Pneumocystis strains are widely disseminated geographically and provide a new understanding of the evolution of these pathogens.

Published
2018

3. Findings from the Morquio A Registry Study (MARS) after 6 years: Long-term outcomes of MPS IVA patients treated with elosulfase alfa

Author

John J. Mitchell, Barbara K. Burton, Michael B. Bober, Philippe M. Campeau, Shelda Cohen, Sara Dosenovic, Carolyn Ellaway, Kaustuv Bhattacharya, Nathalie Guffon, David Hinds, Alice Lail, Shuan-Pei Lin, Martin Magner, Julian Raiman, Liat Schwartz-Sagi, and Karolina M. Stepien

Subjects
Endocrinology, Double-Blind Method, Keratan Sulfate, Endocrinology, Diabetes and Metabolism, Genetics, Humans, Mucopolysaccharidosis IV, Enzyme Replacement Therapy, Registries, Child, Molecular Biology, Biochemistry
Abstract

The Morquio A Registry Study (MARS) is an ongoing, multinational, observational study of patients with MPS IVA. Key objectives of MARS are to characterize the heterogeneity and natural history of disease and to evaluate long-term effectiveness and safety of elosulfase alfa enzyme replacement therapy (ERT). Enrollment began in September 2014; data on medical history, clinical outcomes, and safety assessments are collected as part of routine care.As of February 2021, 381 subjects from 17 countries had enrolled in MARS: 58 ERT-naïve subjects and 323 ERT-treated subjects (≥1 infusion), with a mean ERT exposure of 5.5 years (SD 2.8) and median age at first ERT treatment of 9.8 years. ERT-treated subjects were younger at diagnosis (median 3.4 vs 6.5 years) relative to ERT-naïve subjects. Among ERT-treated subjects, urinary keratan sulfate (uKS) levels declined from pre-ERT baseline to last follow-up on treatment (mean % change [95% confidence interval]: -52.5% [-57.5%, -47.4%]; n = 115) and 6-min walk test distance remained stable (mean change: -6.1 [-27.6, 15.5] m; n = 131) over a mean follow-up of 5.5 years. Forced expiratory volume in 1 s (FEVMARS is the longest and largest observational study of MPS IVA patients to date, with a heterogenous population that is representative of the MPS IVA population overall. Data collected over the first 6 years of MARS provide real-world evidence for long-term stabilization of endurance and respiratory function among ERT-treated patients, with no new safety concerns identified.

Published
2022

4. Fibronectin isoforms in skeletal development and associated disorders

Author

Neha E. H. Dinesh, Philippe M. Campeau, and Dieter P. Reinhardt

Subjects
Physiology, Humans, Protein Isoforms, Cell Differentiation, Cell Biology, Osteochondrodysplasias, Extracellular Matrix, Fibronectins
Abstract

The extracellular matrix is an intricate and essential network of proteins and nonproteinaceous components that provide a conducive microenvironment for cells to regulate cell function, differentiation, and survival. Fibronectin is one key component in the extracellular matrix that participates in determining cell fate and function crucial for normal vertebrate development. Fibronectin undergoes time-dependent expression patterns during stem cell differentiation, providing a unique stem cell niche. Mutations in fibronectin have been recently identified to cause a rare form of skeletal dysplasia with scoliosis and abnormal growth plates. Even though fibronectin has been extensively analyzed in developmental processes, the functional role and importance of this protein and its various isoforms in skeletal development remain less understood. This review attempts to provide a concise and critical overview of the role of fibronectin isoforms in cartilage and bone physiology and associated pathologies. This will facilitate a better understanding of the possible mechanisms through which fibronectin exerts its regulatory role on cellular differentiation during skeletal development. The review discusses the consequences of mutations in fibronectin leading to corner fracture type spondylometaphyseal dysplasia and presents a new outlook toward matrix-mediated molecular pathways in relation to therapeutic and clinical relevance.

Published
2022

5. Functional correlation of genome-wide DNA methylation profiles in genetic neurodevelopmental disorders

Author

Michael A. Levy, Raissa Relator, Haley McConkey, Erinija Pranckeviciene, Jennifer Kerkhof, Mouna Barat‐Houari, Sara Bargiacchi, Elisa Biamino, María Palomares Bralo, Gerarda Cappuccio, Andrea Ciolfi, Angus Clarke, Barbara R. DuPont, Mariet W. Elting, Laurence Faivre, Timothy Fee, Marco Ferilli, Robin S. Fletcher, Florian Cherick, Aidin Foroutan, Michael J. Friez, Cristina Gervasini, Sadegheh Haghshenas, Benjamin A. Hilton, Zandra Jenkins, Simranpreet Kaur, Suzanne Lewis, Raymond J. Louie, Silvia Maitz, Donatella Milani, Angela T. Morgan, Renske Oegema, Elsebet Østergaard, Nathalie R. Pallares, Maria Piccione, Astrid S. Plomp, Cathryn Poulton, Jack Reilly, Rocio Rius, Stephen Robertson, Kathleen Rooney, Justine Rousseau, Gijs W. E. Santen, Fernando Santos‐Simarro, Josephine Schijns, Gabriella M. Squeo, Miya St John, Christel Thauvin‐Robinet, Giovanna Traficante, Pleuntje J. van der Sluijs, Samantha A. Vergano, Niels Vos, Kellie K. Walden, Dimitar Azmanov, Tugce B. Balci, Siddharth Banka, Jozef Gecz, Peter Henneman, Jennifer A. Lee, Marcel M. A. M. Mannens, Tony Roscioli, Victoria Siu, David J. Amor, Gareth Baynam, Eric G. Bend, Kym Boycott, Nicola Brunetti‐Pierri, Philippe M. Campeau, Dominique Campion, John Christodoulou, David Dyment, Natacha Esber, Jill A. Fahrner, Mark D. Fleming, David Genevieve, Delphine Heron, Thomas Husson, Kristin D. Kernohan, Alisdair McNeill, Leonie A. Menke, Giuseppe Merla, Paolo Prontera, Cheryl Rockman‐Greenberg, Charles Schwartz, Steven A. Skinner, Roger E. Stevenson, Marie Vincent, Antonio Vitobello, Marco Tartaglia, Marielle Alders, Matthew L. Tedder, Bekim Sadikovic, Human genetics, Amsterdam Reproduction & Development (AR&D), Pediatrics, Levy M.A., Relator R., McConkey H., Pranckeviciene E., Kerkhof J., Barat-Houari M., Bargiacchi S., Biamino E., Palomares Bralo M., Cappuccio G., Ciolfi A., Clarke A., DuPont B.R., Elting M.W., Faivre L., Fee T., Ferilli M., Fletcher R.S., Cherick F., Foroutan A., Friez M.J., Gervasini C., Haghshenas S., Hilton B.A., Jenkins Z., Kaur S., Lewis S., Louie R.J., Maitz S., Milani D., Morgan A.T., Oegema R., Ostergaard E., Pallares N.R., Piccione M., Plomp A.S., Poulton C., Reilly J., Rius R., Robertson S., Rooney K., Rousseau J., Santen G.W.E., Santos-Simarro F., Schijns J., Squeo G.M., John M.S., Thauvin-Robinet C., Traficante G., van der Sluijs P.J., Vergano S.A., Vos N., Walden K.K., Azmanov D., Balci T.B., Banka S., Gecz J., Henneman P., Lee J.A., Mannens M.M.A.M., Roscioli T., Siu V., Amor D.J., Baynam G., Bend E.G., Boycott K., Brunetti-Pierri N., Campeau P.M., Campion D., Christodoulou J., Dyment D., Esber N., Fahrner J.A., Fleming M.D., Genevieve D., Heron D., Husson T., Kernohan K.D., McNeill A., Menke L.A., Merla G., Prontera P., Rockman-Greenberg C., Schwartz C., Skinner S.A., Stevenson R.E., Vincent M., Vitobello A., Tartaglia M., Alders M., Tedder M.L., Sadikovic B., Levy, Michael A, Relator, Raissa, Mcconkey, Haley, Pranckeviciene, Erinija, Kerkhof, Jennifer, Barat-Houari, Mouna, Bargiacchi, Sara, Biamino, Elisa, Bralo, María Palomare, Cappuccio, Gerarda, Ciolfi, Andrea, Clarke, Angu, Dupont, Barbara R, Elting, Mariet W, Faivre, Laurence, Fee, Timothy, Ferilli, Marco, Fletcher, Robin S, Cherick, Florian, Foroutan, Aidin, Friez, Michael J, Gervasini, Cristina, Haghshenas, Sadegheh, Hilton, Benjamin A, Jenkins, Zandra, Kaur, Simranpreet, Lewis, Suzanne, Louie, Raymond J, Maitz, Silvia, Milani, Donatella, Morgan, Angela T, Oegema, Renske, Østergaard, Elsebet, Pallares, Nathalie Ruiz, Piccione, Maria, Plomp, Astrid S, Poulton, Cathryn, Reilly, Jack, Rius, Rocio, Robertson, Stephen, Rooney, Kathleen, Rousseau, Justine, Santen, Gijs W E, Santos-Simarro, Fernando, Schijns, Josephine, Squeo, Gabriella Maria, John, Miya St, Thauvin-Robinet, Christel, Traficante, Giovanna, van der Sluijs, Pleuntje J, Vergano, Samantha A, Vos, Niel, Walden, Kellie K, Azmanov, Dimitar, Balci, Tugce B, Banka, Siddharth, Gecz, Jozef, Henneman, Peter, Lee, Jennifer A, Mannens, Marcel M A M, Roscioli, Tony, Siu, Victoria, Amor, David J, Baynam, Gareth, Bend, Eric G, Boycott, Kym, Brunetti-Pierri, Nicola, Campeau, Philippe M, Campion, Dominique, Christodoulou, John, Dyment, David, Esber, Natacha, Fahrner, Jill A, Fleming, Mark D, Genevieve, David, Heron, Delphine, Husson, Thoma, Kernohan, Kristin D, Mcneill, Alisdair, Menke, Leonie A, Merla, Giuseppe, Prontera, Paolo, Rockman-Greenberg, Cheryl, Schwartz, Charle, Skinner, Steven A, Stevenson, Roger E, Vincent, Marie, Vitobello, Antonio, Tartaglia, Marco, Alders, Marielle, Tedder, Matthew L, Sadikovic, Bekim, Human Genetics, General Paediatrics, Graduate School, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, ARD - Amsterdam Reproduction and Development, ANS - Cellular & Molecular Mechanisms, ANS - Complex Trait Genetics, and ACS - Pulmonary hypertension & thrombosis

Subjects
DNA methylation, clinical diagnostics, Syndrome, DNA methylation, clinical diagnostics, episignatures, neurodevelopmental syndromes, neurodevelopmental syndromes, Epigenesis, Genetic, Neurodevelopmental Disorders, Genetics, Humans, CpG Islands, DNA, Intergenic, episignatures, Episignature, Genetics (clinical)
Abstract

An expanding range of genetic syndromes are characterized by genome-wide disruptions in DNA methylation profiles referred to as episignatures. Episignatures are distinct, highly sensitive and specific biomarkers that have recently been applied in clinical diagnosis of genetic syndromes. Episignatures are contained within the broader disorder-specific genome-wide DNA methylation changes which can share significant overlap amongst different conditions. In this study we performed functional genomic assessment and comparison of disorder-specific and overlapping genome-wide DNA methylation changes related to 65 genetic syndromes with previously described episignatures. We demonstrate evidence of disorder-specific and recurring genome-wide differentially methylated probes (DMPs) and regions (DMRs). The overall distribution of DMPs and DMRs across the majority of the neurodevelopmental genetic syndromes analyzed showed substantial enrichment in gene promoters and CpG islands, and under-representation of the more variable intergenic regions. Analysis showed significant enrichment of the DMPs and DMRs in gene pathways and processes related to neurodevelopment, including neurogenesis, synaptic signaling and synaptic transmission. This study expands beyond the diagnostic utility of DNA methylation episignatures by demonstrating correlation between the function of the mutated genes and the consequent genomic DNA methylation profiles as a key functional element in the molecular etiology of genetic neurodevelopmental disorders. This article is protected by copyright. All rights reserved.

Published
2022

6. Inherited variants in CHD3 show variable expressivity in Snijders Blok-Campeau syndrome

Author

Jet van der Spek, Joery den Hoed, Lot Snijders Blok, Alexander J.M. Dingemans, Dick Schijven, Christoffer Nellaker, Hanka Venselaar, Galuh D.N. Astuti, Tahsin Stefan Barakat, E. Martina Bebin, Stefanie Beck-Wödl, Gea Beunders, Natasha J. Brown, Theresa Brunet, Han G. Brunner, Philippe M. Campeau, Goran Čuturilo, Christian Gilissen, Tobias B. Haack, Irina Hüning, Ralf A. Husain, Benjamin Kamien, Sze Chern Lim, Luca Lovrecic, Janine Magg, Ales Maver, Valancy Miranda, Danielle C. Monteil, Charlotte W. Ockeloen, Lynn S. Pais, Vasilica Plaiasu, Laura Raiti, Christopher Richmond, Angelika Rieß, Eva M.C. Schwaibold, Marleen E.H. Simon, Stephanie Spranger, Tiong Yang Tan, Michelle L. Thompson, Bert B.A. de Vries, Ella J. Wilkins, Marjolein H. Willemsen, Clyde Francks, Lisenka E.L.M. Vissers, Simon E. Fisher, Tjitske Kleefstra, Clinical Genetics, MUMC+: DA Klinische Genetica (5), Klinische Genetica, and RS: GROW - R4 - Reproductive and Perinatal Medicine

Subjects
Neuroinformatics, Heterozygote, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], DNA Helicases, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Syndrome, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], CHD3, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Reduced penetrance, Phenotype, All institutes and research themes of the Radboud University Medical Center, RARE, SDG 3 - Good Health and Well-being, Neurodevelopmental disorder, Neurodevelopmental Disorders, Variable expressivity, Humans, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19], Genetics (clinical), Mi-2 Nucleosome Remodeling and Deacetylase Complex, Inherited variants
Abstract

PURPOSE: Common diagnostic next-generation sequencing strategies are not optimized to identify inherited variants in genes associated with dominant neurodevelopmental disorders as causal when the transmitting parent is clinically unaffected, leaving a significant number of cases with neurodevelopmental disorders undiagnosed.METHODS: We characterized 21 families with inherited heterozygous missense or protein-truncating variants in CHD3, a gene in which de novo variants cause Snijders Blok-Campeau syndrome.RESULTS: Computational facial and Human Phenotype Ontology-based comparisons showed that the phenotype of probands with inherited CHD3 variants overlaps with the phenotype previously associated with de novo CHD3 variants, whereas heterozygote parents are mildly or not affected, suggesting variable expressivity. In addition, similarly reduced expression levels of CHD3 protein in cells of an affected proband and of healthy family members with a CHD3 protein-truncating variant suggested that compensation of expression from the wild-type allele is unlikely to be an underlying mechanism. Notably, most inherited CHD3 variants were maternally transmitted.CONCLUSION: Our results point to a significant role of inherited variation in Snijders Blok-Campeau syndrome, a finding that is critical for correct variant interpretation and genetic counseling and warrants further investigation toward understanding the broader contributions of such variation to the landscape of human disease.

Published
2022

7. Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition

Author

Elizabeth E. Palmer, Michael Pusch, Alessandra Picollo, Caitlin Forwood, Matthew H. Nguyen, Vanessa Suckow, Jessica Gibbons, Alva Hoff, Lisa Sigfrid, Andre Megarbane, Mathilde Nizon, Benjamin Cogné, Claire Beneteau, Fowzan S. Alkuraya, Aziza Chedrawi, Mais O. Hashem, Hannah Stamberger, Sarah Weckhuysen, Arnaud Vanlander, Berten Ceulemans, Sulekha Rajagopalan, Kenneth Nunn, Stéphanie Arpin, Martine Raynaud, Constance S. Motter, Catherine Ward-Melver, Katrien Janssens, Marije Meuwissen, Diane Beysen, Nicola Dikow, Mona Grimmel, Tobias B. Haack, Emma Clement, Amy McTague, David Hunt, Sharron Townshend, Michelle Ward, Linda J. Richards, Cas Simons, Gregory Costain, Lucie Dupuis, Roberto Mendoza-Londono, Tracy Dudding-Byth, Jackie Boyle, Carol Saunders, Emily Fleming, Salima El Chehadeh, Marie-Aude Spitz, Amelie Piton, Bénédicte Gerard, Marie-Thérèse Abi Warde, Gillian Rea, Caoimhe McKenna, Sofia Douzgou, Siddharth Banka, Cigdem Akman, Jennifer M. Bain, Tristan T. Sands, Golder N. Wilson, Erin J. Silvertooth, Lauren Miller, Damien Lederer, Rani Sachdev, Rebecca Macintosh, Olivier Monestier, Deniz Karadurmus, Felicity Collins, Melissa Carter, Luis Rohena, Marjolein H. Willemsen, Charlotte W. Ockeloen, Rolph Pfundt, Sanne D. Kroft, Michael Field, Francisco E. R. Laranjeira, Ana M. Fortuna, Ana R. Soares, Vincent Michaud, Sophie Naudion, Sailaja Golla, David D. Weaver, Lynne M. Bird, Jennifer Friedman, Virginia Clowes, Shelagh Joss, Laura Pölsler, Philippe M. Campeau, Maria Blazo, Emilia K. Bijlsma, Jill A. Rosenfeld, Christian Beetz, Zöe Powis, Kirsty McWalter, Tracy Brandt, Erin Torti, Mikaël Mathot, Shekeeb S. Mohammad, Ruth Armstrong, Vera M. Kalscheuer, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Service de pédiatrie, Growth and Development, Pediatrics, Centre for Medical Genetics, Brussels Heritage Lab, and Medical Genetics

Subjects
Male, DISRUPTION, Chloride Channels/genetics, EXCHANGER, Mutation, Missense, LYSOSOMAL STORAGE DISEASE, VARIANTS, Neurodevelopmental Disorders/genetics, PHENOTYPE, Cellular and Molecular Neuroscience, All institutes and research themes of the Radboud University Medical Center, Genes, X-Linked, CLC CHLORIDE, Medicine and Health Sciences, Humans, Molecular Biology, MUTATION, Biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], CHANNELS, LINKED MENTAL-RETARDATION, ASSOCIATION, GENE, Psychiatry and Mental health, Chemistry, Female, Human medicine
Abstract

Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a “shift” of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.

Published
2023

8. A Discussion With Dr. Philippe Campeau, Medical Geneticist and Clinician-Scientist

Author

Danny Jomaa and Philippe M. Campeau

Subjects
Canada, Biomedical Research, Physicians, Mentors, Humans, Medicine, General Medicine
Abstract

Dr. Philippe Campeau is the recipient of the 2021 Canadian Society for Clinical Investigation (CSCI) Joe Doupe Young Investigator Award—given in recognition of his early career achievements as a clinician-scientist and his mentorship to trainees. In honor of his success, this article discusses Dr. Campeau’s journey to a career as clinician-scientist and his successes and challenges along the way. In answering these questions, Dr. Campeau shares encouraging insights and advice for clinician-scientist trainees who are building the foundations of their own careers in medicine and research.

Published
2022

9. Variant-specific effects define the phenotypic spectrum of HNRNPH2-associated neurodevelopmental disorders in males

Author

Hans-Jürgen Kreienkamp, Matias Wagner, Heike Weigand, Allyn McConkie-Rossell, Marie McDonald, Boris Keren, Cyril Mignot, Julie Gauthier, Jean-François Soucy, Jacques L. Michaud, Meghan Dumas, Rosemarie Smith, Ulrike Löbel, Maja Hempel, Christian Kubisch, Jonas Denecke, Philippe M. Campeau, Jennifer M. Bain, and Davor Lessel

Subjects
Male, Adolescent, Mutation, Missense, Original Investigation, Human Genetics, Molecular Medicine, Gene Function, Metabolic Diseases, Young Adult, Intellectual Disability, Diseases in Twins, Genetics, Humans, RNA-Seq, Child, Frameshift Mutation, Genetic Association Studies, Genetics (clinical), Chromosomes, Human, X, Heterogeneous-Nuclear Ribonucleoprotein Group F-H, Brain, Genetic Variation, Twins, Monozygotic, ddc, Alternative Splicing, Phenotype, Amino Acid Substitution, Codon, Nonsense, Neurodevelopmental Disorders, Child, Preschool, Mutation, Female
Abstract

Bain type of X-linked syndromic intellectual developmental disorder, caused by pathogenic missense variants in HRNRPH2, was initially described in six female individuals affected by moderate-to-severe neurodevelopmental delay. Although it was initially postulated that the condition would not be compatible with life in males, several affected male individuals harboring pathogenic variants in HNRNPH2 have since been documented. However, functional in-vitro analyses of identified variants have not been performed and, therefore, possible genotype–phenotype correlations remain elusive. Here, we present eight male individuals, including a pair of monozygotic twins, harboring pathogenic or likely pathogenic HNRNPH2 variants. Notably, we present the first individuals harboring nonsense or frameshift variants who, similarly to an individual harboring a de novo p.(Arg29Cys) variant within the first quasi-RNA-recognition motif (qRRM), displayed mild developmental delay, and developed mostly autistic features and/or psychiatric co-morbidities. Additionally, we present two individuals harboring a recurrent de novo p.(Arg114Trp), within the second qRRM, who had a severe neurodevelopmental delay with seizures. Functional characterization of the three most common HNRNPH2 missense variants revealed dysfunctional nucleocytoplasmic shuttling of proteins harboring the p.(Arg206Gln) and p.(Pro209Leu) variants, located within the nuclear localization signal, whereas proteins with p.(Arg114Trp) showed reduced interaction with members of the large assembly of splicing regulators (LASR). Moreover, RNA-sequencing of primary fibroblasts of the individual harboring the p.(Arg114Trp) revealed substantial alterations in the regulation of alternative splicing along with global transcriptome changes. Thus, we further expand the clinical and variant spectrum in HNRNPH2-associated disease in males and provide novel molecular insights suggesting the disorder to be a spliceopathy on the molecular level.

