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1. Vascular adhesion protein-1 blockade in primary sclerosing cholangitis: Open-label, multicenter, single-arm, phase II trial

Author: Gideon M. Hirschfield, Katherine Arndtz, Amanda Kirkham, Yung-Yi Chen, Richard Fox, Anna Rowe, Jessica Douglas-Pugh, Douglas Thorburn, Eleanor Barnes, Guruprasad P. Aithal, Diana Hull, Khushpreet Bhandal, Kathryn Olsen, Paul Woodward, Siân Lax, Philip Newsome, David J. Smith, Antero Kallio, David H. Adams, Victoria Homer, and Chris J. Weston
Subjects: Diseases of the digestive system. Gastroenterology, RC799-869
Abstract: Background:. Primary sclerosing cholangitis is a progressive inflammatory liver disease characterized by biliary and liver fibrosis. Vascular adhesion protein-1 (VAP-1) is important in the inflammatory process driving liver fibrosis. We evaluated the safety and efficacy of VAP-1 blockade with a monoclonal antibody (timolumab, BTT1023) in patients with primary sclerosing cholangitis. Methods:. BUTEO was a prospective, single-arm, open-label, multicenter, phase II trial, conducted in 6 centers in the United Kingdom. Patients with primary sclerosing cholangitis aged 18–75 years had an alkaline phosphatase value of >1.5 times the upper limit of normal. The dose-confirmatory stage aimed to confirm the safety of timolumab through the incidence of dose-limiting toxicity and sufficient trough levels of circulating antibody to block VAP-1 function. The primary outcome of the dose-expansion portion of the trial was patient’s response to timolumab at day 99, as measured by a reduction in serum alkaline phosphatase by 25% or more from baseline to day 99. Results:. Twenty-three patients were recruited: 7 into the initial dose-confirmatory stage and a further 16 into an expansion stage. Timolumab (8 mg/kg) was confirmed to be safe for the duration of administration with sufficient circulating levels. Only 2 of the 18 evaluable patients (11.1%) achieved a reduction in alkaline phosphatase levels of 25% or more, and both the proportion of circulating inflammatory cell populations and biomarkers of fibrosis remained unchanged from baseline. Conclusions:. The BUTEO trial confirmed 8 mg/kg timolumab had no short-term safety signals and resulted in sufficient circulating levels of VAP-1 blocking timolumab. However, the trial was stopped after an interim assessment due to a lack of efficacy as determined by no significant change in serum liver tests.
Published: 2024
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2. Implementation of rapid genomic sequencing in safety-net neonatal intensive care units: protocol for the VIrtual GenOme CenteR (VIGOR) proof-of-concept study

Author: Pankaj Agrawal, Vineet Bhandari, Casie A Genetti, Margaret Parker, Timothy Yu, Lawrence Rhein, Jessica Douglas, Bharati Sinha, Pankaj B Agrawal, Alissa M D'Gama, Sonia Hills, Vanessa Young, Monica H Wojcik, Henry A Feldman, Timothy W Yu, Margaret G Parker, Tyler Allcroft, Luis Cantu, Alissa M D’Gama, Dynio Honrubia, Amy Kritzer, Robert Rothstein, Odalys Salinas, Andres Santana, Anyssa Serna, Faye Shapiro, Anjana Bhami Shenoy, Lindsey Simoncini, Aubrie Soucy Verran, Anéya Sousa, Qifei Li, Catherine Brownstein, Klaus Schmitz-Abe, and Marione Tamase Newsam
Subjects: Medicine
Abstract: Introduction Rapid genomic sequencing (rGS) in critically ill infants with suspected genetic disorders has high diagnostic and clinical utility. However, rGS has primarily been available at large referral centres with the resources and expertise to offer state-of-the-art genomic care. Critically ill infants from racial and ethnic minority and/or low-income populations disproportionately receive care in safety-net and/or community settings lacking access to state-of-the-art genomic care, contributing to unacceptable health equity gaps. VIrtual GenOme CenteR is a ‘proof-of-concept’ implementation science study of an innovative delivery model for genomic care in safety-net neonatal intensive care units (NICUs).Methods and analysis We developed a virtual genome centre at a referral centre to remotely support safety-net NICU sites predominantly serving racial and ethnic minority and/or low-income populations and have limited to no access to rGS. Neonatal providers at each site receive basic education about genomic medicine from the study team and identify eligible infants. The study team enrols eligible infants (goal n of 250) and their parents and follows families for 12 months. Enrolled infants receive rGS, the study team creates clinical interpretive reports to guide neonatal providers on interpreting results, and neonatal providers return results to families. Data is collected via (1) medical record abstraction, (2) surveys, interviews and focus groups with neonatal providers and (3) surveys and interviews with families. We aim to examine comprehensive implementation outcomes based on the Proctor Implementation Framework using a mixed methods approach.Ethics and dissemination This study is approved by the institutional review board of Boston Children’s Hospital (IRB-P00040496) and participating sites. Participating families are required to provide electronic written informed consent and neonatal provider consent is implied through the completion of surveys. The results will be disseminated via peer-reviewed publications and data will be made accessible per National Institutes of Health (NIH) policies.Trial registration number NCT05205356/clinicaltrials.gov.
Published: 2024
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3. P551: Provider perspectives on genomic care in safety-net neonatal intensive care units

Author: Monica Wojcik, Alissa D'Gama, Sonia Hills, Jessica Douglas, Timothy Yu, Pankaj Agrawal, and Margaret Parker
Subjects: Genetics, QH426-470, Medicine
Published: 2024
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4. Variants in PHF8 cause a spectrum of X-linked neurodevelopmental disorders and facial dysmorphology

Author: Andrew K. Sobering, Laura M. Bryant, Dong Li, Julie McGaughran, Isabelle Maystadt, Stephanie Moortgat, John M. Graham, Jr., Arie van Haeringen, Claudia Ruivenkamp, Roos Cuperus, Julie Vogt, Jenny Morton, Charlotte Brasch-Andersen, Maria Steenhof, Lars Kjærsgaard Hansen, Élodie Adler, Stanislas Lyonnet, Veronique Pingault, Marlin Sandrine, Alban Ziegler, Tyhiesia Donald, Beverly Nelson, Brandon Holt, Oleksandra Petryna, Helen Firth, Kirsty McWalter, Jacob Zyskind, Aida Telegrafi, Jane Juusola, Richard Person, Michael J. Bamshad, Dawn Earl, Anne Chun-Hui Tsai, Katherine R. Yearwood, Elysa Marco, Catherine Nowak, Jessica Douglas, Hakon Hakonarson, and Elizabeth J. Bhoj
Subjects: Genetics, QH426-470
Published: 2023
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5. Echofilter: A Deep Learning Segmention Model Improves the Automation, Standardization, and Timeliness for Post-Processing Echosounder Data in Tidal Energy Streams

Author: Scott C. Lowe, Louise P. McGarry, Jessica Douglas, Jason Newport, Sageev Oore, Christopher Whidden, and Daniel J. Hasselman
Subjects: machine learning, deep learning, hydroacoustics, entrained air, marine renewable energy, tidal energy, Science, General. Including nature conservation, geographical distribution, QH1-199.5
Abstract: Understanding the abundance and distribution of fish in tidal energy streams is important for assessing the risks presented by the introduction of tidal energy devices into the habitat. However, tidal current flows suitable for tidal energy development are often highly turbulent and entrain air into the water, complicating the interpretation of echosounder data. The portion of the water column contaminated by returns from entrained air must be excluded from data used for biological analyses. Application of a single algorithm to identify the depth-of-penetration of entrained air is insufficient for a boundary that is discontinuous, depth-dynamic, porous, and varies with tidal flow speed.Using a case study at a tidal energy demonstration site in the Bay of Fundy, we describe the development and application of deep machine learning models with a U-Net based architecture that produce a pronounced and substantial improvement in the automated detection of the extent to which entrained air has penetrated the water column.Our model, Echofilter, was found to be highly responsive to the dynamic range of turbulence conditions and sensitive to the fine-scale nuances in the boundary position, producing an entrained-air boundary line with an average error of 0.33 m on mobile downfacing and 0.5–1.0 m on stationary upfacing data, less than half that of existing algorithmic solutions. The model’s overall annotations had a high level of agreement with the human segmentation, with an intersection-over-union score of 99% for mobile downfacing recordings and 92–95% for stationary upfacing recordings. This resulted in a 50% reduction in the time required for manual edits when compared to the time required to manually edit the line placement produced by the currently available algorithms. Because of the improved initial automated placement, the implementation of the models permits an increase in the standardization and repeatability of line placement.
Published: 2022
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6. Variants in PHF8 cause a spectrum of X-linked neurodevelopmental disorders and facial dysmorphology