Published
2021

10. PIGG variant pathogenicity assessment reveals characteristic features within 19 families

Author

Anna Lehman, Christina T. Rüsch, Angela F. Brady, Julie S. Cohen, Millan S. Patel, Rani Sachdev, Usha Kini, Elizabeth E. Palmer, Reza Maroofian, Sonal Mahida, Karen Stals, Roger L. Ladda, Yoshiko Murakami, Camille Tremblay-Laganière, Tahsin Stefan Barakat, Scott D. McLean, Fizza Akbar, Marilena Christoforou, Farah Ashrafzadeh, Melissa A. Walker, Grazia M.S. Mancini, Salman Kirmani, Kimberly Nugent, Philippe M. Campeau, Fatima Y. Ismail, Amanda Nagy, Sian Ellard, Stephanie Efthymiou, Bushra Afroze, Rebecca Macintosh, Saskia B. Wortmann, Danilo Bernardo, Rebecca Truty, Matias Wagner, Shahnaz Ibrahim, Tipu Sultan, Kristin W. Barañano, Stylianos E. Antonarakis, Yuta Maki, Thi Tuyet Mai Nguyen, Henry Houlden, Robert Steinfeld, Saadet Mercimek-Andrews, Taroh Kinoshita, Georg M. Stettner, Andrew C. Edmondson, Naila Ismayilova, Meisam Babaei, Heather M. McLaughlin, Mohammad Doosti, Ehsan Ghayoor Karimiani, and Clinical Genetics

Subjects
Autism Spectrum Disorder, Immunoglobulin D, Article, Cell membrane, chemistry.chemical_compound, Biosynthesis, Seizures, Intellectual Disability, medicine, Humans, Transferase, Gene, Genetics (clinical), Genetics, chemistry.chemical_classification, Virulence, biology, Membrane Proteins, Hypotonia, In vitro, Pedigree, Phosphotransferases (Alcohol Group Acceptor), Enzyme, medicine.anatomical_structure, chemistry, biology.protein, medicine.symptom
Abstract

Purpose Phosphatidylinositol Glycan Anchor Biosynthesis, class G (PIGG) is an ethanolamine phosphate transferase catalyzing the modification of glycosylphosphatidylinositol (GPI). GPI serves as an anchor on the cell membrane for surface proteins called GPI-anchored proteins (GPI-APs). Pathogenic variants in genes involved in the biosynthesis of GPI cause inherited GPI deficiency (IGD), which still needs to be further characterized. Methods We describe 22 individuals from 19 unrelated families with biallelic variants in PIGG. We analyzed GPI-AP surface levels on granulocytes and fibroblasts for three and two individuals, respectively. We demonstrated enzymatic activity defects for PIGG variants in vitro in a PIGG/PIGO double knockout system. Results Phenotypic analysis of reported individuals reveals shared PIGG deficiency–associated features. All tested GPI-APs were unchanged on granulocytes whereas CD73 level in fibroblasts was decreased. In addition to classic IGD symptoms such as hypotonia, intellectual disability/developmental delay (ID/DD), and seizures, individuals with PIGG variants of null or severely decreased activity showed cerebellar atrophy, various neurological manifestations, and mitochondrial dysfunction, a feature increasingly recognized in IGDs. Individuals with mildly decreased activity showed autism spectrum disorder. Conclusion This in vitro system is a useful method to validate the pathogenicity of variants in PIGG and to study PIGG physiological functions. Unlabelled Image

Published
2021

11. [Approach to the athlete with low back pain]

Author

Charlotte, Pripp, Philippe M, Tscholl, and Maximilian, Schindler

Subjects
Ligaments, Athletes, Back Pain, Athletic Injuries, Humans, Low Back Pain, Sports
Abstract

Low back pain is a common symptom in athletes, hindering their activity. The etiology is tightly linked to the type of sport, often a consequence of repetitive movements, high pressures and strain being applied to the spine and adjacent muscular and ligamentous structures and a high degree of activity. The diagnosis is the key and causes are usually not severe. However, some red flags may indicate a more serious origin. Treatment is mostly conservative and based on functional therapies with the goal of a rapid and secure return to sports. As such, sedentary lifestyle should be avoided.La lombalgie est un symptôme courant chez les athlètes pouvant entraver leur pratique sportive. L’étiologie est intimement liée au type d’activité pratiquée, souvent secondaire aux mouvements répétitifs, aux forces appliquées sur les structures musculosquelettiques et au degré d’activité. Le diagnostic clinique reste essentiel pour la prise en charge et les causes sont le plus souvent peu sévères. Des drapeaux rouges peuvent néanmoins alerter la présence d’une atteinte grave nécessitant une prise en charge urgente. L’imagerie immédiate étant indiquée uniquement en leur présence. Le traitement est dans la majeure partie des cas conservateur et basé sur les thérapies fonctionnelles dans l’objectif d’un retour sécuritaire au sport de prédilection dès que possible. La sédentarité, quant à elle, est à proscrire.

Published
2022

12. [How and why to monitor apprehension after anterior cruciate ligament surgery]

Author

Honoré, Fell, Alice, Moeschler, Mélanie, Hindi, Maximilian, Schindler, and Philippe M, Tscholl

Subjects
Anterior Cruciate Ligament Reconstruction, Knee Joint, Anterior Cruciate Ligament Injuries, Humans, Knee Injuries, Anterior Cruciate Ligament, Anxiety, Return to Sport
Abstract

Numerous studies highlight the psychological aspect being the most frequent factors limiting the resumption of sport, following an anterior cruciate ligament reconstruction surgery, even before strength, the capacity of performing high impact pivoting movements, endurance, or joint stability. Scores that quantify apprehension, have been developed as clinical tool to monitor psychological readiness and in some cases to delay the moment for return to sport. Unfortunately, there are no established cut-off values for these scores to predict when and if return to sport at the same level as pre-traumatically can be resumed. The psychological aspect of return to sport remains individual, and influenced by age, type, and level of physical activity.De nombreuses études mettent en avant l’aspect psychologique comme étant l’un des principaux facteurs limitant la reprise de sport après reconstruction du ligament croisé antérieur, même avant le manque de force, les sauts et mouvements en pivot à haute intensité, l’endurance ou la stabilité mécanique du genou. Des scores, permettant de quantifier le degré d’appréhension, ont été élaborés afin de suivre la confiance ressentie du patient lors de mouvements liés au sport et de retarder la reprise sportive si nécessaire. Malheureusement, pour l’instant, aucun consensus n’est établi dans la littérature autour d’une valeur seuil de ces différents scores pour la reprise de sport. L’interprétation de ces scores reste pour l’instant une évaluation individualisée, influencée par l’âge, le type et le niveau du sport pratiqué par le patient.

Published
2022

13. Missense and truncating variants in CHD5 in a dominant neurodevelopmental disorder with intellectual disability, behavioral disturbances, and epilepsy

Author

Parenti, Ilaria, Lehalle, Daphné, Nava, Caroline, Torti, Erin, Leitão, Elsa, Person, Richard, Mizuguchi, Takeshi, Matsumoto, Naomichi, Kato, Mitsuhiro, Nakamura, Kazuyuki, de Man, Stella A., Cope, Heidi, Shashi, Vandana, Friedman, Jennifer, Joset, Pascal, Steindl, Katharina, Rauch, Anita, Muffels, Irena, van Hasselt, Peter M., Petit, Florence, Smol, Thomas, Le Guyader, Gwenaël, Bilan, Frédéric, Sorlin, Arthur, Vitobello, Antonio, Philippe, Christophe, van de Laar, Ingrid M. B. H., van Slegtenhorst, Marjon A., Campeau, Philippe M., Au, Ping Yee Billie, Nakashima, Mitsuko, Saitsu, Hirotomo, Yamamoto, Tatsuya, Nomura, Yumiko, Louie, Raymond J., Lyons, Michael J., Dobson, Amy, Plomp, Astrid S., Motazacker, M. Mahdi, Kaiser, Frank J., Timberlake, Andrew T., Fuchs, Sabine A., Depienne, Christel, Mignot, Cyril, Acosta, Maria T., Adam, Margaret, Adams, David R., Agrawal, Pankaj B., Alejandro, Mercedes E., Alvey, Justin, Amendola, Laura, Andrews, Ashley, Ashley, Euan A., Azamian, Mahshid S., Bacino, Carlos A., Bademci, Guney, Baker, Eva, Balasubramanyam, Ashok, Baldridge, Dustin, Bale, Jim, Bamshad, Michael, Barbouth, Deborah, Bayrak-Toydemir, Pinar, Beck, Anita, Beggs, Alan H., Behrens, Edward, Bejerano, Gill, Bennet, Jimmy, Berg-Rood, Beverly, Bernstein, Jonathan A., Berry, Gerard T., Bican, Anna, Bivona, Stephanie, Blue, Elizabeth, Bohnsack, John, Bonnenmann, Carsten, Bonner, Devon, Botto, Lorenzo, Boyd, Brenna, Briere, Lauren C., Brokamp, Elly, Brown, Gabrielle, Burke, Elizabeth A., Burrage, Lindsay C., Butte, Manish J., Byers, Peter, Byrd, William E., Carey, John, Carrasquillo, Olveen, Chang, Ta Chen Peter, Chanprasert, Sirisak, Chao, Hsiao-Tuan, Clark, Gary D., Coakley, Terra R., Cobban, Laurel A., Cogan, Joy D., Coggins, Matthew, Cole, F. Sessions, Colley, Heather A., Cooper, Cynthia M., Craigen, William J., Crouse, Andrew B., Cunningham, Michael, D’Souza, Precilla, Dai, Hongzheng, Dasari, Surendra, Davis, Joie, Dayal, Jyoti G., Deardorff, Matthew, Dell’Angelica, Esteban C., Dhar, Shweta U., Dipple, Katrina, Doherty, Daniel, Dorrani, Naghmeh, Doss, Argenia L., Douine, Emilie D., Draper, David D., Duncan, Laura, Earl, Dawn, Eckstein, David J., Emrick, Lisa T., Eng, Christine M., Esteves, Cecilia, Falk, Marni, Fernandez, Liliana, Ferreira, Carlos, Fieg, Elizabeth L., Findley, Laurie C., Fisher, Paul G., Fogel, Brent L., Forghani, Irman, Fresard, Laure, Gahl, William A., Glass, Ian, Gochuico, Bernadette, Godfrey, Rena A., Golden-Grant, Katie, Goldman, Alica M., Goldrich, Madison P., Goldstein, David B., Grajewski, Alana, Groden, Catherine A., Gutierrez, Irma, Hahn, Sihoun, Hamid, Rizwan, Hanchard, Neil A., Hassey, Kelly, Hayes, Nichole, High, Frances, Hing, Anne, Hisama, Fuki M., Holm, Ingrid A., Hom, Jason, Horike-Pyne, Martha, Huang, Alden, Huang, Yong, Huryn, Laryssa, Isasi, Rosario, Jamal, Fariha, Jarvik, Gail P., Jarvik, Jeffrey, Jayadev, Suman, Karaviti, Lefkothea, Kennedy, Jennifer, Kiley, Dana, Kohane, Isaac S., Kohler, Jennefer N., Krakow, Deborah, Krasnewich, Donna M., Kravets, Elijah, Korrick, Susan, Koziura, Mary, Krier, Joel B., Lalani, Seema R., Lam, Byron, Lam, Christina, LaMoure, Grace L., Lanpher, Brendan C., Lanza, Ian R., Latham, Lea, LeBlanc, Kimberly, Lee, Brendan H., Lee, Hane, Levitt, Roy, Lewis, Richard A., Lincoln, Sharyn A., Liu, Pengfei, Liu, Xue Zhong, Longo, Nicola, Loo, Sandra K., Loscalzo, Joseph, Maas, Richard L., MacDowall, John, Macnamara, Ellen F., Mac-Rae, Calum A., Maduro, Valerie V., Majcherska, Marta M., Mak, Bryan C., Malicdan, May Christine V., Mamounas, Laura A., Manolio, Teri A., Mao, Rong, Maravilla, Kenneth, Markello, Thomas C., Marom, Ronit, Marth, Gabor, Martin, Beth A., Martin, Martin G., Martínez-Agosto, Julian A., Marwaha, Shruti, McCauley, Jacob, McConkie-Rosell, Allyn, McCormack, Colleen E., McCray, Alexa T., McGee, Elisabeth, Mefford, Heather, Merritt, J. Lawrence, Might, Matthew, Mirzaa, Ghayda, Morava, Eva, Moretti, Paolo M., Mosbrook-Davis, Deborah, Mulvihill, John J., Murdock, David R., Nagy, Anna, Nakano-Okuno, Mariko, Nath, Avi, Nelson, Stan F., Newman, John H., Nicholas, Sarah K., Nickerson, Deborah, Nieves-Rodriguez, Shirley, Novacic, Donna, Oglesbee, Devin, Orengo, James P., Pace, Laura, Pak, Stephen, Pallais, J. Carl, Palmer, Christina GS., Papp, Jeanette C., Parker, Neil H., Phillips, John A., Posey, Jennifer E., Potocki, Lorraine, Power, Bradley, Pusey, Barbara N., Quinlan, Aaron, Raskind, Wendy, Raja, Archana N., Rao, Deepak A., Renteria, Genecee, Reuter, Chloe M., Rives, Lynette, Robertson, Amy K., Rodan, Lance H., Rosenfeld, Jill A., Rosenwasser, Natalie, Rossignol, Francis, Ruzhnikov, Maura, Sacco, Ralph, Sampson, Jacinda B., Samson, Susan L., Saporta, Mario, Scott, C. Ron, Schaechter, Judy, Schedl, Timothy, Schoch, Kelly, Scott, Daryl A., Shin, Jimann, Signer, Rebecca, Silverman, Edwin K., Sinsheimer, Janet S., Sisco, Kathy, Smith, Edward C., Smith, Kevin S., Solem, Emily, Solnica-Krezel, Lilianna, Solomon, Ben, Spillmann, Rebecca C., Stoler, Joan M., Sullivan, Jennifer A., Sullivan, Kathleen, Sun, Angela, Sutton, Shirley, Sweetser, David A., Sybert, Virginia, Tabor, Holly K., Tan, Amelia L. M., Tan, Queenie K.-G., Tekin, Mustafa, Telischi, Fred, Thorson, Willa, Thurm, Audrey, Tifft, Cynthia J., Toro, Camilo, Tran, Alyssa A., Tucker, Brianna M., Urv, Tiina K., Vanderver, Adeline, Velinder, Matt, Viskochil, Dave, Vogel, Tiphanie P., Wahl, Colleen E., Wallace, Stephanie, Walley, Nicole M., Walsh, Chris A., Walker, Melissa, Wambach, Jennifer, Wan, Jijun, Wang, Lee-kai, Wangler, Michael F., Ward, Patricia A., Wegner, Daniel, Wener, Mark, Wenger, Tara, Perry, Katherine Wesseling, Westerfield, Monte, Wheeler, Matthew T., Whitlock, Jordan, Wolfe, Lynne A., Woods, Jeremy D., Yamamoto, Shinya, Yang, John, Yousef, Muhammad, Zastrow, Diane B., Zein, Wadih, Zhao, Chunli, Zuchner, Stephan, Clinical Genetics, Human Genetics, ACS - Pulmonary hypertension & thrombosis, and ANS - Complex Trait Genetics

Subjects
Male, Adolescent, Mutation, Missense, Medizin, Nerve Tissue Proteins, Biology, Frameshift mutation, Chromodomain, Cohort Studies, Young Adult, Epilepsy, Neurodevelopmental disorder, Catalytic Domain, Intellectual Disability, Intellectual disability, Genetics, medicine, Humans, Missense mutation, Child, Genetics (clinical), Exome sequencing, Original Investigation, Genes, Dominant, DNA Helicases, medicine.disease, Pedigree, Neurodevelopmental Disorders, Child, Preschool, Speech delay, Female, medicine.symptom
Abstract

Located in the critical 1p36 microdeletion region, the chromodomain helicase DNA-binding protein 5 (CHD5) gene encodes a subunit of the nucleosome remodeling and deacetylation (NuRD) complex required for neuronal development. Pathogenic variants in six of nine chromodomain (CHD) genes cause autosomal dominant neurodevelopmental disorders, while CHD5-related disorders are still unknown. Thanks to GeneMatcher and international collaborations, we assembled a cohort of 16 unrelated individuals harboring heterozygous CHD5 variants, all identified by exome sequencing. Twelve patients had de novo CHD5 variants, including ten missense and two splice site variants. Three familial cases had nonsense or missense variants segregating with speech delay, learning disabilities, and/or craniosynostosis. One patient carried a frameshift variant of unknown inheritance due to unavailability of the father. The most common clinical features included language deficits (81%), behavioral symptoms (69%), intellectual disability (64%), epilepsy (62%), and motor delay (56%). Epilepsy types were variable, with West syndrome observed in three patients, generalized tonic–clonic seizures in two, and other subtypes observed in one individual each. Our findings suggest that, in line with other CHD-related disorders, heterozygous CHD5 variants are associated with a variable neurodevelopmental syndrome that includes intellectual disability with speech delay, epilepsy, and behavioral problems as main features.

Published
2021

14. Genetic burden linked to founder effects in Saguenay–Lac-Saint-Jean illustrates the importance of genetic screening test availability

Author

Anne-Marie Laberge, Philippe M. Campeau, Charles Morin, Diane Brisson, Jean Mathieu, Daniel Gaudet, Hélène Vézina, Catherine Laprise, Mbarka Bchetnia, and Luigi Bouchard

Subjects
Genetic counseling, Population, Genes, Recessive, Population health, community medicine, 030204 cardiovascular system & hematology, Carrier testing, genetic background, 03 medical and health sciences, 0302 clinical medicine, Genetics, Population Database, Prevalence, Humans, Mass Screening, Genetic Predisposition to Disease, 030212 general & internal medicine, Genetic Testing, education, Genetics (clinical), education.field_of_study, congenital, genetic load, Genetic Diseases, Inborn, Quebec, Genealogy, Founder Effect, Genetic load, Geography, Phenotype, Genetic structure, and neonatal diseases and abnormalities, France, hereditary, Population Genetics, genetic counselling, Founder effect
Abstract

The Saguenay–Lac-Saint-Jean (SLSJ) region located in the province of Quebec was settled in the 19th century by pioneers issued from successive migration waves starting in France in the 17th century and continuing within Quebec until the beginning of the 20th century. The genetic structure of the SLSJ population is considered to be the product of a triple founder effect and is characterised by a higher prevalence of some rare genetic diseases. Several studies were performed to elucidate the historical, demographic and genetic background of current SLSJ inhabitants to assess the origins of these rare disorders and their distribution in the population. Thanks to the development of new sequencing technologies, the genes and the variants responsible for the most prevalent conditions were identified. Combined with other resources such as the BALSAC population database, identifying the causal genes and the pathogenic variants allowed to assess the impacts of some of these founder mutations on the population health and to design precision medicine public health strategies based on carrier testing. Furthermore, it stimulated the establishment of many public programmes.We report here a review and an update of a subset of inherited disorders and founder mutations in the SLSJ region. Data were collected from published scientific sources. This work expands the knowledge about the current frequencies of these rare disorders, the frequencies of other rare genetic diseases in this population, the relevance of the carrier tests offered to the population, as well as the current available treatments and research about future therapeutic avenues for these inherited disorders.

Published
2021

15. DNA Methylation Signature for

Author

Eline A, Verberne, Liselot, van der Laan, Sadegheh, Haghshenas, Kathleen, Rooney, Michael A, Levy, Mariëlle, Alders, Saskia M, Maas, Sandra, Jansen, Agne, Lieden, Britt-Marie, Anderlid, Louise, Rafael-Croes, Philippe M, Campeau, Ayeshah, Chaudhry, David A, Koolen, Rolph, Pfundt, Anna C E, Hurst, Frederic, Tran-Mau-Them, Ange-Line, Bruel, Laetitia, Lambert, Bertrand, Isidor, Marcel M A M, Mannens, Bekim, Sadikovic, Peter, Henneman, and Mieke M, van Haelst

Subjects
Phenotype, Polycomb Repressive Complex 2, Humans, Syndrome, DNA Methylation, Nucleotide Motifs, Protein Processing, Post-Translational
Published
2022

16. Hypomorphic GINS3 variants alter DNA replication and cause Meier-Gorlin syndrome

Author

Mary E. McQuaid, Kashif Ahmed, Stephanie Tran, Justine Rousseau, Ranad Shaheen, Kristin D. Kernohan, Kyoko E. Yuki, Prerna Grover, Ema S. Dreseris, Sameen Ahmed, Lucie Dupuis, Jennifer Stimec, Mary Shago, Zuhair N. Al-Hassnan, Roch Tremblay, Philipp G. Maass, Michael D. Wilson, Eyal Grunebaum, Kym M. Boycott, François-Michel Boisvert, Sateesh Maddirevula, Eissa A. Faqeih, Fahad Almanjomi, Zaheer Ullah Khan, Fowzan S. Alkuraya, Philippe M. Campeau, Peter Kannu, Eric I. Campos, and Hugo Wurtele

Subjects
DNA Replication, Mice, Minichromosome Maintenance Proteins, Chromosomal Proteins, Non-Histone, Micrognathism, Animals, Humans, Patella, Saccharomyces cerevisiae, General Medicine, Growth Disorders, Congenital Microtia
Abstract

The eukaryotic CDC45/MCM2-7/GINS (CMG) helicase unwinds the DNA double helix during DNA replication. The GINS subcomplex is required for helicase activity and is, therefore, essential for DNA replication and cell viability. Here, we report the identification of 7 individuals from 5 unrelated families presenting with a Meier-Gorlin syndrome-like (MGS-like) phenotype associated with hypomorphic variants of GINS3, a gene not previously associated with this syndrome. We found that MGS-associated GINS3 variants affecting aspartic acid 24 (D24) compromised cell proliferation and caused accumulation of cells in S phase. These variants shortened the protein half-life, altered key protein interactions at the replisome, and negatively influenced DNA replication fork progression. Yeast expressing MGS-associated variants of PSF3 (the yeast GINS3 ortholog) also displayed impaired growth, S phase progression defects, and decreased Psf3 protein stability. We further showed that mouse embryos homozygous for a D24 variant presented intrauterine growth retardation and did not survive to birth, and that fibroblasts derived from these embryos displayed accelerated cellular senescence. Taken together, our findings implicate GINS3 in the pathogenesis of MGS and support the notion that hypomorphic variants identified in this gene impaired cell and organismal growth by compromising DNA replication.

Published
2022

17. Drugs used for the treatment of cerebral and disseminated infections caused by free‐living amoebae

Author

Philippe M. Loiseau, Zineb Fechtali-Moute, Alexandre Taravaud, and Sébastien Pomel

Subjects
Drug, 030213 general clinical medicine, media_common.quotation_subject, Reviews, Central Nervous System Protozoal Infections, RM1-950, Balamuthia, Review, 030226 pharmacology & pharmacy, General Biochemistry, Genetics and Molecular Biology, Balamuthia mandrillaris, 03 medical and health sciences, 0302 clinical medicine, parasitic diseases, Medicine, Humans, Amebicides, General Pharmacology, Toxicology and Pharmaceutics, Granulomatous amoebic encephalitis, Amoeba, media_common, Naegleria fowleri, biology, business.industry, General Neuroscience, Meningoencephalitis, Acanthamoeba infection, General Medicine, Amebiasis, biology.organism_classification, medicine.disease, Acanthamoeba, Survival Rate, Treatment Outcome, Immunology, Drug Therapy, Combination, Therapeutics. Pharmacology, Public aspects of medicine, RA1-1270, business
Abstract

Free‐living amoebae (FLAs) are protozoa developing autonomously in diverse natural or artificial environments. The FLAs Acanthamoeba spp., Balamuthia mandrillaris, and Naegleria fowleri represent a risk for human health as they can become pathogenic and cause severe cerebral infections, named granulomatous amoebic encephalitis (GAE), Balamuthia amoebic encephalitis (BAE), and primary amoebic meningoencephalitis (PAM), respectively. Additionally, Acanthamoeba sp. can also rarely disseminate to diverse organs, such as the skin, sinuses, or bones, and cause extracerebral disseminated acanthamebiasis (EDA). No consensus treatment has been established for cerebral FLA infections or EDA. The therapy of cerebral and disseminated FLA infections often empirically associates a large diversity of drugs, all exhibiting a high toxicity. Nevertheless, these pathologies lead to a high mortality, above 90% of the cases, even in the presence of a treatment. In the present work, a total of 474 clinical cases of FLA infections gathered from the literature allowed to determine the frequency of usage, as well as the efficacy of the main drugs and drug combinations used in the treatment of these pathologies. The efficacy of drug usage was determined based on the survival rate after drug administration. The most efficient drugs, drug combinations, and their mechanism of action were discussed in regard to the present recommendations for the treatment of GAE, EDA, BAE, and PAM. At the end, this review aims to provide a useful tool for physicians in their choice to optimize the treatment of FLA infections.

Published
2021

18. JARID2 haploinsufficiency is associated with a clinically distinct neurodevelopmental syndrome

Author

Ange Line Bruel, Katherine A. Bosanko, Abeltje M. Polstra, Agne Liedén, Marcel M.A.M. Mannens, R. Pfundt, Frédérick A. Mallette, Britt-Marie Anderlid, Kieran B. Pechter, Louise Rafael-Croes, Madhura Bakshi, Saskia M. Maas, Dagmar Glatz, R. Frank Kooy, Natalie Lippa, Philippe M. Campeau, Yuri A. Zarate, Jade England, Mieke M. van Haelst, Megan Boothe, Kosuke Izumi, Manon van Ginkel, Vimla Aggarwal, Anna Lehman, Eline A. Verberne, Zornitza Stark, Christopher M. Richmond, Marije Meuwissen, Darryl C. De Vivo, Pankaj B. Agrawal, Shuxiang Goh, Jennifer M. Lemons, Bertrand Isidor, Ayeshah Chaudhry, Causes Study, Emma Bedoukian, Nathaniel H. Robin, David A. Koolen, Sylvia Stockler, David Rodriguez-Buritica, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), Human Genetics, Graduate School, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, and ACS - Pulmonary hypertension & thrombosis

Subjects
0301 basic medicine, Heterozygote, Haploinsufficiency, 030105 genetics & heredity, Biology, 03 medical and health sciences, Exome Sequencing, Intellectual disability, medicine, Humans, Copy-number variation, Gene, Genetics (clinical), Exome sequencing, Genetics, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], neurodevelopment, Microarray analysis techniques, Polycomb Repressive Complex 2, Chromosome, Syndrome, medicine.disease, developmental delay, Phenotype, 030104 developmental biology, Neurodevelopmental Disorders, intellectual disability, Histone methyltransferase, Human medicine, JARID2
Abstract

Item does not contain fulltext PURPOSE: JARID2, located on chromosome 6p22.3, is a regulator of histone methyltransferase complexes that is expressed in human neurons. So far, 13 individuals sharing clinical features including intellectual disability (ID) were reported with de novo heterozygous deletions in 6p22-p24 encompassing the full length JARID2 gene (OMIM 601594). However, all published individuals to date have a deletion of at least one other adjoining gene, making it difficult to determine if JARID2 is the critical gene responsible for the shared features. We aim to confirm JARID2 as a human disease gene and further elucidate the associated clinical phenotype. METHODS: Chromosome microarray analysis, exome sequencing, and an online matching platform (GeneMatcher) were used to identify individuals with single-nucleotide variants or deletions involving JARID2. RESULTS: We report 16 individuals in 15 families with a deletion or single-nucleotide variant in JARID2. Several of these variants are likely to result in haploinsufficiency due to nonsense-mediated messenger RNA (mRNA) decay. All individuals have developmental delay and/or ID and share some overlapping clinical characteristics such as facial features with those who have larger deletions involving JARID2. CONCLUSION: We report that JARID2 haploinsufficiency leads to a clinically distinct neurodevelopmental syndrome, thus establishing gene-disease validity for the purpose of diagnostic reporting.

Published
2021

19. Disruption of exon-bridging interactions between the minor and major spliceosomes results in alternative splicing around minor introns

Author

Karen Doggett, Almahdi Chakroun, Alisa K. White, Joan K. Heath, Stephen Mieruszynski, Alice Abdel Aleem, Madisen F. Lee, Cinzia Magnani, Anouk M. Olthof, Rahul N. Kanadia, Justine Rousseau, Philippe M. Campeau, and Chaim M. Roifman

Subjects
Spliceosome, Cerebellar Ataxia, AcademicSubjects/SCI00010, Primary Immunodeficiency Diseases, Biology, Osteochondrodysplasias, 03 medical and health sciences, Exon, Mice, 0302 clinical medicine, Retinal Diseases, Minor spliceosome, Intellectual Disability, RNA, Small Nuclear, Genetics, RNA and RNA-protein complexes, Animals, Humans, Cells, Cultured, Growth Disorders, 030304 developmental biology, 0303 health sciences, Alternative splicing, Intron, RNA, Exons, Exon skipping, Introns, Nonsense Mediated mRNA Decay, Alternative Splicing, Polyribosomes, RNA splicing, Mental Retardation, X-Linked, Microcephaly, Spliceosomes, Apoptosis Regulatory Proteins, Cardiomyopathies, 030217 neurology & neurosurgery, Transcription Factors
Abstract

Vertebrate genomes contain major (>99.5%) and minor (

Published
2021

20. In vitro antileishmanial potentialities of essential oils from Citrus limon and Pistacia lentiscus harvested in Tunisia

Author

Marwa Yahyaoui, Ghozlene Mekhloufi, Florence Agnely, Sandrine Cojean, Zeineb Maaroufi, Philippe M. Loiseau, and Manef Abderraba

Subjects
Citrus, Tunisia, 030231 tropical medicine, Antiprotozoal Agents, Leishmaniasis, Cutaneous, Gas Chromatography-Mass Spectrometry, 030308 mycology & parasitology, law.invention, 03 medical and health sciences, 0302 clinical medicine, Phenols, law, Oils, Volatile, medicine, Animals, Humans, Plant Oils, Leishmania major, Amastigote, Axenic, Essential oil, 0303 health sciences, Miltefosine, General Veterinary, biology, Pistacia, Traditional medicine, food and beverages, Leishmaniasis, General Medicine, biology.organism_classification, medicine.disease, Plant Leaves, Infectious Diseases, Insect Science, Pistacia lentiscus, Parasitology, medicine.drug
Abstract

Leishmaniasis is a tropical parasitic disease that affects up to 12 million people worldwide. Current chemotherapies have limitations such as toxicity, high cost, and parasite resistance. This work aims to select an essential oil (EssOil) isolated from the Tunisian flora as a new antileishmanial candidate. Two plants were chosen for their antileishmanial potential: Citrus limon (Citrus) and Pistacia lentiscus (Pistacia). Each of these plants was harvested from two different sites (area 1 and area 2). Extracted EssOils were characterized using GC-MS. Their antiparasitic activity against axenic and intracellular Leishmania major amastigotes and their cytotoxicity were assessed. Citrus EssOil from area 1 displayed an interesting activity against L. major intramacrophage amastigotes with IC50 value at 4.2 ± 1.3 μg/mL. Interestingly, this activity was close to that of miltefosine. Moderate activities against intracellular amastigote were observed for Pistacia EssOil from area 1 and Citrus EssOil from area 2. However, low cytotoxicity with high selectivity index was proved only for Citrus EssOil from area 1, revealing its safety for macrophages. This study also demonstrated for the first time the antileishmanial activity of EssOil extracted from Citrus limon leaves. The EssOil interesting activity could be related to the lipophilic properties of terpenes that were shown in literature to contribute to the disruption of parasite intracellular metabolic pathways.

Published
2021

21. A 4-days-on and 3-days-off maintenance treatment strategy for adults with HIV-1 (ANRS 170 QUATUOR): a randomised, open-label, multicentre, parallel, non-inferiority trial

Author

Roland, L, Pierre de Truchis, Lambert, A, Sidonie, L, Jonathan, B, Karine, A, B??n??dicte, L, Clotilde, A, Christine, K, Yazdan, Y, Jean-Michel, M, Ventzislava, P, S??verine, G, Jean, Ca, Jacques, L, Jacqueline, C, Soraya, F, Martin, D, Laurence, M, Dominique, C, Jean-Claude, A, Pierre-Marie, G, Isabelle, L, Firouz??, B, Gilles, F, Am??lie, C, Fabienne, C, Olivier, P, Anne, F, Amandine, G, Catherine, C, Claudine, D, J??r??mie, L, Violaine, T, C??cile, J, Nathalie, L, Pilartxo, C, Agathe, R, Lucile DE PONTHAUD, Gilles, P, Safa, N, St??phanie, L, Julie, B, Flory MFUTILA KAYKAY, Olivier, B, Sophie, A, Caroline, G, Laurence, W, Juliette, P, Dominique, S, David, Z, Jean-Daniel, L, Romain, P, Anne, S, Marie-Caroline, M, Julien, G, Andr??, C, Mathilde, P, Philippe, M, Mojgam, H, Didier, N, Charles, C, Claire, G, Jean-Fran??ois, F, Djamila, M, Andr??, B, Sylvie, B, H??l??ne, L, Aur??lie, S, Jacques, R, Alain, M, Fran??ois, R, Alissa, N, Eric, C, Eric, R, C??drick, A, Rodolphe, B, David, R, Marie-Laure, B, Louis, B, Pierre, D, Marie, P, Renaud, V, Lionel, P, Mathieu, B, Pascale, L, Thomas, H, Agn??s, M, Thierry, M, Patrick, M, Thomas, P, Alix, G, Brigitte, E, Marie-Aude, K, Laurent, B, Christophe, M, Thierry, P, Patrick, P, Laurence, S, Hitoto, H, Iuliana, D, Dominique, M, Pierre DE TRUCHIS, Jean-Luc, M, Damien LE DU, Christian, P, Jean-Claude, M, A??da, B, Babacar, S, Ambre, G, Guillaume LE MEUT, Rodolphe, T, Nathan, C, Vincent, L, CECCHERINI SILBERSTEIN, F, and Laurent, D

Subjects
Adult, Epidemiology, Anti-HIV Agents, Immunology, HIV Infections, Viral Load, CD4 Lymphocyte Count, Settore MED/07, Infectious Diseases, Hepatitis B, Chronic, Treatment Outcome, Virology, HIV-1, Humans, Reverse Transcriptase Inhibitors
Abstract

Intermittent (on 4 days per week) antiretroviral therapy (ART) for patients with HIV-1 might be more convenient, better tolerated, and cheaper than continuous treatment. We aimed to establish the efficacy and safety of a 4-days-on and 3-days-off (intermittent) maintenance regimen versus a standard 7 day (continuous) maintenance regimen.In a randomised, open-label, multicentre, parallel, non-inferiority trial, we randomly assigned (1:1) adults with HIV-1 infection with a plasma viral load (pVL) of less than 50 copies per mL for more than 12 months and no drug-resistance mutations to either the intermittent regimen or their existing continuous maintenance regimen, with stratification according to third therapeutic agent (protease inhibitor, non-nucleoside reverse transcriptase inhibitor, or integrase-strand transfer inhibitor). Participants were recruited from 59 hospitals throughout France. The main exclusion criteria were CD4 cell count lower than 250 cells per μL and chronic hepatitis B virus infection. The primary endpoint was the proportion of participants in the modified intention-to-treat (mITT) population who started the study strategy presenting treatment success at week 48 (pVL50 copies per mL without strategy modification), estimated using the US Federal Drug Administration snapshot approach, with a 5% non-inferiority margin. The study was registered with ClinicalTrials.gov (NCT03256422) and EudraCT (2017-000040-17). The trial is now closed.From Sept 7, 2017, to Jan 22, 2018, 850 potential participants were screened for eligibility. 647 participants were enrolled and randomly assigned (1:1) to either the intermittent or the continuous treatment group. The mITT population included 636 participants (318 per group). At week 48, in the mITT population, treatment success was recorded in 304 (96%) of 318 participants in the intermittent treatment group and 308 (97%) of 318 in the continuous treatment group (adjusted difference -1·3%, 95% CI -4·2 to 1·7). Six (2%) participants in the intermittent treatment group and four (1%) participants in the continuous treatment group had virological failure. Grade 3-4 adverse events were reported in 29 (9%) participants in the intermittent treatment group and 39 (12%) participants in the continuous treatment group (p=0·320). Daily life satisfaction improved in 153 (59%) of 258 participants in the intermittent treatment group versus 19 (7%) of 255 in the continuous treatment group (p0·0001). ART costs were 43% lower in the intermittent treatment group than in the continuous treatment group (p0·0001).These findings show the non-inferiority of the treatment strategy of 4-consecutive-days-on and 3-days-off strategy maintenance regimen relative to standard continuous ART triple therapy over 48 weeks. 4 days on and off treatment represents a workable, effective alternative strategy for patients with high adherence to ART, and using a drug combination with a high genetic barrier to resistance.Institut National de la Santé et de la Recherche Médicale Agence Nationale de Recherche sur le Sida et les Hépatites Virales, Maladies Infectieuses Emergentes.

Published
2022

22. The ARID1B spectrum in 143 patients

Author

Catherine Vincent-Delorme, Claudia A. L. Ruivenkamp, Marjan De Rademaeker, Francisco Martínez, Tracy Dudding-Byth, Marianne McGuire, Bert B.A. de Vries, Mitsuhiro Kato, Levinus A. Bok, Hülya Kayserili, Jeff M. Milunsky, Suzanne C E H Sallevelt, Alwin F. J. Brouwer, Jill Clayton-Smith, Emilia K. Bijlsma, Miranda Splitt, Patricia G. Wheeler, Philippe M. Campeau, Fatma Mujgan Sonmez, Kylin Lammers, Stefanie Beck-Wödl, Caroline Rooryck, Louise C. Wilson, Evan E. Eichler, Sarina G. Kant, Johanna C. Herkert, Karin R. Heitink, Eyyup Uctepe, Pleuntje J. van der Sluijs, Miho Adachi-Fukuda, Lone W. Laulund, Sandra Jansen, Nicolette S. den Hollander, Damien Lederer, Tomoki Kosho, Constance T. R. M. Stumpel, Saskia M. Maas, Esra Kılıç, Erica H. Gerkes, Duco Steenbeek, Melissa Lees, Kay Metcalfe, Karin Dahan, Ineke van der Burgt, Isabelle Maystadt, Christian Netzer, Ute Grasshoff, Carmen Orellana, Mahmut Şamil Sağıroğlu, Gijs W. E. Santen, Pelin Ozlem Simsek-Kiper, Mónica Roselló, Gabriela Soares, Alexander P.A. Stegmann, Stephen P. Robertson, Adila Al-Kindy, Maian Roifman, Saori Tanabe, Vera Riehmer, Brain H Y Chung, Arie van Haeringen, G. Eda Utine, Yasemin Alanay, Rogier Kersseboom, John B. Moeschler, Barbara Oehl-Jaschkowitz, Katherine Berry, Denise Horn, Alice Gardham, Shane McKee, Anwar Baban, Amparo Sanchis Calvo, Golder N. Wilson, Krystyna H. Chrzanowska, G. M. S. Mancini, Ellen R. Elias, Małgorzata Krajewska-Walasek, Rolph Pfundt, Sarju G. Mehta, Fabienne G. Ropers, Seiji Mizuno, David Hunt, Caroline Pottinger, Dagmar Wieczorek, Yoyo W. Y. Chu, Laurent Pasquier, Bernd Wollnik, Nobuhiko Okamoto, Sunita Venkateswaran, Vanesa López-González, Natalie Canham, Blanca Gener, Anne Destree, Christina Fagerberg, Rachel K. Earl, Sharon N M Olminkhof, Nursel Elcioglu, Charlotte W. Ockeloen, Carlo Marcelis, Samantha A. Vergano, Hermine E. Veenstra-Knol, Anneke T. Vulto-van Silfhout, Allan Bayat, Catheline Vilain, Lucia Solaeche, MUMC+: DA KG Polikliniek (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, Genetica & Celbiologie, MUMC+: DA KG Lab Centraal Lab (9), MUMC+: DA Pat Cytologie (9), Klinische Genetica, van der Sluijs, Pleuntje J., Jansen, Sandra, Vergano, Samantha A., Adachi-Fukuda, Miho, Alanay, Yasemin, AlKindy, Adila, Baban, Anwar, Bayat, Allan, Beck-Woedl, Stefanie, Berry, Katherine, Bijlsma, Emilia K., Bok, Levinus A., Brouwer, Alwin F. J., van der Burgt, Ineke, Campeau, Philippe M., Canham, Natalie, Chrzanowska, Krystyna, Chu, Yoyo W. Y., Chung, Brain H. Y., Dahan, Karin, De Rademaeker, Marjan, Destree, Anne, Dudding-Byth, Tracy, Earl, Rachel, Elcioglu, Nursel, Elias, Ellen R., Fagerberg, Christina, Gardham, Alice, Gener, Blanca, Gerkes, Erica H., Grasshoff, Ute, van Haeringen, Arie, Heitink, Karin R., Herkert, Johanna C., den Hollander, Nicolette S., Horn, Denise, Hunt, David, Kant, Sarina G., Kato, Mitsuhiro, Kayserili, Hulya, Kersseboom, Rogier, Kilic, Esra, Krajewska-Walasek, Malgorzata, Lammers, Kylin, Laulund, Lone W., Lederer, Damien, Lees, Melissa, Lopez-Gonzalez, Vanesa, Maas, Saskia, Mancini, Grazia M. S., Marcelis, Carlo, Martinez, Francisco, Maystadt, Isabelle, McGuire, Marianne, McKee, Shane, Mehta, Sarju, Metcalfe, Kay, Milunsky, Jeff, Mizuno, Seiji, Moeschler, John B., Netzer, Christian, Ockeloen, Charlotte W., Oehl-Jaschkowitz, Barbara, Okamoto, Nobuhiko, Olminkhof, Sharon N. M., Orellana, Carmen, Pasquier, Laurent, Pottinger, Caroline, Riehmer, Vera, Robertson, Stephen P., Roifman, Maian, Rooryck, Caroline, Ropers, Fabienne G., Rosello, Monica, Ruivenkamp, Claudia A. L., Sagiroglu, Mahmut S., Sallevelt, Suzanne C. E. H., Sanchis Calvo, Amparo, Simsek-Kiper, Pelin O., Soares, Gabriela, Solaeche, Lucia, Sonmez, Fatma Mujgan, Splitt, Miranda, Steenbeek, Duco, Stegmann, Alexander P. A., Stumpel, Constance T. R. M., Tanabe, Saori, Uctepe, Eyyup, Utine, G. Eda, Veenstra-Knol, Hermine E., Venkateswaran, Sunita, Vilain, Catheline, Vincent-Delorme, Catherine, Vulto-van Silfhout, Anneke T., Wheeler, Patricia, Wilson, Golder N., Wilson, Louise C., Wollnik, Bernd, Kosho, Tomoki, Wieczorek, Dagmar, Eichler, Evan, Pfundt, Rolph, de Vries, Bert B. A., Clayton-Smith, Jill, Santen, Gijs W. E., Erasmus MC other, Clinical Genetics, Human Genetics, and Acibadem University Dspace

Subjects
Male, 0301 basic medicine, Hypertrichosis, Pediatrics, cuello, bias, Coffin–Siris syndrome, Chromosomal Proteins, Non-Histone, humanos, adolescente, Penetrance, PHENOTYPE, 0302 clinical medicine, Genotype, Intellectual disability, Exome, Coffin-Siris syndrome, Child, mediana edad, Genetics (clinical), Exome sequencing, factores de transcripción, adulto, Middle Aged, estudios de asociación genética, 3. Good health, DNA-Binding Proteins, intellectual disability, Child, Preschool, discapacidad intelectual, penetrancia, Female, Hand Deformities, Congenital, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Adult, medicine.medical_specialty, Adolescent, Micrognathism, Article, CHROMATIN-REMODELING COMPLEX, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, cara, micrognatismo, Human Phenotype Ontology, medicine, Humans, Abnormalities, Multiple, mutación, Long eyelashes, Genetic Association Studies, lactante, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, MUTATIONS, proteínas de unión al ADN, Infant, Newborn, Genetic Variation, Infant, ARID1B, Hand Deformities, Phalanx, medicine.disease, variación genética, deformidades de la mano, exoma, 030104 developmental biology, Face, Mutation, business, Neck, 030217 neurology & neurosurgery, Transcription Factors
Abstract

Purpose: Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin-Siris patients (ARID1BCSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting. Methods: Clinicians entered clinical data in an extensive webbased survey. Results: 79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified. Conclusion: There are only minor differences between ARID1BID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features., We are grateful for the assistance of Pepijn Cox in setting up the website www.arid1bgene.com. This study has made use of data generated by the Human Disease Genes website series, www.humandiseasegenes.com. This work was financially supported by grants from the Netherlands Organisation for Health Research and Development (917-86-319 to B.B.A.d.V., 912-12-109 to B.B.A.d.V.)