Author: Andrew K. Sobering, Laura M. Bryant, Dong Li, Julie McGaughran, Isabelle Maystadt, Stephanie Moortgat, John M. Graham, Jr., Arie van Haeringen, Claudia Ruivenkamp, Roos Cuperus, Julie Vogt, Jenny Morton, Charlotte Brasch-Andersen, Maria Steenhof, Lars Kjærsgaard Hansen, Élodie Adler, Stanislas Lyonnet, Veronique Pingault, Marlin Sandrine, Alban Ziegler, Tyhiesia Donald, Beverly Nelson, Brandon Holt, Oleksandra Petryna, Helen Firth, Kirsty McWalter, Jacob Zyskind, Aida Telegrafi, Jane Juusola, Richard Person, Michael J. Bamshad, Dawn Earl, Anne Chun-Hui Tsai, Katherine R. Yearwood, Elysa Marco, Catherine Nowak, Jessica Douglas, Hakon Hakonarson, and Elizabeth J. Bhoj
Subjects: PHF8, X-linked intellectual disability, orofacial clefting, epigenetic gene regulation, histone demethylation, Genetics, QH426-470
Abstract: Summary: Loss-of-function variants in PHD Finger Protein 8 (PHF8) cause Siderius X-linked intellectual disability (ID) syndrome, hereafter called PHF8-XLID. PHF8 is a histone demethylase that is important for epigenetic regulation of gene expression. PHF8-XLID is an under-characterized disorder with only five previous reports describing different PHF8 predicted loss-of-function variants in eight individuals. Features of PHF8-XLID include ID and craniofacial dysmorphology. In this report we present 16 additional individuals with PHF8-XLID from 11 different families of diverse ancestry. We also present five individuals from four different families who have ID and a variant of unknown significance in PHF8 with no other explanatory variant in another gene. All affected individuals exhibited developmental delay and all but two had borderline to severe ID. Of the two who did not have ID, one had dyscalculia and the other had mild learning difficulties. Craniofacial findings such as hypertelorism, microcephaly, elongated face, ptosis, and mild facial asymmetry were found in some affected individuals. Orofacial clefting was seen in three individuals from our cohort, suggesting that this feature is less common than previously reported. Autism spectrum disorder and attention deficit hyperactivity disorder, which were not previously emphasized in PHF8-XLID, were frequently observed in affected individuals. This series expands the clinical phenotype of this rare ID syndrome caused by loss of PHF8 function.
Published: 2022
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7. Monoclonal antibody BTT1023 targeting vascular adhesion protein 1 for treating primary sclerosing cholangitis: BUTEO single-arm Phase II trial

Author: Katherine Arndtz, Yung-Yi Chen, Anna Rowe, Victoria Homer, Amanda Kirkham, Jessica Douglas-Pugh, Daniel Slade, Douglas Thorburn, Eleanor Barnes, Guruprasad Aithal, Philip Newsome, David Smith, David Adams, Christopher Weston, and Gideon Hirschfield
Subjects: alkaline phosphatase (alp), buteo, btt1023, dose-limiting toxicity (dlt), primary sclerosing cholangitis (psc), vascular adhesion protein-1 (vap-1), Medicine
Abstract: Background: Primary sclerosing cholangitis is a progressive and fibrotic liver disease. Treatments remain inadequate, and patients with persistent elevations in activity of alkaline phosphatase are at greatest risk of disease progression. Studies in patient cohorts have implicated the serum amine oxidase vascular adhesion protein 1 in the pathophysiology of disease, including liver fibrogenesis. We hypothesised that blockade of serum amine oxidase by a monoclonal antibody would result in a reduction in liver fibrosis/injury, as evaluated by serum liver tests and other non-invasive markers of liver injury. Objectives: To evaluate the open-label effect on liver injury markers of treatment with the anti-vascular adhesion protein 1 monoclonal antibody BTT1023 in patients with primary sclerosing cholangitis over a 78-day treatment period. Design: A single-arm, two-stage, open-label, multicentre, Phase II clinical trial. Setting: Ambulatory liver disease practices in tertiary care hospitals. Participants: Patients with primary sclerosing cholangitis at risk of disease progression, based on elevated activity of serum alkaline phosphatase, and without evidence of infection, liver failure or advanced disease. Intervention: Seven intravenous infusions of BTT1023 (8 mg/kg of timolumab) over a 78-day treatment period. The intervention was split into a dose-confirmatory stage (to confirm pharmacokinetics), followed by a confirmed expansion cohort stage. Main outcome measures: Our primary outcome measure was patient response to treatment at day 99, measured by a reduction in activity of serum alkaline phosphatase of ≥ 25% from baseline to day 99. Secondary markers of efficacy were assessed based on evaluation of changes in markers of liver injury and liver fibrosis. Safety assessments were performed throughout. Results: Thirty-five patients were consented and screened for eligibility. Twenty-three patients were treated across the two stages of the trial. Interim assessment demonstrated a failure to meet the primary end point, leading to trial discontinuation on the grounds of futility. Multiple exploratory markers were evaluated in a final cohort of 22 patients (modified intention-to-treat analysis). No treatment-related effects were evident. No new safety concerns were seen. Conclusions: No preliminary evidence for disease modification was demonstrated. Limitations: It is clear that this study is limited in its design. Even if there were a better biomarker of fibrosis turnover that could be considered the ‘gold standard’, the design and duration would have had real-world resource limitations. With limited opportunity to test a new agent in large numbers of patients over a prolonged period, it was necessary to aim to see efficacy in a small cohort over a short period. Given the absence of any proven biochemical surrogate of disease activity in primary sclerosing cholangitis, alkaline phosphatase was chosen as an end point. This remains a difficult end point (yet one that does capture biliary injury) and, therefore, despite limitations, this study did demonstrate short-term safety. Future work: Future research will require attention to an ongoing debate regarding the optimal end points for assessing efficacy, as well as consideration of duration of treatment, even in early-phase studies. This raises the challenge of how to fund early experimental trials with ‘high risk of failure’ adequately to ensure that clearer results (negative or positive) arise by the end of the study. Trial registration: Current Controlled Trials ISRCTN11233255, EudraCT 2014-002393-37 and NCT02239211. Funding: This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 9, No. 1. See the NIHR Journals Library website for further project information.
Published: 2022
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8. The Ups and Downs of Using Active Acoustic Technologies to Study Fish at Tidal Energy Sites

Author: Haley A. Viehman, Daniel J. Hasselman, Jessica Douglas, and Tyler Boucher
Subjects: active acoustics, hydroacoustics, fish, entrained air, data quality, marine renewable energy, Science, General. Including nature conservation, geographical distribution, QH1-199.5
Abstract: Active acoustic instruments (echosounders) are well-suited for collecting high-resolution information on fish abundance and distribution in the areas targeted for tidal energy development, which is necessary for understanding the potential risks tidal energy devices pose to fish. However, a large proportion of echosounder data must often be omitted due to high levels of backscatter from air entrained into the water column. To effectively use these instruments at tidal energy sites, we need a better understanding of this data loss and how it may affect estimates of fish abundance and vertical distribution. We examined entrained air contamination in echosounder data from the Fundy Ocean Research Center for Energy (FORCE) tidal energy test site in Minas Passage, Nova Scotia, where current speeds can exceed 5 m·s-1. Entrained air depth was highly variable and increased with current speed, and contamination was lowest during neap tides. The lower 70% of the water column and current speeds
Published: 2022
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9. Author Correction: CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language

Author: Lot Snijders Blok, Justine Rousseau, Joanna Twist, Sophie Ehresmann, Motoki Takaku, Hanka Venselaar, Lance H. Rodan, Catherine B. Nowak, Jessica Douglas, Kathryn J. Swoboda, Marcie A. Steeves, Inderneel Sahai, Connie T. R. M. Stumpel, Alexander P. A. Stegmann, Patricia Wheeler, Marcia Willing, Elise Fiala, Aaina Kochhar, William T. Gibson, Ana S. A. Cohen, Ruky Agbahovbe, A. Micheil Innes, P. Y. Billie Au, Julia Rankin, Ilse J. Anderson, Steven A. Skinner, Raymond J. Louie, Hannah E. Warren, Alexandra Afenjar, Boris Keren, Caroline Nava, Julien Buratti, Arnaud Isapof, Diana Rodriguez, Raymond Lewandowski, Jennifer Propst, Ton van Essen, Murim Choi, Sangmoon Lee, Jong H. Chae, Susan Price, Rhonda E. Schnur, Ganka Douglas, Ingrid M. Wentzensen, Christiane Zweier, André Reis, Martin G. Bialer, Christine Moore, Marije Koopmans, Eva H. Brilstra, Glen R. Monroe, Koen L. I. van Gassen, Ellen van Binsbergen, Ruth Newbury-Ecob, Lucy Bownass, Ingrid Bader, Johannes A. Mayr, Saskia B. Wortmann, Kathy J. Jakielski, Edythe A. Strand, Katja Kloth, Tatjana Bierhals, The DDD study, John D. Roberts, Robert M. Petrovich, Shinichi Machida, Hitoshi Kurumizaka, Stefan Lelieveld, Rolph Pfundt, Sandra Jansen, Pelagia Deriziotis, Laurence Faivre, Julien Thevenon, Mirna Assoum, Lawrence Shriberg, Tjitske Kleefstra, Han G. Brunner, Paul A. Wade, Simon E. Fisher, and Philippe M. Campeau
Subjects: Science
Abstract: The HTML and PDF versions of this Article were updated after publication to remove images of one individual from Figure 1.
Published: 2019
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10. CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language

Author: Lot Snijders Blok, Justine Rousseau, Joanna Twist, Sophie Ehresmann, Motoki Takaku, Hanka Venselaar, Lance H. Rodan, Catherine B. Nowak, Jessica Douglas, Kathryn J. Swoboda, Marcie A. Steeves, Inderneel Sahai, Connie T. R. M. Stumpel, Alexander P. A. Stegmann, Patricia Wheeler, Marcia Willing, Elise Fiala, Aaina Kochhar, William T. Gibson, Ana S. A. Cohen, Ruky Agbahovbe, A. Micheil Innes, P. Y. Billie Au, Julia Rankin, Ilse J. Anderson, Steven A. Skinner, Raymond J. Louie, Hannah E. Warren, Alexandra Afenjar, Boris Keren, Caroline Nava, Julien Buratti, Arnaud Isapof, Diana Rodriguez, Raymond Lewandowski, Jennifer Propst, Ton van Essen, Murim Choi, Sangmoon Lee, Jong H. Chae, Susan Price, Rhonda E. Schnur, Ganka Douglas, Ingrid M. Wentzensen, Christiane Zweier, André Reis, Martin G. Bialer, Christine Moore, Marije Koopmans, Eva H. Brilstra, Glen R. Monroe, Koen L. I. van Gassen, Ellen van Binsbergen, Ruth Newbury-Ecob, Lucy Bownass, Ingrid Bader, Johannes A. Mayr, Saskia B. Wortmann, Kathy J. Jakielski, Edythe A. Strand, Katja Kloth, Tatjana Bierhals, The DDD study, John D. Roberts, Robert M. Petrovich, Shinichi Machida, Hitoshi Kurumizaka, Stefan Lelieveld, Rolph Pfundt, Sandra Jansen, Pelagia Deriziotis, Laurence Faivre, Julien Thevenon, Mirna Assoum, Lawrence Shriberg, Tjitske Kleefstra, Han G. Brunner, Paul A. Wade, Simon E. Fisher, and Philippe M. Campeau
Subjects: Science
Abstract: Chromodomain Helicase DNA-binding (CHD) proteins have been implicated in neurodevelopmental processes. Here, the authors identify missense variants in CHD3 that disturb its chromatin remodeling activities and cause a neurodevelopmental disorder with macrocephaly and speech and language impairment.
Published: 2018
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11. Molecular Analysis of Central Nervous System Disease Spectrum in Childhood Acute Lymphoblastic Leukemia

Author: Chindo Hicks, Jitsuda Sitthi-Amorn, Jessica Douglas, Ritika Ramani, Lucio Miele, Vani Vijayakumar, Cynthia Karlson, James Chipeta, and Gail Megason
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Published: 2016

12. William Simmonds: The Silent Heart of the Arts and Crafts Movement

Author: Jessica Douglas-Home
Published: 2018

13. Deleterious, protein-altering variants in the transcriptional coregulator ZMYM3 in 27 individuals with a neurodevelopmental delay phenotype

Author: Susan M. Hiatt, Slavica Trajkova, Matteo Rossi Sebastiano, E. Christopher Partridge, Fatima E. Abidi, Ashlyn Anderson, Muhammad Ansar, Stylianos E. Antonarakis, Azadeh Azadi, Ruxandra Bachmann-Gagescu, Andrea Bartuli, Caroline Benech, Jennifer L. Berkowitz, Michael J. Betti, Alfredo Brusco, Ashley Cannon, Giulia Caron, Yanmin Chen, Meagan E. Cochran, Tanner F. Coleman, Molly M. Crenshaw, Laurence Cuisset, Cynthia J. Curry, Hossein Darvish, Serwet Demirdas, Maria Descartes, Jessica Douglas, David A. Dyment, Houda Zghal Elloumi, Giuseppe Ermondi, Marie Faoucher, Emily G. Farrow, Stephanie A. Felker, Heather Fisher, Anna C.E. Hurst, Pascal Joset, Melissa A. Kelly, Stanislav Kmoch, Benjamin R. Leadem, Michael J. Lyons, Marina Macchiaiolo, Martin Magner, Giorgia Mandrile, Francesca Mattioli, Megan McEown, Sarah K. Meadows, Livija Medne, Naomi J.L. Meeks, Sarah Montgomery, Melanie P. Napier, Marvin Natowicz, Kimberly M. Newberry, Marcello Niceta, Lenka Noskova, Catherine B. Nowak, Amanda G. Noyes, Matthew Osmond, Eloise J. Prijoles, Jada Pugh, Verdiana Pullano, Chloé Quélin, Simin Rahimi-Aliabadi, Anita Rauch, Sylvia Redon, Alexandre Reymond, Caitlin R. Schwager, Elizabeth A. Sellars, Angela E. Scheuerle, Elena Shukarova-Angelovska, Cara Skraban, Elliot Stolerman, Bonnie R. Sullivan, Marco Tartaglia, Isabelle Thiffault, Kevin Uguen, Luis A. Umaña, Yolande van Bever, Saskia N. van der Crabben, Marjon A. van Slegtenhorst, Quinten Waisfisz, Camerun Washington, Lance H. Rodan, Richard M. Myers, Gregory M. Cooper, Human Genetics, Amsterdam Cardiovascular Sciences, Human genetics, CCA - Cancer biology and immunology, HudsonAlpha Institute for Biotechnology [Huntsville, AL], Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), 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 de Génétique et Développement de Rennes (IGDR), 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 ), CHU Pontchaillou [Rennes], Centre de référence Maladies Rares CLAD-Ouest [Rennes], and Clinical Genetics
Subjects: [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, ZMYM3, transcriptional coregulators, MESH: Phenotype, MESH: Gene Expression Regulation, MESH: Nervous System Malformations, neurodevelopmental disorder, MESH: Male, MESH: Intellectual Disability, X-linked intellectual disability, chromatin modifiers, MESH: Histone Demethylases, Genetics, MESH: Female, MESH: Face, MESH: Nuclear Proteins, Genetics (clinical), MESH: Neurodevelopmental Disorders
Abstract: Neurodevelopmental disorders (NDDs) result from highly penetrant variation in hundreds of different genes, some of which have not yet been identified. Using the MatchMaker Exchange, we assembled a cohort of 27 individuals with rare, protein-altering variation in the transcriptional coregulator ZMYM3, located on the X chromosome. Most (n = 24) individuals were males, 17 of which have a maternally inherited variant; six individuals (4 male, 2 female) harbor de novo variants. Overlapping features included developmental delay, intellectual disability, behavioral abnormalities, and a specific facial gestalt in a subset of males. Variants in almost all individuals (n = 26) are missense, including six that recurrently affect two residues. Four unrelated probands were identified with inherited variation affecting Arg441, a site at which variation has been previously seen in NDD-affected siblings, and two individuals have de novo variation resulting in p.Arg1294Cys (c.3880C>T). All variants affect evolutionarily conserved sites, and most are predicted to damage protein structure or function. ZMYM3 is relatively intolerant to variation in the general population, is widely expressed across human tissues, and encodes a component of the KDM1A-RCOR1 chromatin-modifying complex. ChIP-seq experiments on one variant, p.Arg1274Trp, indicate dramatically reduced genomic occupancy, supporting a hypomorphic effect. While we are unable to perform statistical evaluations to definitively support a causative role for variation in ZMYM3, the totality of the evidence, including 27 affected individuals, recurrent variation at two codons, overlapping phenotypic features, protein-modeling data, evolutionary constraint, and experimentally confirmed functional effects strongly support ZMYM3 as an NDD-associated gene.
Published: 2023