Published
2019

23. De Novo KAT5 Variants Cause a Syndrome with Recognizable Facial Dysmorphisms, Cerebellar Atrophy, Sleep Disturbance, and Epilepsy

Author

Philippe M. Campeau, Gabrielle Lemire, Smrithi Salian, Thomas Garcia, Stylianos E. Antonarakis, Sophie Ehresmann, Seth I. Berger, Justine Rousseau, Sylviane Hanquinet, Armand Bottani, Xiang-Jiao Yang, Jacques Côté, Ann C.M. Smith, Jonathan Humbert, Jennifer Heeley, Rami Alasiri, Erin Beaver, and Periklis Makrythanasis

Subjects
Adult, Male, Heterozygote, Adolescent, DNA Repair, Mutation, Missense, ddc:616.0757, Lysine Acetyltransferase 5, Chromatin remodeling, Chromodomain, Histones, Histone H4, 03 medical and health sciences, 0302 clinical medicine, Cerebellar Diseases, Intellectual Disability, Report, Genetics, Humans, ddc:576.5, Abnormalities, Multiple, Epigenetics, KAT5, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Epilepsy, biology, Histone acetyltransferase, Chromatin Assembly and Disassembly, Chromatin, Histone, Child, Preschool, biology.protein, Female, Cerebellar atrophy, Atrophy, Protein Processing, Post-Translational, 030217 neurology & neurosurgery
Abstract

KAT5 encodes an essential lysine acetyltransferase, previously called TIP60, which is involved in regulating gene expression, DNA repair, chromatin remodeling, apoptosis, and cell proliferation; but it remains unclear whether variants in this gene cause a genetic disease. Here, we study three individuals with heterozygous de novo missense variants in KAT5 that affect normally invariant residues, with one at the chromodomain (p.Arg53His) and two at or near the acetyl-CoA binding site (p.Cys369Ser and p.Ser413Ala). All three individuals have cerebral malformations, seizures, global developmental delay or intellectual disability, and severe sleep disturbance. Progressive cerebellar atrophy was also noted. Histone acetylation assays with purified variant KAT5 demonstrated that the variants decrease or abolish the ability of the resulting NuA4/TIP60 multi-subunit complexes to acetylate the histone H4 tail in chromatin. Transcriptomic analysis in affected individual fibroblasts showed deregulation of multiple genes that control development. Moreover, there was also upregulated expression of PER1 (a key gene involved in circadian control) in agreement with sleep anomalies in all of the individuals. In conclusion, dominant missense KAT5 variants cause histone acetylation deficiency with transcriptional dysregulation of multiples genes, thereby leading to a neurodevelopmental syndrome with sleep disturbance, cerebellar atrophy, and facial dysmorphisms, and suggesting a recognizable syndrome.

Published
2020

24. Clinical characteristics of patients from Quebec, Canada, with Morquio A syndrome: a longitudinal observational study

Author

David Iannuzzi, Bruno Maranda, Philippe M. Campeau, John J. Mitchell, and Lina Moisan

Subjects
medicine.medical_specialty, Canada, Mucopolysaccharidosis, Population, lcsh:Medicine, Physical examination, chemistry.chemical_compound, Elosulfase alfa, Internal medicine, medicine, Humans, Pharmacology (medical), Respiratory function, Medical history, Mucopolysaccharidosis IVA, education, Genetics (clinical), Retrospective Studies, education.field_of_study, medicine.diagnostic_test, business.industry, Research, lcsh:R, Quebec, Founder effects, Activities of daily living, Mucopolysaccharidosis IV, General Medicine, Enzyme replacement therapy, medicine.disease, Natural history, chemistry, Walk test, business, Genetic disorders
Abstract

Background Morquio A syndrome is a rare, autosomal recessive, progressively debilitating disorder, with multi-system impairments and high medical burden. Quebec, Canada has a large Morquio A population, which is considered unique due to the presence of founder pathogenic variants. The objectives of this study were to document the genetic and clinical heterogeneity of patients with Morquio A in Quebec, to better characterize the phenotype of those with the French Canadian founder pathogenic variant (NM_000512.5: c.1171A>G, p.Met391Val), and to describe the natural history of the patients treated with elosulfase alfa enzyme replacement therapy. Patients with Morquio A were genotyped for pathogenic variants in the lysosomal enzyme N-acetylgalactosamine-6-sulfatase. Clinical data were retrospectively collected from medical charts of patients and included medical history, height, physical examination, respiratory function tests, electrocardiogram, echocardiogram, endurance in the 6-min walk test (6MWT), and activities of daily living (ADL) as assessed by the Mucopolysaccharidosis Health Assessment Questionnaire (MPS-HAQ). Longitudinal data were collected retrospectively and prospectively for patients treated with elosulfase alfa. Results A total of 33 patients, aged 5–63 years, were included in the analysis. Patients with the founder pathogenic variant (n = 17) generally exhibited a non-classical form of Morquio A. As compared with patients with a non-founder pathogenic variant (n = 16), these patients were generally taller, had greater endurance and were better able to perform ADL. However, they still had significant musculoskeletal disease. Most of the 26 patients treated with elosulfase alfa, regardless of pathogenic variant, showed improvements in endurance and ADL. After 5 to 12 months of treatment, the mean improvement from baseline in the 6MWT was 23% and 10 of 14 patients improved in at least one MPS-HAQ domain. Endurance and ADL generally continued to improve or maintained stable in the long term (up to 7 years). Four out of 19 treated patients with echocardiogram data at follow-up showed progression of cardiac disease. Conclusions In Quebec, Canada, Morquio A frequently manifests as a non-classical form of the syndrome due to a founder effect. Patients treated with elosulfase alfa generally show long-term improvement or stability in endurance and function, regardless of pathogenic variant.

Published
2020

25. Early infantile epileptic encephalopathy due to biallelic pathogenic variants in <scp> PIGQ </scp> : Report of seven new subjects and review of the literature

Author

Rebecca C. Spillmann, Nissan V. Baratang, Kym M. Boycott, Karen W. Gripp, Taila Hartley, Anik St-Denis, Philippe M. Campeau, Kristin D. Kernohan, Erik A. Eklund, Jessica L. Zambonin, Loren D M Pena, Michael T. Geraghty, Andrew C. Edmondson, Jacek Majewski, Hugh J. McMillan, Allan Bayat, Miao He, Manuela Pendziwiat, Eric Bareke, Andrea Guerin, Thi Tuyet Mai Nguyen, Julie Richer, Devon L. Johnstone, and Hilde M. H. Braakman

Subjects
HYPERPHOSPHATASIA, Male, GLYCOSYLPHOSPHATIDYLINOSITOL, Disease, Immunoglobulin D, Fatal Outcome, 0302 clinical medicine, 1ST STEP, PIGQ, Child, Genetics (clinical), Exome sequencing, 0303 health sciences, biology, medicine.diagnostic_test, rare diseases, DEFECTS, Transfection, Phenotype, 3. Good health, epileptic encephalopathy, Child, Preschool, Muscle Hypotonia, Original Article, Female, medicine.symptom, Spasms, Infantile, DISORDERS, Mutation, Missense, Status epilepticus, Flow cytometry, 03 medical and health sciences, Seizures, Exome Sequencing, Genetics, medicine, Humans, BIOSYNTHESIS, Abnormalities, Multiple, IGD, Gene, 030304 developmental biology, MUTATIONS, business.industry, Infant, Newborn, Infant, Membrane Proteins, Original Articles, GENE, GPI, Immunology, biology.protein, business, exome sequencing, 030217 neurology & neurosurgery
Abstract

We investigated seven children from six families to expand the phenotypic spectrum associated with an early infantile epileptic encephalopathy caused by biallelic pathogenic variants in the phosphatidylinositol glycan anchor biosynthesis class Q (PIGQ) gene. The affected children were all identified by clinical or research exome sequencing. Clinical data, including EEGs and MRIs, was comprehensively reviewed and flow cytometry and transfection experiments were performed to investigate PIGQ function. Pathogenic biallelic PIGQ variants were associated with increased mortality. Epileptic seizures, axial hypotonia, developmental delay and multiple congenital anomalies were consistently observed. Seizure onset occurred between 2.5 months and 7 months of age and varied from treatable seizures to recurrent episodes of status epilepticus. Gastrointestinal issues were common and severe, two affected individuals had midgut volvulus requiring surgical correction. Cardiac anomalies including arrythmias were observed. Flow cytometry using granulocytes and fibroblasts from affected individuals showed reduced expression of glycosylphosphatidylinositol (GPI)‐anchored proteins. Transfection of wildtype PIGQ cDNA into patient fibroblasts rescued this phenotype. We expand the phenotypic spectrum of PIGQ‐related disease and provide the first functional evidence in human cells of defective GPI‐anchoring due to pathogenic variants in PIGQ.

Published
2020

26. Expression Pattern of the Pneumocystis jirovecii Major Surface Glycoprotein Superfamily in Patients with Pneumonia

Author

Emanuel Schmid-Siegert, Sophie Richard, Marco Pagni, Amanda Luraschi, Konrad Mühlethaler, and Philippe M. Hauser

Subjects
0301 basic medicine, Gene isoform, 030106 microbiology, Population, Pneumocystis carinii, Polymorphism, Single Nucleotide, Genome, Fungal Proteins, 03 medical and health sciences, Gene Expression Regulation, Fungal, Antigenic variation, Humans, Immunology and Allergy, Pneumocystis jirovecii, 610 Medicine & health, education, Gene, Genomic organization, Genetics, chemistry.chemical_classification, education.field_of_study, Membrane Glycoproteins, biology, Pneumonia, Pneumocystis, Genetic Variation, biology.organism_classification, 030104 developmental biology, Infectious Diseases, chemistry, Multigene Family, RNAseq, colonization factor, surface antigenic variation, virulence factor, Host-Pathogen Interactions, 570 Life sciences, Glycoprotein
Abstract

Background The human pathogen Pneumocystis jirovecii harbors 6 families of major surface glycoproteins (MSGs) encoded by a single gene superfamily. MSGs are presumably responsible for antigenic variation and adhesion to host cells. The genomic organization suggests that a single member of family I is expressed at a given time per cell, whereas members of the other families are simultaneously expressed. Methods We analyzed RNA sequences expressed in several clinical samples, using specific weighted profiles for sorting of reads and calling of single-nucleotide variants to estimate the diversity of the expressed genes. Results A number of different isoforms of at least 4 MSG families were expressed simultaneously, including isoforms of family I, for which confirmation was obtained in the wet laboratory. Conclusion These observations suggest that every single P. jirovecii population is made of individual cells with distinct surface properties. Our results enhance our understanding of the unique antigenic variation system and cell surface structure of P. jirovecii.

Published
2020

27. Complete response to talimogene laherparepvec in a primary acral lentiginous melanoma

Author

Alexander C.J. van Akkooi, Jacqueline E. van der Wal, Philippe M G Smeets, and Viola Franke

Subjects
0301 basic medicine, Cancer Research, medicine.medical_specialty, Skin Neoplasms, Herpesvirus 1, Human, Dermatology, medicine.disease_cause, Acral lentiginous melanoma, 03 medical and health sciences, 0302 clinical medicine, Pharmacotherapy, Humans, Medicine, Stage (cooking), Melanoma, Aged, 80 and over, Biological Products, business.industry, medicine.disease, Oncolytic virus, 030104 developmental biology, Herpes simplex virus, Lymphatic system, Oncology, 030220 oncology & carcinogenesis, Female, Talimogene laherparepvec, business
Abstract

Talimogene laherparepvec (T-VEC) is an oncolytic virus, approved for the treatment of stage IIIb-IVM1a melanoma with injectable disease (cutaneous, subcutaneous or lymphatic). It is a modified herpes simplex virus type 1 that induces tumor-specific T-cell responses via reduction of virally mediated suppression of antigen presentation, stimulation of viral pathogenicity and enhancement of tumor-selective replication. Response rates up to 82.6% have been reported for stage III disease. Acral lentiginous melanoma (ALM) is a rare subtype of melanoma with a poor prognosis. Here, we present a case of an elderly and frail patient with primary ALM who refused surgical treatment and consented to receive T-VEC as first-line drug therapy. After 10 courses of treatment, a histopathologically confirmed complete response was achieved. To our knowledge, this is the first case ever reported in which a primary ALM is (successfully) treated with T-VEC.

Published
2020

28. A second cohort of CHD3 patients expands the molecular mechanisms known to cause Snijders Blok-Campeau syndrome

Author

Ann Seman, Rixa Woitschach, Duygu Selcen, Divya Nair, Lauren Gunderson, Mahim Jain, Sha Tang, Giuseppe Zampino, Julien L. Marcadier, Marielle Alders, Jason Pinner, Melanie Napier, Linda Hasadsri, Marina Macchiaiolo, Alyssa Blesson, Pavel N. Pichurin, Joseph T. Alaimo, Arjan Bouman, Philippe M. Campeau, Catherine Karimov, Chitra Prasad, Anne Dieux-Coeslier, Nicole L. Bertsch, Bernd Wollnik, Janine Altmüller, Zöe Powis, Holly Dubbs, Tahsin Stefan Barakat, Gregory M. Cooper, Kristen J. Rasmussen, Perrine Brunelle, Patrick R. Blackburn, Erica D. Smith, Jeff M. Milunsky, Katja Kloth, E. Martina Bebin, Lot Snijders Blok, Knut Brockmann, Karin Weiss, Xilma R. Ortiz-Gonzalez, Danna Gal, Dong Li, Francesca Clementina Radio, Joan M. Stoler, Elaine H. Zackai, Jiddeke M. van de Kamp, Deepali N. Shinde, Huifang Yan, Thomas Smol, Alejandro Ferrer, Dagmar Weise, Baiba Lace, Deborah L. Renaud, Lauren E. Bartik, Beth Keena, Michelle L. Thompson, Carol J Saunders, Theodore G. Drivas, Elizabeth J. Bhoj, Eric T. Rush, Marco Tartaglia, Eric W. Klee, Margit Burmeister, Jingmin Wang, Jonas Denecke, Clinical genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Gastroenterology Endocrinology Metabolism, Human Genetics, ACS - Pulmonary hypertension & thrombosis, ARD - Amsterdam Reproduction and Development, and Clinical Genetics

Subjects
Adult, Male, CHD3 variants, Genetic testing, Adolescent, Snijders Blok-Campeau syndrome, Developmental Disabilities, medicine.disease_cause, Pediatrics, Article, Chromodomain, Craniofacial Abnormalities, Catalytic Domain, Intellectual Disability, Genetics, medicine, Missense mutation, Humans, Child, Genetics (clinical), Mutation, medicine.diagnostic_test, biology, Significant difference, DNA Helicases, Helicase, Infant, Syndrome, Autism spectrum disorders, Phenotype, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, Child, Preschool, Cohort, biology.protein, Female, Mi-2 Nucleosome Remodeling and Deacetylase Complex
Abstract

There has been one previous report of a cohort of patients with variants in Chromodomain Helicase DNA-binding 3 (CHD3), now recognized as Snijders Blok-Campeau syndrome. However, with only three previously-reported patients with variants outside the ATPase/helicase domain, it was unclear if variants outside of this domain caused a clinically similar phenotype. We have analyzed 24 new patients with CHD3 variants, including nine outside the ATPase/helicase domain. All patients were detected with unbiased molecular genetic methods. There is not a significant difference in the clinical or facial features of patients with variants in or outside this domain. These additional patients further expand the clinical and molecular data associated with CHD3 variants. Importantly we conclude that there is not a significant difference in the phenotypic features of patients with various molecular disruptions, including whole gene deletions and duplications, and missense variants outside the ATPase/helicase domain. This data will aid both clinical geneticists and molecular geneticists in the diagnosis of this emerging syndrome.

Published
2020

29. Loss of Oxidation Resistance 1, OXR1, Is Associated with an Autosomal-Recessive Neurological Disease with Cerebellar Atrophy and Lysosomal Dysfunction

Author

Caroline Nava, Justine Rousseau, Hugo J. Bellen, Yi Ting Cheng, Jiani Chen, Julia Wang, Philippe M. Campeau, Zhongyuan Zuo, Fowzan S. Alkuraya, Weimin Bi, Eissa Faqeih, Alexandra Afenjar, Lee-Jun C. Wong, Klaas J. Wierenga, Jill A. Rosenfeld, Jane Juusola, Joseph G. Gleeson, Sophie Ehresmann, Boris Keren, Diane Doummar, David Li-Kroeger, Ye Jin Park, Emily Kim, Markus Grompe, and Lita Duraine

Subjects
Adult, Male, 0301 basic medicine, Adolescent, Mutant, Biology, medicine.disease_cause, Article, Mitochondrial Proteins, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Cerebellar Diseases, Genetics, medicine, Animals, Humans, V-ATPase, Global developmental delay, Child, Gene, Genetics (clinical), Fibroblasts, Phenotype, Pedigree, Cell biology, Oxidative Stress, Drosophila melanogaster, 030104 developmental biology, Speech delay, Female, Cerebellar atrophy, Atrophy, Nervous System Diseases, medicine.symptom, Lysosomes, 030217 neurology & neurosurgery, Oxidative stress
Abstract

We report an early-onset autosomal-recessive neurological disease with cerebellar atrophy and lysosomal dysfunction. We identified bi-allelic loss-of-function (LoF) variants in Oxidative Resistance 1 (OXR1) in five individuals from three families; these individuals presented with a history of severe global developmental delay, current intellectual disability, language delay, cerebellar atrophy, and seizures. While OXR1 is known to play a role in oxidative stress resistance, its molecular functions are not well established. OXR1 contains three conserved domains: LysM, GRAM, and TLDc. The gene encodes at least six transcripts, including some that only consist of the C-terminal TLDc domain. We utilized Drosophila to assess the phenotypes associated with loss of mustard (mtd), the fly homolog of OXR1. Strong LoF mutants exhibit late pupal lethality or pupal eclosion defects. Interestingly, although mtd encodes 26 transcripts, severe LoF and null mutations can be rescued by a single short human OXR1 cDNA that only contains the TLDc domain. Similar rescue is observed with the TLDc domain of NCOA7, another human homolog of mtd. Loss of mtd in neurons leads to massive cell loss, early death, and an accumulation of aberrant lysosomal structures, similar to what we observe in fibroblasts of affected individuals. Our data indicate that mtd and OXR1 are required for proper lysosomal function; this is consistent with observations that NCOA7 is required for lysosomal acidification.

Published
2019

30. A variant of neonatal progeroid syndrome, or Wiedemann–Rautenstrauch syndrome, is associated with a nonsense variant in POLR3GL

Author

Sophie Ehresmann, Hyunyun Kim, Virginie Saillour, Smrithi Salian, Guylaine DʹAmours, Philippe M. Campeau, Julie Gauthier, Jean-François Soucy, Grant A. Mitchell, Eliane Beauregard-Lacroix, Geneviève Bernard, and Jacques L. Michaud

Subjects
media_common.quotation_subject, Nonsense, Biology, Article, Neonatal Progeroid Syndrome, 03 medical and health sciences, Progeria, 0302 clinical medicine, Protein Domains, Genetics, medicine, Humans, Allele, Gene, Genetics (clinical), Exome sequencing, 030304 developmental biology, media_common, 0303 health sciences, Fetal Growth Retardation, RNA Polymerase III, RNA, medicine.disease, Phenotype, 3. Good health, Codon, Nonsense, Child, Preschool, Female, Lipodystrophy, 030217 neurology & neurosurgery
Abstract

Neonatal progeroid syndrome, also known as Wiedemann–Rautenstrauch syndrome, is a rare condition characterized by severe growth retardation, apparent macrocephaly with prominent scalp veins, and lipodystrophy. It is caused by biallelic variants in POLR3A, a gene encoding for a subunit of RNA polymerase III. All variants reported in the literature lead to at least a partial loss-of-function (when considering both alleles together). Here, we describe an individual with several clinical features of neonatal progeroid syndrome in whom exome sequencing revealed a homozygous nonsense variant in POLR3GL (NM_032305.2:c.358C>T; p.(Arg120Ter)). POLR3GL also encodes a subunit of RNA polymerase III and has recently been associated with endosteal hyperostosis and oligodontia in three patients with a phenotype distinct from the patient described here. Given the important role of POLR3GL in the same complex as the protein implicated in neonatal progeroid syndrome, the nature of the variant identified, our RNA studies suggesting nonsense-mediated decay, and the clinical overlap, we propose POLR3GL as a gene causing a variant of neonatal progeroid syndrome and therefore expand the phenotype associated with POLR3GL variants.

Published
2019

31. Variable expressivity in a family with an aggrecanopathy

Author

Antoine Denis, Sami Chergui, Shuaa Basalom, Philippe M. Campeau, Chantal Janelle, and Thierry Pauyo

Subjects
Male, Heterozygote, Adolescent, Dwarfism, Original Articles, QH426-470, skeletal dysplasia, Osteochondritis Dissecans, chondrodysplasia, familial osteochondritis dissecans, Genetics, Humans, Original Article, Aggrecans, aggrecan, aggrecanopathy, cartilage, Molecular Biology, Intervertebral Disc Displacement, Genetics (clinical)
Abstract

Background Osteochondritis dissecans is a condition wherein there is a subchondral bone lesion that causes pain, inflammation, and cartilage damage. Dominant Familial Osteochondritis Dissecans is a rare and severe form of osteochondritis dissecans (OCD). It is caused by heterozygous pathogenic variants in the gene encoding Aggrecan; ACAN. Aggrecan, a proteoglycan, is an essential component of the articular and growth plate cartilage. Methods Herein, we report three individuals from one family; the proband who presented with short stature, a lower limb bone exostosis, and bilateral knee and elbow OCD at the age of 13 years old. His twin brother presented with isolated short stature and his father with short stature and lumbar disc herniation. Results Next‐generation sequencing of the ACAN gene in the proband identified a frameshift variant which is also present in the brother and father with short stature. The proband was treated surgically with bilateral elbow microfracture, after the failure of conservative therapy. Conclusion To the best of our knowledge, this is the first patient with an aggrecanopathy who presents with osteochondritis dissecans due to a frameshift variant. This family presents with variable expressivity which might be attributed to modifier genes., Dominant Familial Osteochondritis Dissecans is a rare and severe form of osteochondritis dissecans (OCD). It is caused by heterozygous pathogenic variants in the gene encoding Aggrecan; ACAN. Herein, we report 3 individuals from one family; the proband who presented with short stature, a lower limb bone exostosis, and bilateral knee and elbow OCD at the age of 13 years old. Next‐generation sequencing of the ACAN gene in the proband identified a frameshift deletion and this variant was also present in the brother and father with short stature. To the best of our knowledge, this is the first patient with an aggrecanopathy who presents with osteochondritis dissecans due to a frameshift mutation.