14. Deleterious, protein-altering variants in the X-linked transcriptional coregulator ZMYM3 in 22 individuals with a neurodevelopmental delay phenotype

Author: Susan M. Hiatt, Slavica Trajkova, Matteo Rossi Sebastiano, E. Christopher Partridge, Fatima E. Abidi, Ashlyn Anderson, Muhammad Ansar, Stylianos E. Antonarakis, Azadeh Azadi, Ruxandra Bachmann-Gagescu, Andrea Bartuli, Caroline Benech, Jennifer L. Berkowitz, Michael J. Betti, Alfredo Brusco, Ashley Cannon, Giulia Caron, Yanmin Chen, Molly M. Crenshaw, Laurence Cuisset, Cynthia J. Curry, Hossein Darvish, Serwet Demirdas, Maria Descartes, Jessica Douglas, David A. Dyment, Houda Zghal Elloumi, Giuseppe Ermondi, Marie Faoucher, Emily G. Farrow, Stephanie A. Felker, Heather Fisher, Anna C. E. Hurst, Pascal Joset, Stanislav Kmoch, Benjamin R. Leadem, Marina Macchiaiolo, Martin Magner, Giorgia Mandrile, Francesca Mattioli, Megan McEown, Sarah K. Meadows, Livija Medne, Naomi J. L. Meeks, Sarah Montgomery, Melanie P. Napier, Marvin Natowicz, Kimberly M. Newberry, Marcello Niceta, Lenka Noskova, Catherine Nowak, Amanda G. Noyes, Matthew Osmond, Verdiana Pullano, Chloé Quélin, Simin Rahimi-Aliabadi, Anita Rauch, Sylvia Redon, Alexandre Reymond, Caitlin R. Schwager, Elizabeth A. Sellars, Angela Scheuerle, Elena Shukarova-Angelovska, Cara Skraban, Bonnie R. Sullivan, Marco Tartaglia, Isabelle Thiffault, Kevin Uguen, Luis A. Umaña, Yolande van Bever, Saskia N. van der Crabben, Marjon A. van Slegtenhorst, Quinten Waisfisz, Richard M. Myers, and Gregory M. Cooper
Abstract: Neurodevelopmental disorders (NDDs) often result from highly penetrant variation in one of many genes, including genes not yet characterized. Using the MatchMaker Exchange, we assembled a cohort of 22 individuals with rare, protein-altering variation in the X-linked transcriptional coregulator gene ZMYM3. Most (n=19) individuals were males; 15 males had maternally-inherited alleles, three of the variants in males arose de novo, and one had unknown inheritance. Overlapping features included developmental delay, intellectual disability, behavioral abnormalities, and a specific facial gestalt in a subset of males. Variants in almost all individuals (n=21) are missense, two of which are recurrent. Three unrelated males were identified with inherited variation at R441, a site at which variation has been previously reported in NDD-affected males, and two individuals have de novo variation at R1294. All variants affect evolutionarily conserved sites, and most are predicted to damage protein structure or function. ZMYM3 is relatively intolerant to variation in the general population, is highly expressed in the brain, and encodes a component of the KDM1A-RCOR1 chromatin-modifying complex. ChIP-seq experiments on one mutant, ZMYM3R1274W, indicate dramatically reduced genomic occupancy, supporting a hypomorphic effect. While we are unable to perform statistical evaluations to support a conclusive causative role for variation in ZMYM3 in disease, the totality of the evidence, including the presence of recurrent variation, overlapping phenotypic features, protein-modeling data, evolutionary constraint, and experimentally-confirmed functional effects, strongly supports ZMYM3 as a novel NDD gene.
Published: 2022

15. BICRA, a SWI/SNF Complex Member, Is Associated with BAF-Disorder Related Phenotypes in Humans and Model Organisms

Author: Erin Conboy, Catherine Nowak, Karen Stals, Elliot S. Stolerman, Brett Bostwick, Tiana M. Scott, Emma Wakeling, Cyril Mignot, Sian Ellard, Brittany C. Michel, Kayla Treat, Berrak Ugur, Jill A. Rosenfeld, Caroline Nava, Sally Ann Lynch, Victoria M. Pratt, Hugo J. Bellen, Aiko Otsubo, Michael F. Wangler, Jennifer Gass, John Herriges, Jennifer B. Phillips, Gaetan Lesca, Bo Yuan, Shinya Yamamoto, Scott Barish, Marjon van Slegtenhorst, Jessica Douglas, Dihong Zhou, Patrick Edery, David R. Murdock, Jeremy Wegner, Jose Camacho, Marie Faoucher, Boris Keren, Camerun Washington, Elena Perenthaler, Kendra Engleman, Francesco Vetrini, Anita Nikoncuk, Alfredo M. Valencia, Daryl A. Scott, Cigall Kadoch, Isabelle Thiffault, Tahsin Stefan Barakat, Chun-An Chen, Lance H. Rodan, Raymond J. Louie, Hongzheng Dai, Alice S. Brooks, Nazar Mashtalir, Monte Westerfield, Nora Shannon, and Clinical Genetics
Subjects: Male, Adolescent, Chromosomal Proteins, Non-Histone, Developmental Disabilities, Mutation, Missense, Haploinsufficiency, Article, Chromatin remodeling, 03 medical and health sciences, 0302 clinical medicine, Genetics, Animals, Drosophila Proteins, Humans, Missense mutation, Child, Zebrafish, Genetics (clinical), Genes, Dominant, 030304 developmental biology, Neurons, 0303 health sciences, Microscopy, Confocal, biology, SWI/SNF complex, Coarse facial features, Tumor Suppressor Proteins, Genetic Variation, Infant, Zebrafish Proteins, Position-effect variegation, biology.organism_classification, Phenotype, Drosophila melanogaster, Child, Preschool, Female, Neuroglia, 030217 neurology & neurosurgery, Protein Binding
Abstract: SWI/SNF-related intellectual disability disorders (SSRIDDs) are rare neurodevelopmental disorders characterized by developmental disability, coarse facial features, and fifth digit/nail hypoplasia that are caused by pathogenic variants in genes that encode for members of the SWI/SNF (or BAF) family of chromatin remodeling complexes. We have identified 12 individuals with rare variants (10 loss-of-function, 2 missense) in the BICRA (BRD4 interacting chromatin remodeling complex-associated protein) gene, also known as GLTSCR1, which encodes a subunit of the non-canonical BAF (ncBAF) complex. These individuals exhibited neurodevelopmental phenotypes that include developmental delay, intellectual disability, autism spectrum disorder, and behavioral abnormalities as well as dysmorphic features. Notably, the majority of individuals lack the fifth digit/nail hypoplasia phenotype, a hallmark of most SSRIDDs. To confirm the role of BICRA in the development of these phenotypes, we performed functional characterization of the zebrafish and Drosophila orthologs of BICRA. In zebrafish, a mutation of bicra that mimics one of the loss-of-function variants leads to craniofacial defects possibly akin to the dysmorphic facial features seen in individuals harboring putatively pathogenic BICRA variants. We further show that Bicra physically binds to other non-canonical ncBAF complex members, including the BRD9/7 ortholog, CG7154, and is the defining member of the ncBAF complex in flies. Like other SWI/SNF complex members, loss of Bicra function in flies acts as a dominant enhancer of position effect variegation but in a more context-specific manner. We conclude that haploinsufficiency of BICRA leads to a unique SSRIDD in humans whose phenotypes overlap with those previously reported.
Published: 2020

16. De Novo ZMYND8 variants result in an autosomal dominant neurodevelopmental disorder with cardiac malformations

Author: Kerith-Rae Dias, Colleen M. Carlston, Laura E.R. Blok, Lachlan De Hayr, Urwah Nawaz, Carey-Anne Evans, Pinar Bayrak-Toydemir, Stephanie Htun, Ying Zhu, Alan Ma, Sally Ann Lynch, Catherine Moorwood, Karen Stals, Sian Ellard, Matthew N. Bainbridge, Jennifer Friedman, John G. Pappas, Rachel Rabin, Catherine B. Nowak, Jessica Douglas, Theodore E. Wilson, Maria J. Guillen Sacoto, Sureni V. Mullegama, Timothy Blake Palculict, Edwin P. Kirk, Jason R. Pinner, Matthew Edwards, Francesca Montanari, Claudio Graziano, Tommaso Pippucci, Bri Dingmann, Ian Glass, Heather C. Mefford, Takeyoshi Shimoji, Toshimitsu Suzuki, Kazuhiro Yamakawa, Haley Streff, Christian P. Schaaf, Anne M. Slavotinek, Irina Voineagu, John C. Carey, Michael F. Buckley, Annette Schenck, Robert J. Harvey, and Tony Roscioli
Subjects: All institutes and research themes of the Radboud University Medical Center, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Gene Expression Regulation, Protein Domains, Neurodevelopmental Disorders, Intellectual Disability, Exome Sequencing, Brain, Humans, Genetics (clinical)
Abstract: ZMYND8 encodes a multidomain protein that serves as a central interactive hub for coordinating critical roles in transcription regulation, chromatin remodeling, regulation of super-enhancers, DNA damage response and tumor suppression. We delineate a novel neurocognitive disorder caused by variants in the ZMYND8 gene.An international collaboration, exome sequencing, molecular modeling, yeast two-hybrid assays, analysis of available transcriptomic data and a knockdown Drosophila model were used to characterize the ZMYND8 variants.ZMYND8 variants were identified in 11 unrelated individuals; 10 occurred de novo and one suspected de novo; 2 were truncating, 9 were missense, of which one was recurrent. The disorder is characterized by intellectual disability with variable cardiovascular, ophthalmologic and minor skeletal anomalies. Missense variants in the PWWP domain of ZMYND8 abolish the interaction with Drebrin and missense variants in the MYND domain disrupt the interaction with GATAD2A. ZMYND8 is broadly expressed across cell types in all brain regions and shows highest expression in the early stages of brain development. Neuronal knockdown of the DrosophilaZMYND8 ortholog results in decreased habituation learning, consistent with a role in cognitive function.We present genomic and functional evidence for disruption of ZMYND8 as a novel etiology of syndromic intellectual disability.
Published: 2022

17. The value of patient-reported outcomes in early-phase clinical trials

Author: Ameeta Retzer, Olalekan Lee Aiyegbusi, Anna Rowe, Philip N. Newsome, Jessica Douglas-Pugh, Sheeba Khan, Saloni Mittal, Roger Wilson, Daniel O’Connor, Lisa Campbell, Sandra A. Mitchell, and Melanie Calvert
Subjects: Clinical Trials as Topic, Research Design, Data Collection, Humans, General Medicine, Patient Reported Outcome Measures, General Biochemistry, Genetics and Molecular Biology
Published: 2022

18. Variants in

Author: Andrew K, Sobering, Laura M, Bryant, Dong, Li, Julie, McGaughran, Isabelle, Maystadt, Stephanie, Moortgat, John M, Graham, Arie, van Haeringen, Claudia, Ruivenkamp, Roos, Cuperus, Julie, Vogt, Jenny, Morton, Charlotte, Brasch-Andersen, Maria, Steenhof, Lars Kjærsgaard, Hansen, Élodie, Adler, Stanislas, Lyonnet, Veronique, Pingault, Marlin, Sandrine, Alban, Ziegler, Tyhiesia, Donald, Beverly, Nelson, Brandon, Holt, Oleksandra, Petryna, Helen, Firth, Kirsty, McWalter, Jacob, Zyskind, Aida, Telegrafi, Jane, Juusola, Richard, Person, Michael J, Bamshad, Dawn, Earl, Anne Chun-Hui, Tsai, Katherine R, Yearwood, Elysa, Marco, Catherine, Nowak, Jessica, Douglas, Hakon, Hakonarson, and Elizabeth J, Bhoj
Abstract: Loss-of-function variants in
Published: 2021

19. Associations between Health Assessment Questionnaire Disability Index and physical performance in rheumatoid arthritis and osteoarthritis

Author: Kelsi Parker, Tamiho Mitsuhashi, Nicole Hogg, Debra L. Waters, Kate McCulloch, Simon Stebbings, Jessica Douglas‐Withers, J. Haxby Abbott, and Gareth J. Treharne
Subjects: Male, musculoskeletal diseases, medicine.medical_specialty, Time Factors, Health Status, Fitness Trackers, Muscle Strength Dynamometer, Osteoarthritis, Physical function, Osteoarthritis, Hip, Arthritis, Rheumatoid, Disability Evaluation, 03 medical and health sciences, Grip strength, 0302 clinical medicine, Rheumatology, Predictive Value of Tests, Internal medicine, medicine, Humans, Patient Reported Outcome Measures, 030212 general & internal medicine, skin and connective tissue diseases, Aged, 030203 arthritis & rheumatology, Hand Strength, business.industry, Middle Aged, Osteoarthritis, Knee, medicine.disease, Actigraphy, Health assessment, Physical performance, Rheumatoid arthritis, Pedometer, Physical therapy, Female, business, human activities
Abstract: Objectives To investigate whether the Health Assessment Questionnaire Disability Index (HAQ-DI) reflects objective measures of physical function in people with osteoarthritis (OA) and rheumatoid arthritis (RA). Methods In total, 139 people, 71 with RA fulfilling the American College of Rheumatology (ACR) criteria (1987) and 68 with OA fulfilling ACR criteria for OA of the hip or knee, completed the HAQ-DI. Physical function was assessed using Timed Up and Go (TUG), 30 seconds Sit to Stand (STS), grip strength dynamometry and pedometer steps over 7 days. Results The strongest association with HAQ-DI was with the TUG (R2 of 0.671 and 0.512 in RA and OA groups, respectively). HAQ-DI and STS showed a non-linear association in both groups with R2 of 0.380 in RA and 0.359 in OA. A strong association was found between HAQ-DI and grip strength in the OA group (R2 = 0.681), whereas the RA group showed a moderate association (R2 = 0.285). There was a strong association between the HAQ-DI and pedometer measures in RA (R2 = 0.562), although this association was weak in OA (R2 = 0.156). Conclusion The HAQ-DI has a strong association with the TUG in both RA and OA. There was variable association between the HAQ-DI and other physical performance measures, as well as differences between the RA and OA cohorts. In order to form a full and accurate clinical picture, health professionals should perform both subjective patient-reported outcome measures and objective physical performance measures of disability.
Published: 2018