Published
2021

32. Correction to: Establishing a core outcome set for mucopolysaccharidoses (MPS) in children: study protocol for a rapid literature review, candidate outcomes survey, and Delphi surveys

Author

Alison H. Howie, Kylie Tingley, Michal Inbar-Feigenberg, John J. Mitchell, Nancy J. Butcher, Martin Offringa, Maureen Smith, Kim Angel, Jenifer Gentle, Alexandra Wyatt, Philippe M. Campeau, Alicia Chan, Pranesh Chakraborty, Farah El Turk, Eva Mamak, Aizeddin Mhanni, Becky Skidmore, Rebecca Sparkes, Sylvia Stockler, Beth K. Potter, and in collaboration with the INFORM RARE Network

Subjects
Medicine (General), Canada, Delphi Technique, Correction, Medicine (miscellaneous), Mucopolysaccharidoses, Review Literature as Topic, R5-920, Treatment Outcome, Research Design, Outcome Assessment, Health Care, Quality of Life, Humans, Pharmacology (medical), Child
Abstract

Mucopolysaccharidoses (MPS) are a group of inherited metabolic diseases characterized by chronic, progressive multi-system manifestations with varying degrees of severity. Disease-modifying therapies exist to treat some types of MPS; however, they are not curative, underscoring the need to identify and evaluate co-interventions that optimize functioning, participation in preferred activities, and quality of life. A Canadian pediatric MPS registry is under development and may serve as a platform to launch randomized controlled trials to evaluate such interventions. To promote the standardized collection of patient/family-reported and clinical outcomes considered important to patients/families, health care providers (HCPs), and policymakers, the choice of outcomes to include in the registry will be informed by a core outcome set (COS). We aim to establish a patient-oriented COS for pediatric MPS using a multi-stakeholder approach.In step 1 of the six-step process to develop the COS, we will identify relevant outcomes through a rapid literature review and candidate outcomes survey. A two-phase screening approach will be implemented to identify eligible publications, followed by extraction of outcomes and other pre-specified data elements. Simultaneously, we will conduct a candidate outcomes survey with children with MPS and their families to identify outcomes most important to them. In step 2, HCPs experienced in treating patients with MPS will be invited to review the list of outcomes generated in step 1 and identify additional clinically relevant outcomes. We will then ask patients/families, HCPs, and policymakers to rate the outcomes in a set of Delphi Surveys (step 3), and to participate in a subsequent consensus meeting to finalize the COS (step 4). Step 5 involves establishing a set of outcome measurement instruments for the COS. Finally, we will disseminate the COS to knowledge users (step 6).The proposed COS will inform the choice of outcomes to include in the MPS registry and, more broadly, promote the standardized collection of patient-oriented outcomes for pediatric MPS research. By involving patients/families from the earliest stage of the research, we will ensure that the COS will be relevant to those who will ultimately benefit from the research.PROSPERO CRD42021267531 , COMET.

Published
2021

33. Endograft apposition and infrarenal neck enlargement after endovascular aortic aneurysm repair

Author

Nada Y. Elzefzaf, Philippe M. de Rooy, Claire van der Riet, Rogier H.J. Kropman, Ranjeet Narlawar, Jan Wille, George A. Antoniou, Ignace F.J. Tielliu, Jean-Paul P.M. de Vries, Richte C.L. Schuurmann, Multi-Modality Medical Imaging, TechMed Centre, and ​Robotics and image-guided minimally-invasive surgery (ROBOTICS)

Subjects
Time Factors, Computed Tomography Angiography, medicine.medical_treatment, Prosthesis Design, Endovascular aneurysm repair, Aortography, Neck enlargement, Blood Vessel Prosthesis Implantation, Interquartile range, Predictive Value of Tests, medicine.artery, Multidetector Computed Tomography, medicine, Humans, Aorta, Abdominal, Renal artery, Abdominal, imaging, Neck diameter, Computed tomography angiography, Retrospective Studies, Three-dimensional, stents, Aortic aneurysm repair, Aortic aneurysm, medicine.diagnostic_test, business.industry, Endovascular Procedures, General Medicine, Blood Vessel Prosthesis, Apposition, Treatment Outcome, Surgery, Cardiology and Cardiovascular Medicine, Nuclear medicine, business, Aortic Aneurysm, Abdominal
Abstract

BACKGROUND: Sufficient apposition and oversizing of the endograft in the aortic neck are both essential for durable endovascular aneurysm repair (EVAR). These measures are however not regularly stated on post-EVAR computed tomography angiography (CTA) scan reports. In this study endograft apposition and neck enlargement (NE) after EVAR with an Endurant II(s) endograft were analyzed and associated with supra- and infrarenal aortic neck morphology.METHODS: In 97 consecutive elective patients, the aortic neck morphology was measured on the pre-EVAR CTA scan on a 3mensio vascular workstation. The distance between the lowest renal artery and the proximal edge of the fabric (shortest fabric distance, SFD), and the shortest length of circumferential apposition between endograft and aortic wall (shortest apposition length, SAL) was determined on the early post-EVAR CTA scan. NE, defined as the aortic diameter change between pre- and post-EVAR CTA scan, was determined at eight levels: +40, +30, +20, +15, +10, 0, -5 and -10 mm relative to the lowest renal artery baseline. The aortic neck diameter and preoperative oversizing were correlated to NE with the Pearson correlation coefficient. The effective post-EVAR endograft oversizing is calculated from the nominal endograft diameter and the post-EVAR neck diameter where the endograft is circumferentially apposed.RESULTS: The median time (interquartile range, IQR) between the EVAR procedure and the pre- and post-EVAR CTA scan was 40 (25, 71) days and 36 (30, 46) days, respectively. The Endurant II(s) endograft was deployed with a median (IQR) SFD of 1.0 (0.0, 3.0) mm. The SAL was CONCLUSIONS: Circumferential apposition between an endograft and the infrarenal aortic neck, SAL, and NE can be derived from standard postoperative CT scans. These variables provide essential information about the post-procedural endograft and aortic neck morphology regardless of the preoperative measurements. Patients with SAL

Published
2021

34. International Consensus Statement on the diagnosis, multidisciplinary management and lifelong care of individuals with achondroplasia

Author

Virginia Fano, Martyn T. Cobourne, Patricia Carl-Innig, Michael B. Bober, Melita Irving, Fabio Mazzoleni, Jeffrey W. Campbell, Brigitte Fauroux, Dominic Thompson, Judith P Rossiter, Jenna W. Briddell, Yosha Prasad, Mary C. Theroux, Geert Mortier, Antonio Leiva-Gea, Amaka C. Offiah, Klaus Mohnike, Penny Ireland, James A. Betts, Juan Llerena, Steven Powell, Heather Elphick, Pablo Rosselli, Wagner A.R. Baratela, Therese Hannon, Kenneth W. Martin, Marco Sessa, Natsuo Yasui, Michael Wright, Moira Cheung, Matthew Thomas, Inês Alves, Jonathan Gibbins, Cathleen L. Raggio, Muriel Deladure-Molla, Angelo Selicorni, Lars Hagenäs, Sharon McDonnell, William G. Mackenzie, Morrys Kaisermann, Maria Costanza Meazzini, Svein O. Fredwall, Laura Trespedi, Ravi Savarirayan, Philippe M. Campeau, Mari L. Groves, Valérie Cormier-Daire, Keiichi Ozono, Julie Hoover-Fong, David E. Tunkel, John A. Phillips, Josef Milerad, Silvio Boero, C Wallis, and Mariana del Pino

Subjects
musculoskeletal diseases, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Consensus, Statement (logic), Endocrinology, Diabetes and Metabolism, MEDLINE, Achondroplasia, Endocrinology, Quality of life (healthcare), SDG 3 - Good Health and Well-being, Multidisciplinary approach, Osteogenesis, Medicine, Humans, Receptor, Fibroblast Growth Factor, Type 3, Intensive care medicine, business.industry, medicine.disease, Life stage, Optimal management, Mutation, Quality of Life, Human medicine, business, Psychosocial
Abstract

Achondroplasia, the most common skeletal dysplasia, is characterized by a variety of medical, functional and psychosocial challenges across the lifespan. The condition is caused by a common, recurring, gain-of-function mutation in FGFR3, the gene that encodes fibroblast growth factor receptor 3. This mutation leads to impaired endochondral ossification of the human skeleton. The clinical and radiographic hallmarks of achondroplasia make accurate diagnosis possible in most patients. However, marked variability exists in the clinical care pathways and protocols practised by clinicians who manage children and adults with this condition. A group of 55 international experts from 16 countries and 5 continents have developed consensus statements and recommendations that aim to capture the key challenges and optimal management of achondroplasia across each major life stage and sub-specialty area, using a modified Delphi process. The primary purpose of this first International Consensus Statement is to facilitate the improvement and standardization of care for children and adults with achondroplasia worldwide in order to optimize their clinical outcomes and quality of life. Achondroplasia is the most common skeletal dysplasia and is characterized by various lifelong clinical, functional and psychosocial challenges for affected individuals. This first International Consensus Statement on the care of children and adults with achondroplasia aims to facilitate the global standardization and improvement of achondroplasia clinical care.

Published
2021

35. C18orf32 loss-of-function is associated with a neurodevelopmental disorder with hypotonia and contractures

Author

Smrithi Salian, Xin-Yu Guo, Yoshiko Murakami, Taroh Kinoshita, Parneet Kaur, Anju Shukla, Katta M. Girisha, Morihisa Fujita, and Philippe M. Campeau

Subjects
Contracture, HEK293 Cells, Glycosylphosphatidylinositols, Neurodevelopmental Disorders, Genetics, Humans, Muscle Hypotonia, Nervous System Malformations, Genetics (clinical)
Abstract

Glycosylphosphatidylinositol (GPI) functions to anchor certain proteins to the cell surface. Although defects in GPI biosynthesis can result in a wide range of phenotypes, most affected patients present with neurological abnormalities and their diseases are grouped as inherited-GPI deficiency disorders. We present two siblings with global developmental delay, brain anomalies, hypotonia, and contractures. Exome sequencing revealed a homozygous variant, NM_001035005.4:c.90dupC (p.Phe31Leufs*3) in C18orf32, a gene not previously associated with any disease in humans. The encoded protein is known to be important for GPI-inositol deacylation. Knockout of C18orf32 in HEK293 cells followed by a transfection rescue assay revealed that the PIPLC (Phosphatidylinositol-Specific Phospholipase C) sensitivity of GPI-APs (GPI-anchored proteins) was restored only by the wild type and not the mutant C18orf32. Immunofluorescence revealed that the mutant C18orf32 was localized to the endoplasmic reticulum and was also found as aggregates in the nucleus. In conclusion, we identified a pathogenic variant in C18orf32 as the cause of a novel autosomal recessive neurodevelopmental disorder with hypotonia and contractures. Our results demonstrate the importance of C18orf32 in the biosynthesis of GPI-anchors, the molecular impact of the variant on the protein function, and add a novel candidate gene to the existing repertoire of genes implicated in neurodevelopmental disorders.

Published
2021

36. Genome-wide analysis of blood lipid metabolites in over 5000 South Asians reveals biological insights at cardiometabolic disease loci

Author

Zoubia Hina, Julian L. Griffin, Asif Rasheed, Nadeem Qamar, Danish Saleheen, Dirk S. Paul, Imran Saleem, Taniya Sattar, M. Ishaq, Nadeem Hayat Mallick, Adam S. Butterworth, Philippe M. Frossard, Daniel Ziemek, Fazal-ur-Rehman Memon, Syed Nadeem Hasan Rizvi, Albert Koulman, Anjum Jalal, Tahir Saghir, John Danesh, Angela M. Wood, David Stacey, Eric B. Fauman, Unzila Ishtiaq, Anis Memon, Rachel M. Y. Ong, Eric L. Harshfield, Shahid Abbas, Zameer-ul-Asar, Zia Yaqub, Syed Zahed Rasheed, Harshfield, Eric [0000-0001-8767-0928], Paul, Dirk [0000-0002-8230-0116], Danesh, John [0000-0003-1158-6791], Butterworth, Adam [0000-0002-6915-9015], Wood, Angela [0000-0002-7937-304X], Koulman, Albert [0000-0001-9998-051X], Apollo - University of Cambridge Repository, and Paul, Dirk S [0000-0002-8230-0116]

Subjects
South asia, Population, Myocardial Infarction, Blood lipids, Disease, Gaussian Graphical Modelling, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, 0302 clinical medicine, Asian People, Lipidomics, Genetics, Medicine, South Asian, Humans, Genetic Predisposition to Disease, education, Gene, 030304 developmental biology, 0303 health sciences, education.field_of_study, business.industry, General Medicine, Lipidome, Lipids, Genetic architecture, 3. Good health, Network analysis, business, 030217 neurology & neurosurgery, Research Article, Genome-Wide Association Study
Abstract

Background Genetic, lifestyle, and environmental factors can lead to perturbations in circulating lipid levels and increase the risk of cardiovascular and metabolic diseases. However, how changes in individual lipid species contribute to disease risk is often unclear. Moreover, little is known about the role of lipids on cardiovascular disease in Pakistan, a population historically underrepresented in cardiovascular studies. Methods We characterised the genetic architecture of the human blood lipidome in 5662 hospital controls from the Pakistan Risk of Myocardial Infarction Study (PROMIS) and 13,814 healthy British blood donors from the INTERVAL study. We applied a candidate causal gene prioritisation tool to link the genetic variants associated with each lipid to the most likely causal genes, and Gaussian Graphical Modelling network analysis to identify and illustrate relationships between lipids and genetic loci. Results We identified 253 genetic associations with 181 lipids measured using direct infusion high-resolution mass spectrometry in PROMIS, and 502 genetic associations with 244 lipids in INTERVAL. Our analyses revealed new biological insights at genetic loci associated with cardiometabolic diseases, including novel lipid associations at the LPL, MBOAT7, LIPC, APOE-C1-C2-C4, SGPP1, and SPTLC3 loci. Conclusions Our findings, generated using a distinctive lipidomics platform in an understudied South Asian population, strengthen and expand the knowledge base of the genetic determinants of lipids and their association with cardiometabolic disease-related loci.

Published
2021

37. 'What Really Matters When Performing a Laparoscopic Roux-en Y Gastric Bypass?' Literature-Based Key Steps Towards Success and Standardization of the Procedure

Author

Jean-Philippe M. M. K. Magema, Jacques Himpens, UCL - SSS/IREC/MONT - Pôle Mont Godinne, and UCL - (MGD) Service de chirurgie

Subjects
Gastric bypass, Nutrition and Dietetics, Standardization, Gastroplasty, business.industry, Endocrinology, Diabetes and Metabolism, Gastric Bypass, Literature based, Reference Standards, Limb length, Roux-en-Y anastomosis, Obesity, Morbid, Treatment Outcome, Key steps, Weight regain, Key (cryptography), Medicine, Humans, Surgery, Operations management, Laparoscopy, business
Abstract

Lack of standardization in the Roux-en-Y gastric bypass (RY-GBP) is quite well established. We all learned the basics of the technique, but a lot of differences do exist in performing each step of the procedure. Based on scientific evidences, coming from an extensive and meticulous review of the literature of the last 20 years, we thus address the different technical steps of the procedure and their importance to try and propose a standardization of RYGBP. A lot of possibilities exist at each and every step of a RYGBP. They influence the postoperative complications, the end weight loss (EWL), weight regain, and resolution of obesity bounded comorbidities. Furthermore, lack of standardization leads to problems regarding comparison of scientific data in the related literature.

Published
2021

38. [Classification and treatment of modern traumatic meniscal tears]

Author

Filippo, Calanna, Victoria, Duthon, Philippe M, Tscholl, and Jacques, Menetrey

Subjects
Arthroscopy, Humans, Knee Injuries, Cartilage Diseases, Menisci, Tibial, Tibial Meniscus Injuries
Abstract

The menisci have several important biomechanical functions. Traumatic meniscal injuries present a wide spectrum of presentation and several types of lesions. They can concern the body of the meniscus and its fixation. An easy and clear classification of traumatic meniscus tears is essential for helping the physicians to achieve the correct surgical indication and the accurate postoperative rehabilitation protocol. The aim of this current concept review is to clearly describe some classical as well new type of meniscal and menisco-synovial lesions such as ramp lesions, root tears and instability of the lateral meniscus associated to rotational laxity. The goal is to focus on the definition, diagnosis, classification, giving some guidelines and discussing the different rehabilitation protocols.Les ménisques sont essentiels au fonctionnement biomécanique du genou. Les lésions méniscales traumatiques peuvent se manifester par des tableaux cliniques très variés et concerner le corps du ménisque, ses attaches à l’os ou à la capsule articulaire. Une classification simple et claire des déchirures méniscales traumatiques est indispensable. Cette revue de la littérature contemporaine fait un tableau précis des lésions méniscales traumatiques classiques et « nouvelles » telles que celles de la rampe, les avulsions de la racine méniscale et l’instabilité du ménisque externe associée à une laxité rotatoire du genou, en se focalisant sur la définition de chacune de ces déchirures, leur diagnostic, leur classification, afin de proposer des directives de traitement et de rééducation.

Published
2021

39. [Should allografts become gold-standard in ligamentous knee surgery ?]

Author

Philippe M, Tscholl, Jacques, Menetrey, and Morgan, Gauthier

Subjects
Rupture, Knee Joint, Humans, Transplantation, Homologous, Plastic Surgery Procedures, Allografts
Abstract

Allografts in reconstructive knee surgery are an interesting option, due to the absence of donor site morbidity, its rather easy intraoperative handling, the different sizes, shorter surgical time, and therefore less peroperative risks. The risk of infection is very low. Their results are similar when non-irradiated and non-sterilized allografts are used in terms of postoperative strength, return to sport, and comparable stability testing. Nevertheless, allografts have not yet become current practice, due to the costs, the availability, its structural integration and ligamentisation process that might be prolonged and its increased re-rupture rate in the young and active population. Its undeniable value for multiligamentous or complexe knee reconstruction is however undeniable, which should however be reserved for specialized centers.L’allogreffe dans la chirurgie ligamentaire du genou semble être une option intéressante au vu de l’absence de site de prélèvement, d’une facilité d’utilisation, d’un choix des propriétés, d’une durée chirurgicale raccourcie et donc de risques peropératoires diminués. Le risque de transmission infectieuse est très faible. Ses résultats sont comparables à la chirurgie par autogreffe uniquement si non irradiée et non stérilisée en termes de force, retour au sport, et comparables ou légèrement inférieurs en termes de stabilité. Les allogreffes ne sont pas devenues pratiques courantes, en raison des coûts, de la disponibilité, d’une intégration, d’une transformation biologique prolongée et du taux de reruptures plus élevé chez les jeunes patients actifs. Les allogreffes sont par contre indispensables pour les reconstructions multiligamentaires et des révisions complexes.

Published
2021

40. Identifying associations between diabetes and acute respiratory distress syndrome in patients with acute hypoxemic respiratory failure: an analysis of the LUNG SAFE database