20. An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids

Author: Sacha Ferdinandusse, Kirsty McWalter, Heleen te Brinke, Lodewijk IJlst, Petra M. Mooijer, Jos P.N. Ruiter, Alida E.M. van Lint, Mia Pras-Raves, Eric Wever, Francisca Millan, Maria J. Guillen Sacoto, Amber Begtrup, Mark Tarnopolsky, Lauren Brady, Roger L. Ladda, Susan L. Sell, Catherine B. Nowak, Jessica Douglas, Cuixia Tian, Elizabeth Ulm, Seth Perlman, Arlene V. Drack, Karen Chong, Nicole Martin, Jennifer Brault, Elly Brokamp, Camilo Toro, William A. Gahl, Ellen F. Macnamara, Lynne Wolfe, Mercedes E. Alejandro, Mahshid S. Azamian, Carlos A. Bacino, Ashok Balasubramanyam, Lindsay C. Burrage, Hsiao-Tuan Chao, Gary D. Clark, William J. Craigen, Hongzheng Dai, Shweta U. Dhar, Lisa T. Emrick, Alica M. Goldman, Neil A. Hanchard, Fariha Jamal, Lefkothea Karaviti, Seema R. Lalani, Brendan H. Lee, Richard A. Lewis, Ronit Marom, Paolo M. Moretti, David R. Murdock, Sarah K. Nicholas, James P. Orengo, Jennifer E. Posey, Lorraine Potocki, Jill A. Rosenfeld, Susan L. Samson, Daryl A. Scott, Alyssa A. Tran, Tiphanie P. Vogel, Michael F. Wangler, Shinya Yamamoto, Christine M. Eng, Pengfei Liu, Patricia A. Ward, Edward Behrens, Matthew Deardorff, Marni Falk, Kelly Hassey, Kathleen Sullivan, Adeline Vanderver, David B. Goldstein, Heidi Cope, Allyn McConkie-Rosell, Kelly Schoch, Vandana Shashi, Edward C. Smith, Rebecca C. Spillmann, Jennifer A. Sullivan, Queenie K.-G. Tan, Nicole M. Walley, Pankaj B. Agrawal, Alan H. Beggs, Gerard T. Berry, Lauren C. Briere, Laurel A. Cobban, Matthew Coggins, Cynthia M. Cooper, Elizabeth L. Fieg, Frances High, Ingrid A. Holm, Susan Korrick, Joel B. Krier, Sharyn A. Lincoln, Joseph Loscalzo, Richard L. Maas, Calum A. MacRae, J. Carl Pallais, Deepak A. Rao, Lance H. Rodan, Edwin K. Silverman, Joan M. Stoler, David A. Sweetser, Melissa Walker, Chris A. Walsh, Cecilia Esteves, Emily G. Kelley, Isaac S. Kohane, Kimberly LeBlanc, Alexa T. McCray, Anna Nagy, Surendra Dasari, Brendan C. Lanpher, Ian R. Lanza, Eva Morava, Devin Oglesbee, Guney Bademci, Deborah Barbouth, Stephanie Bivona, Olveen Carrasquillo, Ta Chen Peter Chang, Irman Forghani, Alana Grajewski, Rosario Isasi, Byron Lam, Roy Levitt, Xue Zhong Liu, Jacob McCauley, Ralph Sacco, Mario Saporta, Judy Schaechter, Mustafa Tekin, Fred Telischi, Willa Thorson, Stephan Zuchner, Heather A. Colley, Jyoti G. Dayal, David J. Eckstein, Laurie C. Findley, Donna M. Krasnewich, Laura A. Mamounas, Teri A. Manolio, John J. Mulvihill, Grace L. LaMoure, Madison P. Goldrich, Tiina K. Urv, Argenia L. Doss, Maria T. Acosta, Carsten Bonnenmann, Precilla D’Souza, David D. Draper, Carlos Ferreira, Rena A. Godfrey, Catherine A. Groden, Valerie V. Maduro, Thomas C. Markello, Avi Nath, Donna Novacic, Barbara N. Pusey, Colleen E. Wahl, Eva Baker, Elizabeth A. Burke, David R. Adams, May Christine V. Malicdan, Cynthia J. Tifft, Lynne A. Wolfe, John Yang, Bradley Power, Bernadette Gochuico, Laryssa Huryn, Lea Latham, Joie Davis, Deborah Mosbrook-Davis, Francis Rossignol, Ben Solomon, John MacDowall, Audrey Thurm, Wadih Zein, Muhammad Yousef, Margaret Adam, Laura Amendola, Michael Bamshad, Anita Beck, Jimmy Bennett, Beverly Berg-Rood, Elizabeth Blue, Brenna Boyd, Peter Byers, Sirisak Chanprasert, Michael Cunningham, Katrina Dipple, Daniel Doherty, Dawn Earl, Ian Glass, Katie Golden-Grant, Sihoun Hahn, Anne Hing, Fuki M. Hisama, Martha Horike-Pyne, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Christina Lam, Kenneth Maravilla, Heather Mefford, J. Lawrence Merritt, Ghayda Mirzaa, Deborah Nickerson, Wendy Raskind, Natalie Rosenwasser, C. Ron Scott, Angela Sun, Virginia Sybert, Stephanie Wallace, Mark Wener, Tara Wenger, Euan A. Ashley, Gill Bejerano, Jonathan A. Bernstein, Devon Bonner, Terra R. Coakley, Liliana Fernandez, Paul G. Fisher, Laure Fresard, Jason Hom, Yong Huang, Jennefer N. Kohler, Elijah Kravets, Marta M. Majcherska, Beth A. Martin, Shruti Marwaha, Colleen E. McCormack, Archana N. Raja, Chloe M. Reuter, Maura Ruzhnikov, Jacinda B. Sampson, Kevin S. Smith, Shirley Sutton, Holly K. Tabor, Brianna M. Tucker, Matthew T. Wheeler, Diane B. Zastrow, Chunli Zhao, William E. Byrd, Andrew B. Crouse, Matthew Might, Mariko Nakano-Okuno, Jordan Whitlock, Gabrielle Brown, Manish J. Butte, Esteban C. Dell’Angelica, Naghmeh Dorrani, Emilie D. Douine, Brent L. Fogel, Irma Gutierrez, Alden Huang, Deborah Krakow, Hane Lee, Sandra K. Loo, Bryan C. Mak, Martin G. Martin, Julian A. Martínez-Agosto, Elisabeth McGee, Stanley F. Nelson, Shirley Nieves-Rodriguez, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, Genecee Renteria, Rebecca H. Signer, Janet S. Sinsheimer, Jijun Wan, Lee-kai Wang, Katherine Wesseling Perry, Jeremy D. Woods, Justin Alvey, Ashley Andrews, Jim Bale, John Bohnsack, Lorenzo Botto, John Carey, Laura Pace, Nicola Longo, Gabor Marth, Paolo Moretti, Aaron Quinlan, Matt Velinder, Dave Viskochil, Pinar Bayrak-Toydemir, Rong Mao, Monte Westerfield, Anna Bican, Laura Duncan, Rizwan Hamid, Jennifer Kennedy, Mary Kozuira, John H. Newman, John A. Phillips, Lynette Rives, Amy K. Robertson, Emily Solem, Joy D. Cogan, F. Sessions Cole, Nichole Hayes, Dana Kiley, Kathy Sisco, Jennifer Wambach, Daniel Wegner, Dustin Baldridge, Stephen Pak, Timothy Schedl, Jimann Shin, Lilianna Solnica-Krezel, Quinten Waisfisz, Petra J.G. Zwijnenburg, Alban Ziegler, Magalie Barth, Rosemarie Smith, Sara Ellingwood, Deborah Gaebler-Spira, Somayeh Bakhtiari, Michael C. Kruer, Antoine H.C. van Kampen, Ronald J.A. Wanders, Hans R. Waterham, David Cassiman, Frédéric M. Vaz, Laboratory Genetic Metabolic Diseases, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, APH - Methodology, Epidemiology and Data Science, APH - Personalized Medicine, Laboratory for General Clinical Chemistry, ARD - Amsterdam Reproduction and Development, Human genetics, ACS - Atherosclerosis & ischemic syndromes, and Amsterdam Reproduction & Development (AR&D)
Subjects: Candidate gene, Hereditary spastic paraplegia, Undiagnosed Diseases Network, Neurological disorder, Biology, medicine.disease, Molecular biology, Article, Biochemical phenotype, Bilateral Cataracts, Gene panel, medicine, Ether lipid synthesis, In patient, Genetics (clinical)
Abstract: Author(s): Ferdinandusse, Sacha; McWalter, Kirsty; Te Brinke, Heleen; IJlst, Lodewijk; Mooijer, Petra M; Ruiter, Jos PN; van Lint, Alida EM; Pras-Raves, Mia; Wever, Eric; Millan, Francisca; Guillen Sacoto, Maria J; Begtrup, Amber; Tarnopolsky, Mark; Brady, Lauren; Ladda, Roger L; Sell, Susan L; Nowak, Catherine B; Douglas, Jessica; Tian, Cuixia; Ulm, Elizabeth; Perlman, Seth; Drack, Arlene V; Chong, Karen; Martin, Nicole; Brault, Jennifer; Brokamp, Elly; Toro, Camilo; Gahl, William A; Macnamara, Ellen F; Wolfe, Lynne; Undiagnosed Diseases Network; Waisfisz, Quinten; Zwijnenburg, Petra JG; Ziegler, Alban; Barth, Magalie; Smith, Rosemarie; Ellingwood, Sara; Gaebler-Spira, Deborah; Bakhtiari, Somayeh; Kruer, Michael C; van Kampen, Antoine HC; Wanders, Ronald JA; Waterham, Hans R; Cassiman, David; Vaz, Frederic M | Abstract: PurposeIn this study we investigate the disease etiology in 12 patients with de novo variants in FAR1 all resulting in an amino acid change at position 480 (p.Arg480Cys/His/Leu).MethodsFollowing next-generation sequencing and clinical phenotyping, functional characterization was performed in patients' fibroblasts using FAR1 enzyme analysis, FAR1 immunoblotting/immunofluorescence, and lipidomics.ResultsAll patients had spastic paraparesis and bilateral congenital/juvenile cataracts, in most combined with speech and gross motor developmental delay and truncal hypotonia. FAR1 deficiency caused by biallelic variants results in defective ether lipid synthesis and plasmalogen deficiency. In contrast, patients' fibroblasts with the de novo FAR1 variants showed elevated plasmalogen levels. Further functional studies in fibroblasts showed that these variants cause a disruption of the plasmalogen-dependent feedback regulation of FAR1 protein levels leading to uncontrolled ether lipid production.ConclusionHeterozygous de novo variants affecting the Arg480 residue of FAR1 lead to an autosomal dominant disorder with a different disease mechanism than that of recessive FAR1 deficiency and a diametrically opposed biochemical phenotype. Our findings show that for patients with spastic paraparesis and bilateral cataracts, FAR1 should be considered as a candidate gene and added to gene panels for hereditary spastic paraplegia, cerebral palsy, and juvenile cataracts.
Published: 2021