Author

Boyle A. J., Madotto F., Laffey J. G., Bellani G., Pham T., Pesenti A., Thompson B. T., O'Kane C. M., Deane A. M., McAuley D. F, Rios F, Van Haren F, Faruq MO, Sottiaux T, Depuydt P, Lora FS, Azevedo LC, Fan E, Bugedo G, Qiu H, Gonzalez M, Silesky J, Cerny V, Nielsen J, Jibaja M, Pham T, Wrigge H, Matamis D, Ranero JL, Gomersall C, Amin P, Hashemian SM, Clarkson K, Bellani G, Kurahashi K, Koh Y, Villagomez A, Zeggwagh AA, Heunks LM, Laake JH, Kashif W, Synclair J, Palo JE, do Vale Fernandes A, Sandesc D, Arabi Y, Bumbasierevic V, Nin N, Lorente JA, Larsson A, Piquilloud L, Patjanasoontorn B, Abroug F, McAuley DF, McNamee L, Hurtado J, Bajwa E, Démpaire G, Francois GM, Rabboni F, Conti S, Sula H, Cani A, Zazu A, Dellera C, Alejandro RV, Daldin J, Fernandez RO, Cardonnet LP, Bettini LR, Bisso MC, Osman EM, Setten MG, Lovazzano P, Alvarez J, Villar V, Pozo NC, Grubissich N, Plotnikow GA, Vasquez DN, Ilutovich S, Tiribelli N, Chena A, Pellegrini CA, Saenz MG, Estenssoro E, Brizuela M, Gianinetto H, Gomez PE, Cerrato VI, Bezzi MG, Borello SA, Loiacono FA, Fernandez AM, Knowles S, Reynolds C, Inskip DM, Miller JJ, Kong J, Whitehead C, Bihari S, Seven A, Krstevski A, Rodgers HJ, Millar RT, Mckenna TE, Bailey IM, Hanlon GC, Aneman A, Lynch JM, Azad R, Neal J, Woods PW, Roberts BL, Kol MR, Wong HS, Riss KC, Staudinger T, Wittebole X, Bulpa PA, Dive AM, Verstraete R, Lebbinck H, Vermassen J, Philippe M, Ceunen H, Rosa JI, Beraldo DO, Piras C, Rampinelli AM, Nassar AP Jr, Mataloun S, Moock M, Thompson MM, Gonçalves CH, Antônio ACP, Ascoli A, Biondi RS, Fontenele DC, Nobrega D, Sales VM, Shindhe S, Pg Hj Ismail DMAB, Laffey J, Beloncle F, Davies KG, Cirone R, Manoharan V, Ismail M, Goligher EC, Jassal M, Ferguson ND, Nishikawa E, Javeed A, Curley G, Rittayamai N, Parotto M, Mehta S, Knoll J, Pronovost A, Bruhn SCAR, Garcia PH, Aliaga FA, Farías PA, Yumha JS, Ortiz CA, Salas JE, Saez AA, Vega LD, Labarca EF, Martinez FT, Carreño NG, Lora P, Liu H, Liu L, Tang R, Luo X, An Y, Zhao H, Gao Y, Zhai Z, Ye ZL, Wang W, Li W, Li Q, Zheng R, Yu W, Shen J, Li X, Yu T, Lu W, Wu YQ, Huang XB, He Z, Lu Y, Han H, Zhang F, Sun R, Wang HX, Qin SH, Zhu BH, Zhao J, Liu J, Li B, Liu JL, Zhou FC, Li QJ, Zhang XY, Li-Xin Z, Xin-Hua Q, Jiang L, Gao YN, Zhao XY, Li YY, Li XL, Wang C, Yao Q, Yu R, Chen K, Shao H, Qin B, Huang QQ, Zhu WH, Hang AY, Hua MX, Li Y, Xu Y, Di YD, Ling LL, Qin TH, Wang SH, Qin J, Han Y, Zhou S, Vargas MP, Silesky Jimenez JI, González Rojas MA, Solis-Quesada JE, Ramirez-Alfaro CM, Máca J, Sklienka P, Gjedsted J, Christiansen A, Rigshopitalet, Villamagua BG, Llano M, Burtin P, Buzancais G, Beuret P, Pelletier N, Mortaza S, Mercat A, Chelly J, Jochmans S, Terzi N, Daubin C, Carteaux G, de Prost N, Chiche JD, Daviaud F, Fartoukh M, Barberet G, Biehler J, Dellamonica J, Doyen D, Arnal JM, Briquet A, Klasen F, Papazian L, Follin A, Roux D, Messika J, Kalaitzis E, Dangers L, Combes A, Au SM, Béduneau G, Carpentier D, Zogheib EH, Dupont H, Ricome S, Santoli FL, Besset SL, Michel P, Gelée B, Danin PE, Goubaux B, Crova PJ, Phan NT, Berkelmans F, Badie JC, Tapponnier R, Gally J, Khebbeb S, Herbrecht JE, Schneider F, Declercq PM, Rigaud JP, Duranteau J, Harrois A, Chabanne R, Marin J, Constantin JM, Thibault S, Ghazi M, Boukhazna M, Zein SO, Richecoeur JR, Combaux DM, Grelon F, Le Moal C, Sauvadet EP, Robine A, Lemiale V, Reuter D, Dres M, Demoule A, Goldgran-Toledano D, Baboi L, Guérin C, Lohner R, Kraßler J, Schäfer S, Zacharowski KD, Meybohm P, Reske AW, Simon P, Hopf HF, Schuetz M, Baltus T, Papanikolaou MN, Papavasilopoulou TG, Zacharas GA, Ourailogloy V, Mouloudi EK, Massa EV, Nagy EO, Stamou EE, Kiourtzieva EV, Oikonomou MA, Avila LE, Cortez CA, Citalán JE, Jog SA, Sable SD, Shah B, Gurjar M, Baronia AK, Memon M, Muthuchellappan R, Ramesh VJ, Shenoy A, Unnikrishnan R, Dixit SB, Rhayakar RV, Ramakrishnan N, Bhardwaj VK, Mahto HL, Sagar SV, Palaniswamy V, Ganesan D, Jamaati H, Heidari F, Meaney EA, Nichol A, Knapman KM, O'Croinin D, Dunne ES, Breen DM, Clarkson KP, Jaafar RF, Dwyer R, Amir F, Ajetunmobi OO, O'Muircheartaigh AC, Black CS, Treanor N, Collins DV, Altaf W, Zani G, Fusari M, Spadaro S, Volta CA, Graziani R, Brunettini B, Palmese S, Formenti P, Umbrello M, Lombardo A, Pecci E, Botteri M, Savioli M, Protti A, Mattei A, Schiavoni L, Tinnirello A, Todeschini M, Giarratano A, Cortegiani A, Sher S, Rossi A, Antonelli MM, Montini LM, Casalena P, Scafetti S, Panarello G, Occhipinti G, Patroniti N, Pozzi M, Biscione RR, Poli MM, Raimondi F, Albiero D, Crapelli G, Beck E, Pota V, Schiavone V, Molin A, Tarantino F, Monti G, Frati E, Mirabella L, Cinnella G, Fossali T, Colombo R, Pattarino PTI, Mojoli F, Braschi A, Borotto EE, Cracchiolo AN, Palma DM, Raponi F, Foti G, Vascotto ER, Coppadoro A, Brazzi L, Floris L, Iotti GA, Venti A, Yamaguchi O, Takagi S, Maeyama HN, Watanabe E, Yamaji Y, Shimizu K, Shiozaki K, Futami S, Ryosuke S, Saito K, Kameyama Y, Ueno K, Izawa M, Okuda N, Suzuki H, Harasawa T, Nasu M, Takada T, Ito F, Nunomiya S, Koyama K, Abe T, Andoh K, Kusumoto K, Hirata A, Takaba A, Kimura H, Matsumoto S, Higashijima U, Honda H, Aoki N, 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O., Leemann-Refondini, C., Elatrous, S., Bouchoucha, S., Chouchene, I., Ouanes, I., Souissi, A. B., Kamoun, S., Demirkiran, O., Aker, M., Erbabacan, E., Ceylan, I., Girgin, N. K., Ozcelik, M., Unal, N., Meco, B. C., Akyol, O. O., Derman, S. S., Kennedy, B., Parhar, K., Srinivasa, L., Hopkins, P., Mellis, C., Kakar, V., Hadfield, D., Vercueil, A., Bhowmick, K., Humphreys, S. K., Ferguson, A., Mckee, R., Raj, A. S., Fawkes, D. A., Watt, P., Twohey, L., JhaMatthew Thomas, R. R., Morton, A., Kadaba, V., Smith, M. J., Hormis, A. P., Kannan, S. G., Namih, M., Reschreiter, H., Camsooksai, J., Kumar, A., Rugonfalvi, S., Nutt, C., Oneill, O., Seasman, C., Dempsey, G., Scott, C. J., Ellis, H. E., Mckechnie, S., Hutton, P. J., Di Tomasso, N. N., Vitale, M. N., Griffin, R. O., Dean, M. N., Cranshaw, J. H., Willett, E. L., Ioannou, N., Gillis, S., Csabi, P., Macfadyen, R., Dawson, H., Preez, P. D., Williams, A. J., Boyd, O., De Gordoa, L. O., Bramall, J., Symmonds, S., Chau, S. K., Wenham, T., Szakmany, T., Toth-Tarsoly, P., Mccalman, K. H., Alexander, P., Stephenson, L., Collyer, T., Chapman, R., Cooper, R., Allan, R. M., Sim, M., Wrathall, D. W., Irvine, D. A., Zantua, K. S., Adams, J. C., Burtenshaw, A. J., Sellors, G. P., Welters, I. D., Williams, K. E., Hessell, R. J., Oldroyd, M. G., Battle, C. E., Pillai, S., Kajtor, I., Sivashanmugavel, M., Okane, S. C., Donnelly, A., Frigyik, A. D., Careless, J. P., May, M. M., Stewart, R., John Trinder, T., Hagan, S. J., Wise, M. P., Cole, J. M., Macfie, C. C., Dowling, A. T., Nunez, E., Pittini, G., Rodriguez, R., Imperio, M. C., Santos, C., Franca, A. G., Ebeid, A., Deicas, A., Serra, C., Uppalapati, A., Kamel, G., Banner-Goodspeed, V. M., Beitler, J. R., Mukkera, S. R., Kulkarni, S., Lee, J., Mesar, T., Shinn Iii, J. O., Gomaa, D., Tainter, C., Yeatts, D. J., Warren, J., Lanspa, M. J., Miller, R. R., Grissom, C. K., Brown, S. M., Bauer, P. R., Gosselin, R. J., Kitch, B. T., Cohen, J. E., Beegle, S. H., Gueret, R. M., Tulaimat, A., Choudry, S., Stigler, W., Batra, H., Huff, N. G., Lamb, K. D., Oetting, T. W., Mohr, N. M., Judy, C., Saito, S., Kheir, F. M., Kheir, F., Schlichting, A. B., Delsing, A., Crouch, D. R., Elmasri, M., Ismail, D., Dreyer, K. R., Blakeman, T. C., Baron, R. M., Grijalba, C. Q., Hou, P. C., Seethala, R., Aisiku, I., Henderson, G., Frendl, G., Hou, S. K., Owens, R. L., Schomer, A., Bumbasirevic, V., Jovanovic, B., Surbatovic, M., Veljovic, M., Boyle, A, Madotto, F, Laffey, J, Bellani, G, Pham, T, Pesenti, A, Thompson, B, O'Kane, C, Deane, A, Mcauley, D, Conti, S, Boyle A.J., Madotto F., Laffey J.G., Bellani G., Pham T., Pesenti A., Thompson B.T., O'Kane C.M., Deane A.M., McAuley D.F, Rios F, Van Haren F, Faruq MO, Sottiaux T, Depuydt P, Lora FS, Azevedo LC, Fan E, Bugedo G, Qiu H, Gonzalez M, Silesky J, Cerny V, Nielsen J, Jibaja M, Pham T, Wrigge H, Matamis D, Ranero JL, Gomersall C, Amin P, Hashemian SM, Clarkson K, Bellani G, Kurahashi K, Koh Y, Villagomez A, Zeggwagh AA, Heunks LM, Laake JH, Kashif W, Synclair J, Palo JE, do Vale Fernandes A, Sandesc D, Arabi Y, Bumbasierevic V, Nin N, Lorente JA, Larsson A, Piquilloud L, Patjanasoontorn B, Abroug F, McAuley DF, McNamee L, Hurtado J, Bajwa E, Démpaire G, Francois GM, Rabboni F, Conti S, Sula H, Cani A, Zazu A, Dellera C, Alejandro RV, Daldin J, Fernandez RO, Cardonnet LP, Bettini LR, Bisso MC, Osman EM, Setten MG, Lovazzano P, Alvarez J, Villar V, Pozo NC, Grubissich N, Plotnikow GA, Vasquez DN, Ilutovich S, Tiribelli N, Chena A, Pellegrini CA, Saenz MG, Estenssoro E, Brizuela M, Gianinetto H, Gomez PE, Cerrato VI, Bezzi MG, Borello SA, Loiacono FA, Fernandez AM, Knowles S, Reynolds C, Inskip DM, Miller JJ, Kong J, Whitehead C, Bihari S, Seven A, Krstevski A, Rodgers HJ, Millar RT, Mckenna TE, Bailey IM, Hanlon GC, Aneman A, Lynch JM, Azad R, Neal J, Woods PW, Roberts BL, Kol MR, Wong HS, Riss KC, Staudinger T, Wittebole X, Bulpa PA, Dive AM, Verstraete R, Lebbinck H, Depuydt P, Vermassen J, Philippe M, Ceunen H, Rosa JI, Beraldo DO, Piras C, Rampinelli AM, Nassar AP Jr, Mataloun S, Moock M, Thompson MM, Gonçalves CH, Antônio ACP, Ascoli A, Biondi RS, Fontenele DC, Nobrega D, Sales VM, Shindhe S, Pg Hj Ismail DMAB, Laffey J, Beloncle F, Davies KG, Cirone R, Manoharan V, Ismail M, Goligher EC, Jassal M, Ferguson ND, Nishikawa E, Javeed A, Curley G, Rittayamai N, Parotto M, Mehta S, Knoll J, Pronovost A, Bruhn SCAR, Garcia PH, Aliaga FA, Farías PA, Yumha JS, Ortiz CA, Salas JE, Saez AA, Vega LD, Labarca EF, Martinez FT, Carreño NG, Lora P, Liu H, Qiu H, Liu L, Tang R, Luo X, An Y, Zhao H, Gao Y, Zhai Z, Ye ZL, Wang W, Li W, Li Q, Zheng R, Yu W, Shen J, Li X, Yu T, Lu W, Wu YQ, Huang XB, He Z, Lu Y, Han H, Zhang F, Sun R, Wang HX, Qin SH, Zhu BH, Zhao J, Liu J, Li B, Liu JL, Zhou FC, Li QJ, Zhang XY, Li-Xin Z, Xin-Hua Q, Jiang L, Gao YN, Zhao XY, Li YY, Li XL, Wang C, Yao Q, Yu R, Chen K, Shao H, Qin B, Huang QQ, Zhu WH, Hang AY, Hua MX, Li Y, Xu Y, Di YD, Ling LL, Qin TH, Wang SH, Qin J, Han Y, Zhou S, Vargas MP, Silesky Jimenez JI, González Rojas MA, Solis-Quesada JE, Ramirez-Alfaro CM, Máca J, Sklienka P, Gjedsted J, Christiansen A, Rigshopitalet, Nielsen J, Villamagua BG, Llano M, Burtin P, Buzancais G, Beuret P, Pelletier N, Mortaza S, Mercat A, Chelly J, Jochmans S, Terzi N, Daubin C, Carteaux G, de Prost N, Chiche JD, Daviaud F, Pham T, Fartoukh M, Barberet G, Biehler J, Dellamonica J, Doyen D, Arnal JM, Briquet A, Klasen F, Papazian L, Follin A, Roux D, Messika J, Kalaitzis E, Dangers L, Combes A, Au SM, Béduneau G, Carpentier D, Zogheib EH, Dupont H, Ricome S, Santoli FL, Besset SL, Michel P, Gelée B, Danin PE, Goubaux B, Crova PJ, Phan NT, Berkelmans F, Badie JC, Tapponnier R, Gally J, Khebbeb S, Herbrecht JE, Schneider F, Declercq PM, Rigaud JP, Duranteau J, Harrois A, Chabanne R, Marin J, Constantin JM, Thibault S, Ghazi M, Boukhazna M, Zein SO, Richecoeur JR, Combaux DM, Grelon F, Le Moal C, Sauvadet EP, Robine A, Lemiale V, Reuter D, Dres M, Demoule A, Goldgran-Toledano D, Baboi L, Guérin C, Lohner R, Kraßler J, Schäfer S, Zacharowski KD, Meybohm P, Reske AW, Simon P, Hopf HF, Schuetz M, Baltus T, Papanikolaou MN, Papavasilopoulou TG, Zacharas GA, Ourailogloy V, Mouloudi EK, Massa EV, Nagy EO, Stamou EE, Kiourtzieva EV, Oikonomou MA, Avila LE, Cortez CA, Citalán JE, Jog SA, Sable SD, Shah B, Gurjar M, Baronia AK, Memon M, Muthuchellappan R, Ramesh VJ, Shenoy A, Unnikrishnan R, Dixit SB, Rhayakar RV, Ramakrishnan N, Bhardwaj VK, Mahto HL, Sagar SV, Palaniswamy V, Ganesan D, Hashemian SM, Jamaati H, Heidari F, Meaney EA, Nichol A, Knapman KM, O'Croinin D, Dunne ES, Breen DM, Clarkson KP, Jaafar RF, Dwyer R, Amir F, Ajetunmobi OO, O'Muircheartaigh AC, Black CS, Treanor N, Collins DV, Altaf W, Zani G, Fusari M, Spadaro S, Volta CA, Graziani R, Brunettini B, Palmese S, Formenti P, Umbrello M, Lombardo A, Pecci E, Botteri M, Savioli M, Protti A, Mattei A, Schiavoni L, Tinnirello A, Todeschini M, Giarratano A, Cortegiani A, Sher S, Rossi A, Antonelli MM, Montini LM, Casalena P, Scafetti S, Panarello G, Occhipinti G, Patroniti N, Pozzi M, Biscione RR, Poli MM, Raimondi F, Albiero D, Crapelli G, Beck E, Pota V, Schiavone V, Molin A, Tarantino F, Monti G, Frati E, Mirabella L, Cinnella G, Fossali T, Colombo R, Pattarino PTI, Mojoli F, Braschi A, Borotto EE, Cracchiolo AN, Palma DM, Raponi F, Foti G, Vascotto ER, Coppadoro A, Brazzi L, Floris L, Iotti GA, Venti A, Yamaguchi O, Takagi S, Maeyama HN, Watanabe E, Yamaji Y, Shimizu K, Shiozaki K, Futami S, Ryosuke S, Saito K, Kameyama Y, Ueno K, Izawa M, Okuda N, Suzuki H, Harasawa T, Nasu M, Takada T, Ito F, Nunomiya S, Koyama K, Abe T, Andoh K, Kusumoto K, Hirata A, Takaba A, Kimura H, Matsumoto S, Higashijima U, Honda H, Aoki N, Imai H, Ogino Y, Mizuguchi I, Ichikado K, Nitta K, Mochizuki K, Hashida T, Tanaka H, Nakamura T, Niimi D, Ueda T, Kashiwa Y, Uchiyama A, Sabelnikovs O, Oss P, Haddad Y, Liew KY, Ñamendys-Silva SA, Jarquin-Badiola YD, Sanchez-Hurtado LA, Gomez-Flores SS, Marin MC, Villagomez AJ, Lemus JS, Fierro JM, Cervantes MR, Mejia FJF, Dector D, Dector DM, Gonzalez DR, Estrella CR, Sanchez-Medina JR, Ramirez-Gutierrez A, George FG, Aguirre JS, Buensuseso JA, Poblano M, Dendane T, Zeggwagh AA, Balkhi H, Elkhayari M, Samkaoui N, Ezzouine H, Benslama A, Amor M, Maazouzi W, Cimic N, Beck O, Bruns MM, Schouten JA, Rinia M, Raaijmakers M, Heunks LM, Van Wezel HM, Heines SJ, Strauch U, Buise MP, Simonis FD, Schultz MJ, Goodson JC, Browne TS, Navarra L, Hunt A, Hutchison RA, Bailey MB, Newby L, Mcarthur C, Kalkoff M, Mcleod A, Casement J, Hacking DJ, Andersen FH, Dolva MS, Laake JH, Barratt-Due A, Noremark KAL, Søreide E, Sjøbø BÅ, Guttormsen AB, Leon Yoshido HH, Aguilar RZ, Montes Oscanoa FA, Alisasis AU, Robles JB, Pasanting-Lim RAB, Tan BC, Andruszkiewicz P, Jakubowska K, Coxo CM, Alvarez AM, Oliveira BS, Montanha GM, Barros NC, Pereira CS, Messias AM, Monteiro JM, Araujo AM, Catorze NT, Marum SM, Bouw MJ, Gomes RM, Brito VA, Castro S, Estilita JM, Barros FM, Serra IM, Martinho AM, Tomescu DR, Marcu A, Bedreag OH, Papurica M, Corneci DE, Negoita SI, Grigoriev E, Gritsan AI, Gazenkampf AA, Almekhlafi G, Albarrak MM, Mustafa GM, Maghrabi KA, Salahuddin N, Aisa TM, Al Jabbary AS, Tabhan E, Arabi YM, Arabi YM, Trinidad OA, Al Dorzi HM, Tabhan EE, Bolon S, Smith O, Mancebo J, Aguirre-Bermeo H, Lopez-Delgado JC, Esteve F, Rialp G, Forteza C, De Haro C, Artigas A, Albaiceta GM, De Cima-Iglesias S, Seoane-Quiroga L, Ceniceros-Barros A, Ruiz-Aguilar AL, Claraco-Vega LM, Soler JA, Del Carmen Lorente M, Hermosa C, Gordo F, Prieto-González M, López-Messa JB, Perez MP, Perez CP, Allue RM, Roche-Campo F, Ibañez-Santacruz M, Temprano S, Pintado MC, De Pablo R, Gómez PRA, Ruiz SR, Moles SI, Jurado MT, Arizmendi A, Piacentini EA, Franco N, Honrubia T, Cheng MP, Losada EP, Blanco J, Yuste LJ, Carbayo-Gorriz C, Cazorla-Barranquero FG, Alonso JG, Alda RS, Algaba Á, Navarro G, Cereijo E, Diaz-Rodriguez E, Marcos DP, Montero LA, Para LH, Sanchez RJ, Navalpotro MAB, Abad RD, González RM, Toribio DP, Castro AG, Artiga MJD, Penuelas O, Roser TP, Olga MF, Curto EG, Sánchez RM, Imma VP, Elisabet GM, Claverias L, Magret M, Pellicer AM, Rodriguez LL, Sánchez-Ballesteros J, González-Salamanca Á, Jimenez AG, Huerta FP, Llinares Moya DD, Tallet Alfonso AA, Luis PSE, Cesar PS, Rafael SI, Virgilio CG, Recio NN, Adamsson RO, Rylander CC, Holzgraefe B, Broman LM, Wessbergh J, Persson L, Schiöler F, Kedelv H, Tibblin AO, Appelberg H, Hedlund L, Helleberg J, Eriksson KE, Glietsch R, Larsson N, Nygren I, Nunes SL, Morin AK, Kander T, Adolfsson A, Piquilloud L, Zender HO, Leemann-Refondini C, Elatrous S, Bouchoucha S, Chouchene I, Ouanes I, Souissi AB, Kamoun S, Demirkiran O, Aker M, Erbabacan E, Ceylan I, Girgin NK, Ozcelik M, Ünal N, Meco BC, Akyol OO, Derman SS, Kennedy B, Parhar K, Srinivasa L, McNamee L, McAuley D, Hopkins P, Mellis C, Kakar V, Hadfield D, Vercueil A, Bhowmick K, Humphreys SK, Ferguson A, Mckee R, Raj AS, Fawkes DA, Watt P, Twohey L, JhaMatthew Thomas RR, Morton A, Kadaba V, Smith MJ, Hormis AP, Kannan SG, Namih M, Reschreiter H, Camsooksai J, Kumar A, Rugonfalvi S, Nutt C, Oneill O, Seasman C, Dempsey G, Scott CJ, Ellis HE, Mckechnie S, Hutton PJ, Di Tomasso NN, Vitale MN, Griffin RO, Dean MN, Cranshaw JH, Willett EL, Ioannou N, Gillis S, Csabi P, Macfadyen R, Dawson H, Preez PD, Williams AJ, Boyd O, De Gordoa LO, Bramall J, Symmonds S, Chau SK, Wenham T, Szakmany T, Toth-Tarsoly P, Mccalman KH, Alexander P, Stephenson L, Collyer T, Chapman R, Cooper R, Allan RM, Sim M, Wrathall DW, Irvine DA, Zantua KS, Adams JC, Burtenshaw AJ, Sellors GP, Welters ID, Williams KE, Hessell RJ, Oldroyd MG, Battle CE, Pillai S, Kajtor I, Sivashanmugavel M, Okane SC, Donnelly A, Frigyik AD, Careless JP, May MM, Stewart R, John Trinder T, Hagan SJ, Wise MP, Cole JM, MacFie CC, Dowling AT, Hurtado J, Nin N, Hurtado J, Nuñez E, Pittini G, Rodriguez R, Imperio MC, Santos C, França AG, Ebeid A, Deicas A, Serra C, Uppalapati A, Kamel G, Banner-Goodspeed VM, Beitler JR, Mukkera SR, Kulkarni S, Lee J, Mesar T, Shinn Iii JO, Gomaa D, Tainter C, Lee J, Mesar T, Lee J, Yeatts DJ, Warren J, Lanspa MJ, Miller RR, Grissom CK, Brown SM, Bauer PR, Gosselin RJ, Kitch BT, Cohen JE, Beegle SH, Gueret RM, Tulaimat A, Choudry S, Stigler W, Batra H, Huff NG, Lamb KD, Oetting TW, Mohr NM, Judy C, Saito S, Kheir FM, Kheir F, Schlichting AB, Delsing A, Crouch DR, Elmasri M, Crouch DR, Ismail D, Dreyer KR, Blakeman TC, Dreyer KR, Gomaa D, Baron RM, Grijalba CQ, Hou PC, Seethala R, Aisiku I, Henderson G, Frendl G, Hou SK, Owens RL, Schomer A, Bumbasirevic V, Jovanovic B, Surbatovic M, Veljovic M., UCL - SSS/IREC/MEDA - Pôle de médecine aiguë, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (SLuc) Service de soins intensifs, and UCL - (MGD) Services des soins intensifs

Subjects
Adult, Male, Diabetes mellitu, LUNG SAFE, Organ Dysfunction Scores, humanos, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Socio-culturale, Organ Dysfunction Score, Diabetes Complications, Diabetes mellitus, puntuaciones de disfunción orgánica, Risk Factors, Diabetes Complication, estudios prospectivos, Humans, factores de riesgo, Prospective Studies, Hospital Mortality, Hypoxia, mediana edad, Acute hypoxemic respiratory failure, Aged, Respiratory Distress Syndrome, anciano, Acute respiratory distress syndrome, Research, Respiration, respiración, Respiratory Distress Syndrome, Adult, lcsh:Medical emergencies. Critical care. Intensive care. First aid, lcsh:RC86-88.9, Middle Aged, Respiration, Artificial, insuficiencia respiratoria, Prospective Studie, Artificial, Diabetes Mellitus, Female, Respiratory Insufficiency, mortalidad hospitalaria, complicaciones de la diabetes, Human
Abstract

Background: Diabetes mellitus is a common co-existing disease in the critically ill. Diabetes mellitus may reduce the risk of acute respiratory distress syndrome (ARDS), but data from previous studies are conflicting. The objective of this study was to evaluate associations between pre-existing diabetes mellitus and ARDS in critically ill patients with acute hypoxemic respiratory failure (AHRF). Methods: An ancillary analysis of a global, multi-centre prospective observational study (LUNG SAFE) was undertaken. LUNG SAFE evaluated all patients admitted to an intensive care unit (ICU) over a 4-week period, that required mechanical ventilation and met AHRF criteria. Patients who had their AHRF fully explained by cardiac failure were excluded. Important clinical characteristics were included in a stepwise selection approach (forward and backward selection combined with a significance level of 0.05) to identify a set of independent variables associated with having ARDS at any time, developing ARDS (defined as ARDS occurring after day 2 from meeting AHRF criteria) and with hospital mortality. Furthermore, propensity score analysis was undertaken to account for the differences in baseline characteristics between patients with and without diabetes mellitus, and the association between diabetes mellitus and outcomes of interest was assessed on matched samples. Results: Of the 4107 patients with AHRF included in this study, 3022 (73.6%) patients fulfilled ARDS criteria at admission or developed ARDS during their ICU stay. Diabetes mellitus was a pre-existing co-morbidity in 913 patients (22.2% of patients with AHRF). In multivariable analysis, there was no association between diabetes mellitus and having ARDS (OR 0.93 (0.78-1.11); p = 0.39), developing ARDS late (OR 0.79 (0.54-1.15); p = 0.22), or hospital mortality in patients with ARDS (1.15 (0.93-1.42); p = 0.19). In a matched sample of patients, there was no association between diabetes mellitus and outcomes of interest. Conclusions: In a large, global observational study of patients with AHRF, no association was found between diabetes mellitus and having ARDS, developing ARDS, or outcomes from ARDS., This work was supported by the European Society of Intensive Care Medicine (ESICM), Brussels, Belgium who funded the original LUNG SAFE study.

Published
2018

41. Pneumocystis Mating-Type Locus and Sexual Cycle during Infection

Author

Philippe M. Hauser

Subjects
Homothallism, Review, Microbiology, Airborne transmission, 03 medical and health sciences, medicine, Antigenic variation, Pneumocystis jirovecii, Animals, Humans, DNA, Fungal, Molecular Biology, Lung, 030304 developmental biology, 0303 health sciences, Life Cycle Stages, biology, Obligate, 030306 microbiology, Pneumocystis, Reproduction, biology.organism_classification, medicine.disease, Sexual reproduction, Obligate parasite, Pneumocystis Infections, Infectious Diseases, Genome, Fungal, Pneumonia (non-human)
Abstract

Pneumocystis species colonize mammalian lungs and cause deadly pneumonia if the immune system of the host weakens. Each species presents a specificity for a single mammalian host species. Pneumocystis jirovecii infects humans and provokes pneumonia, which is among the most frequent invasive fungal infections. The lack of in vitro culture methods for these fungi complicates their study. Recently, high-throughput sequencing technologies followed by comparative genomics have allowed a better understanding of the mechanisms involved in the sexuality of Pneumocystis organisms. The structure of their mating-type locus corresponding to a fusion of two loci, Plus and Minus, and the concomitant expression of the three mating-type genes revealed that their mode of sexual reproduction is primarily homothallism. This mode is favored by microbial pathogens and involves a single self-compatible mating type that can enter into the sexual cycle on its own. Pneumocystis sexuality is obligatory within the host's lungs during pneumonia in adults, primary infection in children, and possibly colonization. This sexuality participates in cell proliferation, airborne transmission to new hosts, and probably antigenic variation, processes that are crucial to ensure the survival of the fungus. Thus, sexuality is central in the Pneumocystis life cycle. The obligate biotrophic parasitism with obligate sexuality of Pneumocystis is unique among fungi pathogenic to humans. Pneumocystis organisms are similar to the plant fungal obligate biotrophs that complete their entire life cycle within their hosts, including sex, and that are also difficult to grow in vitro.

Published
2021

42. Nineteen percent of meniscus repairs are being revised and failures frequently occur after the second postoperative year: a systematic review and meta-analysis with a minimum follow-up of 5 years

Author

Robin Ristl, Wenzel Waldstein, Reinhard Windhager, Conradin Schweizer, Sebastian Apprich, Philippe M. Tscholl, and Carola Hanreich

Subjects
Knee arthritis, medicine.medical_specialty, Sports medicine, Anterior cruciate ligament reconstruction, medicine.medical_treatment, Meniscus (anatomy), Menisci, Tibial, Arthroscopy, medicine, Humans, Orthopedics and Sports Medicine, Meniscus, Retrospective Studies, Lateral meniscus, business.industry, Anterior Cruciate Ligament Injuries, musculoskeletal system, medicine.disease, Surgery, Tibial Meniscus Injuries, medicine.anatomical_structure, Orthopedic surgery, Tears, business, Medial meniscus, Follow-Up Studies
Abstract

Purpose Meniscus repair has gained increasing interest over the last two decades as loss of meniscus tissue predisposes to early onset knee arthritis. Although there are many reports of meniscus repair outcome in short-term studies, data on the long-term outcome of meniscus repair are still scarce. The purpose of this meta-analysis was to evaluate the overall failure rate of meniscus repair with a minimum follow-up of 5 years. Additionally, possible factors influencing meniscus repair outcome were assessed. Methods PubMed and Scopus were searched for studies of the last 20 years reporting on meniscus repair outcome with a minimum follow-up of 5 years. The study was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The search terms used for this study were ([meniscus OR meniscal] AND repair). Titles and abstracts were evaluated by two authors independently. Using meta package of R (version 3.6.2), random-effect models were performed to pool failure rates. Subgroup analyses were performed and effect estimates in form of an odds ratio with 95% CIs were established. Results In total, 12 studies with 864 patients were included. Degenerative tears were excluded in two studies and one study only included traumatic meniscus tears. Other studies did not state whether the cause of meniscus tear was degenerative or traumatic. Studies reporting meniscus repair outcome on root repairs, revision anterior cruciate ligament reconstruction, discoid menisci or ramp lesions were excluded. Revision surgery was used as failure definition in all included studies. The overall failure rate of meniscal repair at a mean follow-up of 86 months was 19.1%. There was no significant difference in meniscus repair outcome when performed in combination with anterior cruciate ligament reconstruction compared to isolated meniscus repair (18.7% vs. 28%; n.s.) or when performed on the lateral meniscus compared to the medial meniscus (19.5% vs. 24.4%; n.s.). There was no significant difference of meniscus repair outcome between vertical/longitudinal tears and bucket-handle tears (n.s.). Thirty-six percent of meniscus repair failures occur after the second postoperative year. The only significant finding was that inside-out repair results in a lower failure rate compared to all-inside repair (5.6% vs. 22.3%; p = 0.009) at 5 years. Conclusion The overall meniscus repair failure rate remains nineteen percent in long-term studies. The cause of failure is poorly documented, and it remains unclear whether failure of the meniscus repair itself or additional adjacent tears lead to revision surgery. Despite the given technical advantages of all-inside repair devices, this meta-analysis cannot demonstrate superior outcomes compared to inside-out or outside-in repair at 5 years. Level of evidence IV.

Published
2021

43. Rickets manifestations in a child with metaphyseal anadysplasia, report of a spontaneously resolving case

Author

Patricia Olivier, Patricia Diaz Escagedo, Philippe M. Campeau, Nathalie Alos, Melissa Fiscaletti, Valancy Miranda, Marie-Claude Miron, and Chloé Hudon

Subjects
0301 basic medicine, Rickets mimicking presentation disease, Pediatrics, medicine.medical_specialty, Heterozygote, Metaphyseal anadysplasia, Costochondral junctions, Limb Deformities, Congenital, Rickets, Case Report, 030105 genetics & heredity, Osteochondrodysplasias, Short stature, RJ1-570, 03 medical and health sciences, medicine, Humans, Toddler, Child, business.industry, Metaphyseal flaring, medicine.disease, 030104 developmental biology, Pediatrics, Perinatology and Child Health, Regressive course, Autosomal dominant variant, Differential diagnosis, medicine.symptom, business, Rachitic rosary
Abstract

Introduction Rickets is not an unusual diagnosis for pediatricians even currently in developed countries. Children typically present with leg bowing, enlargement of wrists, rachitic rosary (swelling of costochondral junctions) and/or waddling gait. But not every child with growth delay and enlarged metaphyses is diagnosed with rickets. Metaphyseal anadysplasia (MAD) is a disorder of variable severity with metaphyseal flaring and irregularities, without vertebral abnormalities. MAD is characterized by an early onset and a regressive course in late childhood without treatment, despite persistent short stature. Autosomal dominant or recessive variants in the matrix metalloproteinase 13 gene (MMP13) are responsible for these transient metaphyseal changes. Case presentation We report a new pathogenic heterozygous variant in MMP13 (NM_002427.4: c.216G>C, p.Gln72His) in a toddler, initially thought to have rickets, and his father, with MAD phenotypes. Additionally, we review the seven reported MMP13 variants. Conclusion One should keep a wide differential diagnosis in cases of suspected rickets, including skeletal dysplasias which might have a regressive course.

Published
2021

44. Nonsyndromic erythrodermic ichthyosis resulting from a homozygous mutation in PIGL

Author

J.K. Simpson, John A. McGrath, Michael A. Simpson, Anna E. Martinez, Alexandros Onoufriadis, C. McDonald, T. T. M. Nguyen, and Philippe M. Campeau

Subjects
Genetics, Ichthyosis, business.industry, Homozygote, Infant, Dermatology, N-Acetylglucosaminyltransferases, medicine.disease, Pedigree, Child, Preschool, Mutation, Mutation (genetic algorithm), medicine, Humans, Female, business, Dermatitis, Exfoliative
Published
2019

45. A systematic review of standardized methods for assessment of endograft sealing on computed tomography angiography post-endovascular aortic repair, and its influence on endograft-associated complications

Author

Cornelis G. Vos, Philippe M. De Rooy, Frederico Bastos Gonçalves, Richte C.L. Schuurmann, and Jean-Paul P.M. de Vries

Subjects
PROTOCOLS, medicine.medical_specialty, PREDICTOR, MIGRATION, medicine.medical_treatment, Biomedical Engineering, ZONE, 030204 cardiovascular system & hematology, Aortic repair, Endovascular aneurysm repair, CURVATURE, endovascular aneurysm repair, thoracic endovascular aortic repair, 03 medical and health sciences, stentgraft, Postoperative Complications, 0302 clinical medicine, medicine, Humans, Measurement precision, Arterial wall, EVAR, cardiovascular diseases, Aorta, Computed tomography angiography, practice guidelines, medicine.diagnostic_test, business.industry, Endovascular Procedures, ANEURYSM REPAIR, General Medicine, image reconstruction, abdominal aneurysm, ENDOLEAK, Blood Vessel Prosthesis, Apposition, Landing zone, Systematic review, Surgery, Radiology, Anatomic Landmarks, Abdominal aneurysm, business, FOLLOW-UP, computed tomography angiography, 030217 neurology & neurosurgery, psychological phenomena and processes, INTERVENTIONS
Abstract

Introduction: Although there is much attention for proper sizing of pre-operative anatomy before (thoracic) endovascular aneurysm repair ([T]EVAR), standardized assessment of endograft position and apposition at postoperative imaging is seldom addressed in the international guidelines. The highly detailed three-dimensional computed tomography angiography (CTA) volumes contain valuable information about the apposition of the endograft with the arterial wall and the position of the device relative to anatomical landmarks in the proximal and distal landing zones, which is currently hardly used. With proper assessment on CTA of the endograft after EVAR, the risk for future endograft-related complications may be determined, allowing patient-tailored, risk-stratified surveillance. Areas covered: This systematic review identified three standardized methods for assessing apposition or position of the endograft in the proximal or distal landing zone on CTA after (T)EVAR. Quantification of apposition and position, validation of measurement precision, and association with endograft-related complications were extracted. Short (0 mm) apposition were associated with endograft-associated complications. Expert commentary: Standardized assessment of apposition and position of the endograft in the proximal and distal landing zones on CTA should be incorporated in post-(T)EVAR surveillance. A risk-stratified CTA surveillance protocol is proposed.

Published
2019

46. A new microdeletion syndrome involving TBC1D24, ATP6V0C, and PDPK1 causes epilepsy, microcephaly, and developmental delay

Author

Bettina E. Mucha, Marianne Till, Tobias Linden, Mary Ann Thomas, Carl Ernst, Philippe M. Campeau, Jessica L. Waxler, Sau Wai Cheung, Damien Sanlaville, Jozef Gecz, Lesley M McGregor, Sanjay M. Sisodiya, Gary G. Chen, Michael Harbord, Mary Kay Koenig, Renee Perrier, Jennelle C. Hodge, Rhamat B. Adejumo, Jillian Nicholl, Norbert F. Ajeawung, Emmanuelle Lemyre, Brian G. Skotko, Siddharth Banka, Sirinart Molidperee, and Renee Myriam Boucher

Subjects
Adult, Male, 0301 basic medicine, Vacuolar Proton-Translocating ATPases, Pediatrics, medicine.medical_specialty, Microcephaly, Adolescent, Developmental Disabilities, MEDLINE, Nerve Tissue Proteins, 030105 genetics & heredity, 3-Phosphoinositide-Dependent Protein Kinases, Cohort Studies, Young Adult, 03 medical and health sciences, Epilepsy, Intellectual Disability, medicine, Humans, Child, Genetics (clinical), 16p13.3, business.industry, TBC1D24, Published Erratum, GTPase-Activating Proteins, Infant, Membrane Proteins, Syndrome, Microdeletion syndrome, medicine.disease, Spelling, 030104 developmental biology, Child, Preschool, Microdeletion, Female, Chromosome Deletion, business, Chromosomes, Human, Pair 16
Abstract

PURPOSE: Contiguous gene deletions are known to cause several neurodevelopmental syndromes, many of which are caused by recurrent events on chromosome 16. However, chromosomal microarray studies (CMA) still yield copy-number variants (CNVs) of unknown clinical significance. We sought to characterize eight individuals with overlapping 205-kb to 504-kb 16p13.3 microdeletions that are distinct from previously published deletion syndromes.METHODS: Clinical information on the patients and bioinformatic scores for the deleted genes were analyzed.RESULTS: All individuals in our cohort displayed developmental delay, intellectual disability, and various forms of seizures. Six individuals were microcephalic and two had strabismus. The deletion was absent in all 13 parents who were available for testing. The area of overlap encompasses seven genes including TBC1D24, ATP6V0C, and PDPK1 (also known as PDK1). Bi-allelic TBC1D24 pathogenic variants are known to cause nonsyndromic deafness, epileptic disorders, or DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, seizures). Sanger sequencing of the nondeleted TBC1D24 allele did not yield any additional pathogenic variants.CONCLUSIONS: We propose that 16p13.3 microdeletions resulting in simultaneous haploinsufficiencies of TBC1D24, ATP6V0C, and PDPK1 cause a novel rare contiguous gene deletion syndrome of microcephaly, developmental delay, intellectual disability, and epilepsy.

Published
2019

47. A Syndromic Neurodevelopmental Disorder Caused by Mutations in SMARCD1, a Core SWI/SNF Subunit Needed for Context-Dependent Neuronal Gene Regulation in Flies

Author

Shane McKee, Christel Depienne, Diana Baralle, Ddd Study, Justine Rousseau, Philippe M. Campeau, Sophie Ehresmann, Naomichi Matsumoto, Solveig Heide, Max H. Stone, Hannah Titheradge, Alyssa Ritter, Kevin C J Nixon, Seiji Mizuno, Jamie M. Kramer, Delphine Héron, Noriko Miyake, Mohammed Sarikahya, Kosuke Izumi, Western University [London, ON, Canada], Centre Hospitalier Universitaire Sainte-Justine [Montréal, QC, Canada] (CHU Sainte-Justine), Yokohama City University (YCU), University of Southampton, Belfast City Hospital, Children’s Hospital of Philadelphia (CHOP ), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Trousseau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), 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), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), University of Duisburg-Essen, and Birmingham Women's and Children's NHS Foundation Trust

Subjects
Male, Chromosomal Proteins, Non-Histone, Developmental Disabilities, Medizin, Transcriptome, 0302 clinical medicine, Neurodevelopmental disorder, Drosophila Proteins, Child, Genetics (clinical), Exome sequencing, Neurons, Regulation of gene expression, Genetics, 0303 health sciences, Syndrome, SWI/SNF, Hypotonia, Drosophila melanogaster, intellectual disability, Child, Preschool, Muscle Hypotonia, Female, medicine.symptom, BAFopathies, Mitosis, Context (language use), SMARCD1, Biology, Drosophila mushroom body, Article, Chromatin remodeling, 03 medical and health sciences, long-term memory, Memory, medicine, Animals, Humans, Learning, Mushroom Bodies, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, fungi, medicine.disease, neurodevelopmental disorder, Disease Models, Animal, Gene Expression Regulation, Neurodevelopmental Disorders, Mutation, 030217 neurology & neurosurgery, Transcription Factors
Abstract

Mutations in several genes encoding components of the SWI/SNF chromatin remodeling complex cause neurodevelopmental disorders (NDDs). Here, we report on 5 individuals with mutations in SMARCD1, presenting with developmental delay, intellectual disability, hypotonia, feeding difficulties, and small hands and feet. The mutations were proven to be de novo in 4 of the 5 individuals, by trio exome sequencing. Mutations in other SWI/SNF components cause Coffin-Siris syndrome and Nicolaides-Baraitser syndrome, or other syndromic and non-syndromic NDDs. Although the individuals presented here have dysmorphisms and some clinical overlap with these syndromes, they lack the typical facial dysmorphisms. To gain insight into the function of SMARCD1 in neurons, we investigated the Drosophila ortholog, Bap60, in postmitotic memory-forming neurons of the adult Drosophila mushroom body (MB). Targeted knockdown of Bap60 in the MB of adult flies causes defects in long-term memory. Mushroom body specific transcriptome analysis revealed that Bap60 is required for context-dependent expression of genes involved in neuron function and development in juvenile flies when synaptic connections are actively being formed in response to experience. Taken together, we identify a NDD caused by SMARCD1 mutations and establish a role for the SMARCD1 ortholog Bap60 in regulation of neurodevelopmental genes during a critical time window of juvenile adult brain development that is essential in establishing neuronal circuits that are required for learning and memory.

Published
2019

48. Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability

Author

Philippe M. Campeau, Katherine Agre, Vernon R. Sutton, Kirsty McWalter, Bertrand Isidor, Øystein L. Holla, Anna Lehman, Megha Desai, Jonathan Berg, Stéphane Bézieau, Rolph Pfundt, Jennifer Tarpinian, Jennifer B. Humberson, Holly A.F. Stessman, Madeleine R. Geisheker, Emma Bedoukian, Shalini N. Jhangiani, Marine I. Murphree, Annapurna Poduri, Anne-Sophie Denommé-Pichon, Christian Gilissen, Yaping Yang, Eliane Beauregard-Lacroix, Claude Férec, Francesca Filippini, Anne Guimier, Daryl A. Scott, Stephen Sanders, Julie C. Sapp, Ralitza H. Gavrilova, Slavé Petrovski, Ann Nordgren, Sylvia Redon, Ernie M.H.F. Bongers, Shelagh Joss, Jill A. Rosenfeld, Wallid Deb, Ingrid M. Wentzensen, Usha Kini, Vandana Shashi, Mindy H. Li, Stanislas Lyonnet, Thomas Garcia, Øyvind L. Busk, Christoffer Nellåker, Amber Begtrup, Brigitte Gilbert-Dussardier, Thomas Besnard, Francois V. Bolduc, Patrick R. Blackburn, Justine Rousseau, Frédéric Bilan, Eric W. Klee, Christopher T. Gordon, Pavel N. Pichurin, Peggy Kulch, Kevin P. Lally, Laurie Robak, Arnaud Picard, Kristian Tveten, Meredith Park, Sébastien Küry, Jaya Punetha, Moira Blyth, Asbjørg Stray-Pedersen, Jacqueline Harris, Erin L. Heinzen, Nicholas Stong, Cara M. Skraban, Julie S. Cohen, Aida Telegrafi, Xenia Latypova, Zeynep Coban Akdemir, Jacob Zyskind, Caitlin Troyer, Xiang-Jiao Yang, Tuula Rinne, Leslie G. Biesecker, Jennifer E. Posey, Kyle Retterer, Jeanne Amiel, Rui Xiao, Magnus Nordenskjöld, Tammie Dewan, Jennifer A. Sullivan, Charlotte von der Lippe, Evan E. Eichler, Anna Lindstrand, Dominique Bonneau, Yuri A. Zarate, Elaine H. Zackai, Fayth M. Kalb, Daniel H. Lowenstein, Shiri Avni, Benjamin Cogné, Jennifer J. Johnston, Kerri H. Whitlock, Catherine Shain, Séverine Audebert-Bellanger, Malin Kvarnung, Oana Caluseriu, David Goldstein, Annick Toutain, Andres Hernandez-Garcia, Brina Daniels, Sophie Ehresmann, James R. Lupski, Julie McGaughran, Ashley H Ebanks, Kévin Uguen, Marine Legendre, Sylvie Odent, Richard Redon, Erica H. Gerkes, Xiaofei Song, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Sainte Justine [Montréal], Université du Québec à Montréal = University of Québec in Montréal (UQAM), University of Oxford [Oxford], GeneDx [Gaithersburg, MD, USA], Mayo Clinic [Rochester], University of California [San Francisco] (UCSF), University of California, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Etablissement Français du Sang Bretagne, EFS, Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), Johns Hopkins University School of Medicine [Baltimore], Kennedy Krieger Institute [Baltimore], Chapel Allerton Hospital, University of British Columbia (UBC), University of Dundee, Rush University Medical Center [Chicago], Oxford University Hospitals NHS Trust, Queen Elizabeth University Hospital (Glasgow), Trondheim University, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), University of Virginia [Charlottesville], Texas Children's Hospital [Houston, USA], Baylor College of Medicine (BCM), Baylor University, University of Pennsylvania [Philadelphia], National Human Genome Research Institute (NHGRI), Harvard Medical School [Boston] (HMS), Karolinska University Hospital [Stockholm], Duke University Medical Center, University of Groningen [Groningen], University of Arkansas for Medical Sciences (UAMS), McGovern Medical School [Houston, Texas], The University of Texas Health Science Center at Houston (UTHealth), Phoenix Children's Hospital, Columbia University [New York], University of Southern Queensland (USQ), Telemark Hospital Trust [Skien, Norway], University of Washington [Seattle], Oslo University Hospital [Oslo], Children’s Hospital of Philadelphia (CHOP ), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Radboud University Medical Center [Nijmegen], Ann & Robert H. Lurie Children's Hospital of Chicago, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), 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], Centre de référence Maladies Rares CLAD-Ouest [Rennes], Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre hospitalier universitaire de Poitiers (CHU Poitiers), University of Alberta, Boston Children's Hospital, McGill University Health Center [Montreal] (MUHC), Hôpital Morvan - CHRU de Brest (CHU - BREST ), Creighton University Medical School [Omaha, NE, USA], Howard Hughes Medical Institute [Boston] (HHMI), Howard Hughes Medical Institute (HHMI)-Harvard Medical School [Boston] (HMS), National Institute of Neurological Disorders and Stroke, K08 HG008986, National Human Genome Research Institute, BC Children’s Hospital Foundation, Genome British Columbia, Fonds de Recherche du Québec - Santé, Canadian Institutes of Health Research, Center for Individualized Medicine, Mayo Clinic, Health Regional Agency from Poitou-Charentes, French Ministry of Health, RC14_0107, HUGODIMS, NS053998, The Epilepsy Phenome/Genome Project, NS077303, Epi4K, Duke Genome Sequencing Clinic, NINDS R35 NS105078, National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development, HG200328 12, intramural research program of the NHGRI, Dart NeuroScience, Kids Brain Health Network, Mining for Miracles, UM1 HG006542, National Heart, Lung, and Blood Institute, CIM Investigative and Functional Genomics Program, R01MH101221, National Institute of Mental Health, Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), University of Oxford, University of California [San Francisco] (UC San Francisco), University of California (UC), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of Virginia, University of Pennsylvania, Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 ), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), CCSD, Accord Elsevier, Faculteit Medische Wetenschappen/UMCG, Université de Rennes 1 (UR1), and 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 )