21. NFIB Haploinsufficiency Is Associated with Intellectual Disability and Macrocephaly

Author: Sonal Mahida, Elliott H. Sherr, Elodie Lacaze, William B. Dobyns, Kosuke Izumi, Hilde Peeters, Marielle Alders, Catherine Nowak, Dawn L. Earl, Richard M. Gronostajski, Ryan J. Dean, Megan T. Cho, Anouck Schneider, Siren Berland, Patricia Blanchet, Laurence Faivre, Martin Zenker, Ina Schanze, Caitlin J. Bridges, Daniela T. Pilz, Sangamitra Boppudi, Ilse Wieland, Jens Bunt, Avni Santani, Jessica Douglas, Elaine H. Zackai, Muriel Holder-Espinasse, Linda J. Richards, Jean Baptiste Rivière, Tania Attié-Bitach, Timothy J. Edwards, Vincent Gatinois, Jacques Puechberty, Jonathan W. C. Lim, Ghayda Mirzaa, Sian Morgan, Phillis Lakeman, Steven Boogert, Samuel Huth, Marion Gérard, Denny Schanze, Florence Petit, Xiaonan Zhao, Eyal Reinstein, David Geneviève, Bronwyn Kerr, Dian Donnai, Constance Smith-Hicks, Brieana Fregeau, Amsterdam Reproduction & Development (AR&D), ACS - Pulmonary hypertension & thrombosis, Human Genetics, Otto-von-Guericke-Universität Magdeburg = Otto-von-Guericke University [Magdeburg] (OVGU), Queensland Brain Institute, University of Queensland [Brisbane], University of Amsterdam [Amsterdam] (UvA), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Embryology and genetics of human malformation (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Haukeland University Hospital, University of Bergen (UiB), GeneDx [Gaithersburg, MD, USA], University of Washington [Seattle], Seattle Children’s Hospital, University of Manchester [Manchester], Boston Children's Hospital, Harvard Medical School [Boston] (HMS), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, FHU TRANSLAD (CHU de Dijon), University of California [San Francisco] (UC San Francisco), University of California (UC), Unité fonctionnelle de génétique clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), CHU Lille, Children’s Hospital of Philadelphia (CHOP ), Département de génétique (groupe hospitalier le Havre), Groupe Hospitalier du Havre, Kennedy Krieger Institute [Baltimore], University Hospital of Wales (UHW), University Hospitals Leuven [Leuven], University of Glasgow, Sackler Faculty of Medicine, Tel Aviv University (TAU), Perelman School of Medicine, University of Pennsylvania, This work was supported by grants from the National Healthand Medical Research Council Australia (GNT1100443 to L.J.R.), the French Ministry of Health (PHRC national 2008/2008-A00515-50), Regional Council of Burgundy/Dijon University hospital (PARI 2012), The Genesis Foundation for Children, the US National Institutes of Health under NINDS grants(1R01NS092772 and 234567890 to W.B.D., 1R01NS058721 toW.B.D. and E.H.S., and K08NS092898 to G.M.M.), and Jordan’s Guardian Angels (G.M.M.). J.W.C.L. was supported by an International Postgraduate Research Scholarship and UQ Centennial Scholarship. R.M.G. was supported by NYSTEM grants (C026714,C026429, and C030133). R.J.D. was supported by Brain Injured Children’s Aftercare Recovery Endeavours (BICARE) Fellowship.L.J.R. was supported by an NHMRC Principal Research Fellowship(GNT1005751). M.Z. was supported by a grant from the GermanMinistry of Education and Research (BMBF) (GeNeRARe01GM1519A). We acknowledge the Linkage Infrastructure, Equipment and Facilities (LIEF) grant (LE100100074) awarded to the Queensland Brain Institute for the Slide Scanner and the facilities of the National Imaging Facility (NIF) at the Centre for Advanced Imaging, University of Queensland, used in the animal experiments., European Project: 270259,EC:FP7:ICT,FP7-ICT-2009-6,TBICARE(2011), Institute of Human Genetics (University Hospital Magdeburg), University Hospital of the Otto von Guericke University of Magdeburg, Department of Clinical Genetics, Academic Medical Centre, Amsterdam, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Bergen (UIB), Seattle Children's Research Institute, Department of Neurology (University of California : San Francisco), University of California [San Francisco] (UCSF), University of California-University of California, Department of Medical Genetics, HMNC Brain Health, Seattle Children’s Hospital [Seattle, WA, USA], Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU de Montpellier], Université de Lorraine (UL), Service de Génétique clinique, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Department of Pediatrics (Perelman School of Medicine), University of Pennsylvania [Philadelphia], Regional Genetic Service, St Mary's Hospital, Manchester, Department of Clinical Genetics (Academic Medical Center, University of Amsterdam), VU University Medical Center [Amsterdam], Department of Pediatrics [Seattle, WA, USA] (Division of Genetic Medicine), University of Washington [Seattle]-Seattle Children’s Hospital [Seattle, WA, USA], Institute of Medical Genetics (University Hospital of Wales), University Hospital of Wales, Center for Human Genetics, University Hospitals Leuven, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U837 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille 2 - Faculté de Médecine -Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), West of Scotland Genetics Service (Queen Elizabeth University Hospital), University Hospital Birmingham Queen Elizabeth, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Medical Genetics Institute, Meir Medical Center, Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Department of Pathology and Laboratory Medicine [Philadelphia, PA, USA], University of Pennsylvania [Philadelphia]-Perelman School of Medicine, Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, School of Computer Science and Technology, Northwestern Polytechnical University [Xi'an] (NPU), Department of Biochemistry and Developmental Genomics Group, University at Buffalo [SUNY] (SUNY Buffalo), State University of New York (SUNY)-State University of New York (SUNY)-Center of Excellence in Bioinformatics and Life Sciences, Institute of Human Genetics, University Hospital Magdeburg, université de Bourgogne, LNC, Evidence based Diagnostic and Treatment Planning Solution for Traumatic Brain Injuries - TBICARE - - EC:FP7:ICT2011-02-01 - 2014-07-31 - 270259 - VALID, Otto-von-Guericke University [Magdeburg] (OVGU), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), University of California, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University Hospital of Wales [Cardiff, UK], and Tel Aviv University [Tel Aviv]