Subjects
CHROMATIN, Male, 0301 basic medicine, Autism, Sequence Homology, [SDV.GEN] Life Sciences [q-bio]/Genetics, Medical and Health Sciences, 0302 clinical medicine, SCHIZOPHRENIA, Gene expression, 2.1 Biological and endogenous factors, Missense mutation, Aetiology, Child, de novo variants, Genetics (clinical), Pediatric, Genetics & Heredity, Genetics, biology, neurodevelopmental disorders, histone acetylation, Adaptor Proteins, Nuclear Proteins, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Syndrome, Biological Sciences, Prognosis, Phenotype, Chromatin, Mental Health, Histone, intellectual disability, Child, Preschool, Female, REGULATOR, congenital malformations, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], BRAIN-DEVELOPMENT, Adult, Adolescent, Histone acetyltransferase complex, Intellectual and Developmental Disabilities (IDD), Mutation, Missense, Deciphering Developmental Disorders study, autism spectrum disorder, KAT6B, RNAI SCREEN, Young Adult, 03 medical and health sciences, CAUSES Study, Rare Diseases, Intellectual Disability, Report, COFACTOR, medicine, RUBINSTEIN-TAYBI-SYNDROME, Humans, Amino Acid Sequence, Autistic Disorder, Preschool, Gene, Genetic Association Studies, Adaptor Proteins, Signal Transducing, [SDV.GEN]Life Sciences [q-bio]/Genetics, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Rubinstein–Taybi syndrome, Signal Transducing, Neurosciences, Infant, medicine.disease, TRRAP, Brain Disorders, SELF-RENEWAL, 030104 developmental biology, DE-NOVO MUTATIONS, Mutation, biology.protein, Missense, 030217 neurology & neurosurgery
Abstract

Contains fulltext : 202928.pdf (Publisher’s version ) (Open Access) Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals. A strong genotype-phenotype correlation was observed with two distinct clinical spectra. The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired basic life functions. Individuals with this phenotype had missense variants clustering around the c.3127G>A p.(Ala1043Thr) variant identified in five individuals. The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy. Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip. RNA sequencing analysis of skin fibroblasts derived from affected individuals skin fibroblasts showed significant changes in the expression of several genes implicated in neuronal function and ion transport. Thus, we describe here the clinical spectrum associated with TRRAP pathogenic missense variants, and we suggest a genotype-phenotype correlation useful for clinical evaluation of the pathogenicity of the variants.

Published
2019

49. Author Correction: CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language

Author

Snijders Blok, Lot, Rousseau, Justine, Twist, Joanna, Ehresmann, Sophie, Takaku, Motoki, Venselaar, Hanka, Rodan, Lance H., Nowak, Catherine B., Douglas, Jessica, Swoboda, Kathryn J., Steeves, Marcie A., Sahai, Inderneel, Stumpel, Connie T. R. M., Stegmann, Alexander P. A., Wheeler, Patricia, Willing, Marcia, Fiala, Elise, Kochhar, Aaina, Gibson, William T., Cohen, Ana S. A., Agbahovbe, Ruky, Innes, A. Micheil, Au, P. Y. Billie, Rankin, Julia, Anderson, Ilse J., Skinner, Steven A., Louie, Raymond J., Warren, Hannah E., Afenjar, Alexandra, Keren, Boris, Nava, Caroline, Buratti, Julien, Isapof, Arnaud, Rodriguez, Diana, Lewandowski, Raymond, Propst, Jennifer, van Essen, Ton, Choi, Murim, Lee, Sangmoon, Chae, Jong H., Price, Susan, Schnur, Rhonda E., Douglas, Ganka, Wentzensen, Ingrid M., Zweier, Christiane, Reis, André, Bialer, Martin G., Moore, Christine, Koopmans, Marije, Brilstra, Eva H., Monroe, Glen R., van Gassen, Koen L. I., van Binsbergen, Ellen, Newbury-Ecob, Ruth, Bownass, Lucy, Bader, Ingrid, Mayr, Johannes A., Wortmann, Saskia B., Jakielski, Kathy J., Strand, Edythe A., Kloth, Katja, Bierhals, Tatjana, McRae, Jeremy F., Clayton, Stephen, Fitzgerald, Tomas W., Kaplanis, Joanna, Prigmore, Elena, Rajan, Diana, Sifrim, Alejandro, Aitken, Stuart, Akawi, Nadia, Alvi, Mohsan, Ambridge, Kirsty, Barrett, Daniel M., Bayzetinova, Tanya, Jones, Philip, Jones, Wendy D., King, Daniel, Krishnappa, Netravathi, Mason, Laura E., Singh, Tarjinder, Tivey, Adrian R., Ahmed, Munaza, Anjum, Uruj, Archer, Hayley, Armstrong, Ruth, Awada, Jana, Balasubramanian, Meena, Banka, Siddharth, Baralle, Diana, Barnicoat, Angela, Batstone, Paul, Baty, David, Bennett, Chris, Berg, Jonathan, Bernhard, Birgitta, Bevan, A. Paul, Bitner-Glindzicz, Maria, Blair, Edward, Blyth, Moira, Bohanna, David, Bourdon, Louise, Bourn, David, Bradley, Lisa, Brady, Angela, Brent, Simon, Brewer, Carole, Brunstrom, Kate, Bunyan, David J., Burn, John, Canham, Natalie, Castle, Bruce, Chandler, Kate, Chatzimichali, Elena, Cilliers, Deirdre, Clarke, Angus, Clasper, Susan, Clayton-Smith, Jill, Clowes, Virginia, Coates, Andrea, Cole, Trevor, Colgiu, Irina, Collins, Amanda, Collinson, Morag N., Connell, Fiona, Cooper, Nicola, Cox, Helen, Cresswell, Lara, Cross, Gareth, Crow, Yanick, D’Alessandro, Mariella, Dabir, Tabib, Davidson, Rosemarie, Davies, Sally, de Vries, Dylan, Dean, John, Deshpande, Charu, Devlin, Gemma, Dixit, Abhijit, Dobbie, Angus, Donaldson, Alan, Donnai, Dian, Donnelly, Deirdre, Donnelly, Carina, Douglas, Angela, Douzgou, Sofia, Duncan, Alexis, Eason, Jacqueline, Ellard, Sian, Ellis, Ian, Elmslie, Frances, Evans, Karenza, Everest, Sarah, Fendick, Tina, Fisher, Richard, Flinter, Frances, Foulds, Nicola, Fry, Andrew, Fryer, Alan, Gardiner, Carol, Gaunt, Lorraine, Ghali, Neeti, Gibbons, Richard, Gill, Harinder, Goodship, Judith, Goudie, David, Gray, Emma, Green, Andrew, Greene, Philip, Greenhalgh, Lynn, Gribble, Susan, Harrison, Rachel, Harrison, Lucy, Harrison, Victoria, Hawkins, Rose, He, Liu, Hellens, Stephen, Henderson, Alex, Hewitt, Sarah, Hildyard, Lucy, Hobson, Emma, Holden, Simon, Holder, Muriel, Holder, Susan, Hollingsworth, Georgina, Homfray, Tessa, Humphreys, Mervyn, Hurst, Jane, Hutton, Ben, Ingram, Stuart, Irving, Melita, Islam, Lily, Jackson, Andrew, Jarvis, Joanna, Jenkins, Lucy, Johnson, Diana, Jones, Elizabeth, Josifova, Dragana, Joss, Shelagh, Kaemba, Beckie, Kazembe, Sandra, Kelsell, Rosemary, Kerr, Bronwyn, Kingston, Helen, Kini, Usha, Kinning, Esther, Kirby, Gail, Kirk, Claire, Kivuva, Emma, Kraus, Alison, Kumar, Dhavendra, Kumar, V. K. Ajith, Lachlan, Katherine, Lam, Wayne, Lampe, Anne, Langman, Caroline, Lees, Melissa, Lim, Derek, Longman, Cheryl, Lowther, Gordon, Lynch, Sally A., Magee, Alex, Maher, Eddy, Male, Alison, Mansour, Sahar, Marks, Karen, Martin, Katherine, Maye, Una, McCann, Emma, McConnell, Vivienne, McEntagart, Meriel, McGowan, Ruth, McKay, Kirsten, McKee, Shane, McMullan, Dominic J., McNerlan, Susan, McWilliam, Catherine, Mehta, Sarju, Metcalfe, Kay, Middleton, Anna, Miedzybrodzka, Zosia, Miles, Emma, Mohammed, Shehla, Montgomery, Tara, Moore, David, Morgan, Sian, Morton, Jenny, Mugalaasi, Hood, Murday, Victoria, Murphy, Helen, Naik, Swati, Nemeth, Andrea, Nevitt, Louise, Norman, Andrew, O’Shea, Rosie, Ogilvie, Caroline, Ong, Kai-Ren, Park, Soo-Mi, Parker, Michael J., Patel, Chirag, Paterson, Joan, Payne, Stewart, Perrett, Daniel, Phipps, Julie, Pilz, Daniela T., Pollard, Martin, Pottinger, Caroline, Poulton, Joanna, Pratt, Norman, Prescott, Katrina, Pridham, Abigail, Procter, Annie, Purnell, Hellen, Quarrell, Oliver, Ragge, Nicola, Rahbari, Raheleh, Randall, Josh, Raymond, Lucy, Rice, Debbie, Robert, Leema, Roberts, Eileen, Roberts, Jonathan, Roberts, Paul, Roberts, Gillian, Ross, Alison, Rosser, Elisabeth, Saggar, Anand, Samant, Shalaka, Sampson, Julian, Sandford, Richard, Sarkar, Ajoy, Schweiger, Susann, Scott, Richard, Scurr, Ingrid, Selby, Ann, Seller, Anneke, Sequeira, Cheryl, Shannon, Nora, Sharif, Saba, Shaw-Smith, Charles, Shearing, Emma, Shears, Debbie, Sheridan, Eamonn, Simonic, Ingrid, Singzon, Roldan, Skitt, Zara, Smith, Audrey, Smith, Kath, Smithson, Sarah, Sneddon, Linda, Splitt, Miranda, Squires, Miranda, Stewart, Fiona, Stewart, Helen, Straub, Volker, Suri, Mohnish, Sutton, Vivienne, Swaminathan, Ganesh Jawahar, Sweeney, Elizabeth, Tatton-Brown, Kate, Taylor, Cat, Taylor, Rohan, Tein, Mark, Temple, I. Karen, Thomson, Jenny, Tischkowitz, Marc, Tomkins, Susan, Torokwa, Audrey, Treacy, Becky, Turner, Claire, Turnpenny, Peter, Tysoe, Carolyn, Vandersteen, Anthony, Varghese, Vinod, Vasudevan, Pradeep, Vijayarangakannan, Parthiban, Vogt, Julie, Wakeling, Emma, Wallwark, Sarah, Waters, Jonathon, Weber, Astrid, Wellesley, Diana, Whiteford, Margo, Widaa, Sara, Wilcox, Sarah, Wilkinson, Emily, Williams, Denise, Williams, Nicola, Wilson, Louise, Woods, Geoff, Wragg, Christopher, Wright, Michael, Yates, Laura, Yau, Michael, Nellåker, Chris, Parker, Michael, Firth, Helen V., Wright, Caroline F., FitzPatrick, David R., Barrett, Jeffrey C., Hurles, Matthew E., Roberts, John D., Petrovich, Robert M., Machida, Shinichi, Kurumizaka, Hitoshi, Lelieveld, Stefan, Pfundt, Rolph, Jansen, Sandra, Deriziotis, Pelagia, Faivre, Laurence, Thevenon, Julien, Assoum, Mirna, Shriberg, Lawrence, Kleefstra, Tjitske, Brunner, Han G., Wade, Paul A., Fisher, Simon E., and Campeau, Philippe M.

Subjects
Male, Models, Molecular, Developmental Disabilities, Gene Expression, General Physics and Astronomy, 02 engineering and technology, Chromatin remodelling, Sociology, lcsh:Science, Independent research, Adenosine Triphosphatases, 0303 health sciences, Multidisciplinary, biology, Health innovation, Disease genetics, Published Erratum, Neurodevelopmental disorders, 021001 nanoscience & nanotechnology, Spelling, 3. Good health, Phenotype, General partnership, Child, Preschool, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Female, medicine.symptom, Construct (philosophy), 0210 nano-technology, Psychology, Mi-2 Nucleosome Remodeling and Deacetylase Complex, Clinical epigenetics, Genotype, Science, Mutation, Missense, Library science, Child health, Speech Disorders, General Biochemistry, Genetics and Molecular Biology, Domain (software engineering), 03 medical and health sciences, Protein Domains, Intellectual Disability, medicine, Humans, Author Correction, 030304 developmental biology, Research ethics, Language Disorders, Whole Genome Sequencing, Core Grant, Macrocephaly, DNA Helicases, Helicase, General Chemistry, Chromatin Assembly and Disassembly, Megalencephaly, HEK293 Cells, biology.protein, lcsh:Q, Neuroscience, Impaired speech
Abstract

An Author Correction to this article was published on 15 February 2019 An Author Correction to this article was published on 02 May 2019 We thank all individuals and families for their contribution. We thank Amaia Carrion Castillo and Else Eising for assistance with the WGS analysis of the index individual, and Sarah Graham and Elliot Sollis for cloning the wild-type CHD3 construct for immunofluorescence. This work was supported by the Netherlands Organization for Scientific Research (NWO) Gravitation Grant 24.001.006 to the Language in Interaction Consortium (L.S.B., S.E.F., and H.G.B.), the Max Planck Society (S.E.F.), the National Institute on Deafness and Other Communication Disorders Grant DC000496 (L.Sh.) and a core grant to the Waisman Center from the National Institute of Child Health and Human Development (Grant U54 HD090256) to L.Sh., the Canadian Institutes of Health Research Grants MOP-119595 and PJT-148830 to W.T.G. Individuals 11, 16, 24, and 28 were part of The DDD Study cohort. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund [Grant number HICF-1009-003], a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute [Grant number WT098051]. The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the Department of Health. The DDD study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12, granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network.

Published
2019

50. Expanding the Spectrum of BAF-Related Disorders: De Novo Variants in SMARCC2 Cause a Syndrome with Intellectual Disability and Developmental Delay

Author

Keren Machol, Justine Rousseau, Sophie Ehresmann, Thomas Garcia, Thi Tuyet Mai Nguyen, Rebecca C. Spillmann, Jennifer A. Sullivan, Vandana Shashi, Yong-hui Jiang, Nicholas Stong, Elise Fiala, Marcia Willing, Rolph Pfundt, Tjitske Kleefstra, Megan T. Cho, Heather McLaughlin, Monica Rosello Piera, Carmen Orellana, Francisco Martínez, Alfonso Caro-Llopis, Sandra Monfort, Tony Roscioli, Cheng Yee Nixon, Michael F. Buckley, Anne Turner, Wendy D. Jones, Peter M. van Hasselt, Floris C. Hofstede, Koen L.I. van Gassen, Alice S. Brooks, Marjon A. van Slegtenhorst, Katherine Lachlan, Jessica Sebastian, Suneeta Madan-Khetarpal, Desai Sonal, Naidu Sakkubai, Julien Thevenon, Laurence Faivre, Alice Maurel, Slavé Petrovski, Ian D. Krantz, Jennifer M. Tarpinian, Jill A. Rosenfeld, Brendan H. Lee, Philippe M. Campeau, David R. Adams, Mercedes E. Alejandro, Patrick Allard, Mahshid S. Azamian, Carlos A. Bacino, Ashok Balasubramanyam, Hayk Barseghyan, Gabriel F. Batzli, Alan H. Beggs, Babak Behnam, Anna Bican, David P. Bick, Camille L. Birch, Devon Bonner, Braden E. Boone, Bret L. Bostwick, Lauren C. Briere, Donna M. Brown, Matthew Brush, Elizabeth A. Burke, Lindsay C. Burrage, Shan Chen, Gary D. Clark, Terra R. Coakley, Joy D. Cogan, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Precilla D’Souza, Mariska Davids, Jyoti G. Dayal, Esteban C. Dell’Angelica, Shweta U. Dhar, Ani Dillon, Katrina M. Dipple, Laurel A. Donnell-Fink, Naghmeh Dorrani, Daniel C. Dorset, Emilie D. Douine, David D. Draper, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Ascia Eskin, Cecilia Esteves, Tyra Estwick, Carlos Ferreira, Brent L. Fogel, Noah D. Friedman, William A. Gahl, Emily Glanton, Rena A. Godfrey, David B. Goldstein, Sarah E. Gould, Jean-Philippe F. Gourdine, Catherine A. Groden, Andrea L. Gropman, Melissa Haendel, Rizwan Hamid, Neil A. Hanchard, Lori H. Handley, Matthew R. Herzog, Ingrid A. Holm, Jason Hom, Ellen M. Howerton, Yong Huang, Howard J. Jacob, Mahim Jain, Jean M. Johnston, Angela L. Jones, Isaac S. Kohane, Donna M. Krasnewich, Elizabeth L. Krieg, Joel B. Krier, Seema R. Lalani, C. Christopher Lau, Jozef Lazar, Hane Lee, Shawn E. Levy, Richard A. Lewis, Sharyn A. Lincoln, Allen Lipson, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Marta M. Majcherska, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Thomas C. Markello, Ronit Marom, Julian A. Martínez-Agosto, Shruti Marwaha, Thomas May, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Matthew Might, Paolo M. Moretti, Marie Morimoto, John J. Mulvihill, Jennifer L. Murphy, Donna M. Muzny, Michele E. Nehrebecky, Stan F. Nelson, J. Scott Newberry, John H. Newman, Sarah K. Nicholas, Donna Novacic, Jordan S. Orange, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, Loren D.M. Pena, John A. Phillips, Jennifer E. Posey, John H. Postlethwait, Lorraine Potocki, Barbara N. Pusey, Chloe M. Reuter, Amy K. Robertson, Lance H. Rodan, Jacinda B. Sampson, Susan L. Samson, Kelly Schoch, Molly C. Schroeder, Daryl A. Scott, Prashant Sharma, Rebecca Signer, Edwin K. Silverman, Janet S. Sinsheimer, Kevin S. Smith, Kimberly Splinter, Joan M. Stoler, David A. Sweetser, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Tiina K. Urv, Zaheer M. Valivullah, Eric Vilain, Tiphanie P. Vogel, Colleen E. Wahl, Nicole M. Walley, Chris A. Walsh, Patricia A. Ward, Katrina M. Waters, Monte Westerfield, Anastasia L. Wise, Lynne A. Wolfe, Elizabeth A. Worthey, Shinya Yamamoto, Yaping Yang, Guoyun Yu, Diane B. Zastrow, Allison Zheng, and Clinical Genetics

Subjects
Male, 0301 basic medicine, Hypertrichosis, speech delay, Bafopathy, Developmental Disabilities, CACNB4, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual disability, Bafopathy, developmental delay, dysmorphisms, genotype-phenotype correlation, intellectual disability, neurodevelopmental disorder, speech delay, transcriptome, Genetics(clinical), Child, Genetics (clinical), Genetics, Syndrome, Hypotonia, DNA-Binding Proteins, developmental delay, Corticogenesis, intellectual disability, Child, Preschool, Speech delay, Female, medicine.symptom, Hand Deformities, Congenital, dysmorphisms, Adolescent, Micrognathism, genotype-phenotype correlation, Biology, Chromatin remodeling, 03 medical and health sciences, Journal Article, medicine, Humans, Abnormalities, Multiple, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], medicine.disease, neurodevelopmental disorder, Reelin Protein, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], 030104 developmental biology, Face, Mutation, biology.protein, transcriptome, Neck, 030217 neurology & neurosurgery, Transcription Factors
Abstract

Contains fulltext : 202800.pdf (Publisher’s version ) (Open Access) SMARCC2 (BAF170) is one of the invariable core subunits of the ATP-dependent chromatin remodeling BAF (BRG1-associated factor) complex and plays a crucial role in embryogenesis and corticogenesis. Pathogenic variants in genes encoding other components of the BAF complex have been associated with intellectual disability syndromes. Despite its significant biological role, variants in SMARCC2 have not been directly associated with human disease previously. Using whole-exome sequencing and a web-based gene-matching program, we identified 15 individuals with variable degrees of neurodevelopmental delay and growth retardation harboring one of 13 heterozygous variants in SMARCC2, most of them novel and proven de novo. The clinical presentation overlaps with intellectual disability syndromes associated with other BAF subunits, such as Coffin-Siris and Nicolaides-Baraitser syndromes and includes prominent speech impairment, hypotonia, feeding difficulties, behavioral abnormalities, and dysmorphic features such as hypertrichosis, thick eyebrows, thin upper lip vermilion, and upturned nose. Nine out of the fifteen individuals harbor variants in the highly conserved SMARCC2 DNA-interacting domains (SANT and SWIRM) and present with a more severe phenotype. Two of these individuals present cardiac abnormalities. Transcriptomic analysis of fibroblasts from affected individuals highlights a group of differentially expressed genes with possible roles in regulation of neuronal development and function, namely H19, SCRG1, RELN, and CACNB4. Our findings suggest a novel SMARCC2-related syndrome that overlaps with neurodevelopmental disorders associated with variants in BAF-complex subunits.

Published
2019

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