Subjects: Male, 0301 basic medicine, chromosome 9p23, Medical and Health Sciences, Corpus Callosum, Cohort Studies, Mice, 2.1 Biological and endogenous factors, Megalencephaly, Aetiology, Child, Agenesis of the corpus callosum, Genetics (clinical), Pediatric, Genetics & Heredity, Cerebral Cortex, Mice, Knockout, Genetics, Single Nucleotide, nuclear factor I, Biological Sciences, NFIB, NFIX, developmental delay, Mental Health, Codon, Nonsense, NFIA, intellectual disability, Child, Preschool, chromosome 9p22.3, Neurological, Speech delay, Female, medicine.symptom, Haploinsufficiency, Adult, Adolescent, Knockout, Intellectual and Developmental Disabilities (IDD), [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, macrocephaly, Polymorphism, Single Nucleotide, Article, Young Adult, 03 medical and health sciences, Rare Diseases, Behavioral and Social Science, medicine, megalencephaly, Animals, Humans, Polymorphism, Codon, Preschool, Neurosciences, Macrocephaly, medicine.disease, Brain Disorders, haploinsufficiency, NFI Transcription Factors, 030104 developmental biology, Nonsense, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, biology.protein, agenesis of the corpus callosum
Abstract: The nuclear factor I (NFI) family of transcription factors play an important role in normal development of multiple organs. Three NFI family members are highly expressed in the brain, and deletions or sequence variants in two of these, NFIA and NFIX, have been associated with intellectual disability (ID) and brain malformations. NFIB, however, has not previously been implicated in human disease. Here, we present a cohort of 18 individuals with mild ID and behavioral issues who are haploinsufficient for NFIB. Ten individuals harbored overlapping microdeletions of the chromosomal 9p23-p22.2 region, ranging in size from 225 kb to 4.3 Mb. Five additional subjects had point sequence variations creating a premature termination codon, and three subjects harbored single-nucleotide variations resulting in an inactive protein as determined using an in vitro reporter assay. All individuals presented with additional variable neurodevelopmental phenotypes, including muscular hypotonia, motor and speech delay, attention deficit disorder, autism spectrum disorder, and behavioral abnormalities. While structural brain anomalies, including dysgenesis of corpus callosum, were variable, individuals most frequently presented with macrocephaly. To determine whether macrocephaly could be a functional consequence of NFIB disruption, we analyzed a cortex-specific Nfib conditional knockout mouse model, which is postnatally viable. Utilizing magnetic resonance imaging and histology, we demonstrate that Nfib conditional knockout mice have enlargement of the cerebral cortex but preservation of overall brain structure and interhemispheric connectivity. Based on our findings, we propose that haploinsufficiency of NFIB causes ID with macrocephaly. ispartof: AMERICAN JOURNAL OF HUMAN GENETICS vol:103 issue:5 pages:752-768 ispartof: location:United States status: published
Published: 2018

22. Correction to: An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids

Author: Sacha Ferdinandusse, Kirsty McWalter, Heleen te Brinke, Lodewijk IJlst, Petra M. Mooijer, Jos P.N. Ruiter, Alida E.M. van Lint, Mia Pras-Raves, Eric Wever, Francisca Millan, Maria J. Guillen Sacoto, Amber Begtrup, Mark Tarnopolsky, Lauren Brady, Roger L. Ladda, Susan L. Sell, Catherine B. Nowak, Jessica Douglas, Cuixia Tian, Elizabeth Ulm, Seth Perlman, Arlene V. Drack, Karen Chong, Nicole Martin, Jennifer Brault, Elly Brokamp, Camilo Toro, William A. Gahl, Ellen F. Macnamara, Lynne Wolfe, Mercedes E. Alejandro, Mahshid S. Azamian, Carlos A. Bacino, Ashok Balasubramanyam, Lindsay C. Burrage, Hsiao-Tuan Chao, Gary D. Clark, William J. Craigen, Hongzheng Dai, Shweta U. Dhar, Lisa T. Emrick, Alica M. Goldman, Neil A. Hanchard, Fariha Jamal, Lefkothea Karaviti, Seema R. Lalani, Brendan H. Lee, Richard A. Lewis, Ronit Marom, Paolo M. Moretti, David R. Murdock, Sarah K. Nicholas, James P. Orengo, Jennifer E. Posey, Lorraine Potocki, Jill A. Rosenfeld, Susan L. Samson, Daryl A. Scott, Alyssa A. Tran, Tiphanie P. Vogel, Michael F. Wangler, Shinya Yamamoto, Christine M. Eng, Pengfei Liu, Patricia A. Ward, Edward Behrens, Matthew Deardorff, Marni Falk, Kelly Hassey, Kathleen Sullivan, Adeline Vanderver, David B. Goldstein, Heidi Cope, Allyn McConkie-Rosell, Kelly Schoch, Vandana Shashi, Edward C. Smith, Rebecca C. Spillmann, Jennifer A. Sullivan, Queenie K.-G. Tan, Nicole M. Walley, Pankaj B. Agrawal, Alan H. Beggs, Gerard T. Berry, Lauren C. Briere, Laurel A. Cobban, Matthew Coggins, Cynthia M. Cooper, Elizabeth L. Fieg, Frances High, Ingrid A. Holm, Susan Korrick, Joel B. Krier, Sharyn A. Lincoln, Joseph Loscalzo, Richard L. Maas, Calum A. MacRae, J. Carl Pallais, Deepak A. Rao, Lance H. Rodan, Edwin K. Silverman, Joan M. Stoler, David A. Sweetser, Melissa Walker, Chris A. Walsh, Cecilia Esteves, Emily G. Kelley, Isaac S. Kohane, Kimberly LeBlanc, Alexa T. McCray, Anna Nagy, Surendra Dasari, Brendan C. Lanpher, Ian R. Lanza, Eva Morava, Devin Oglesbee, Guney Bademci, Deborah Barbouth, Stephanie Bivona, Olveen Carrasquillo, Ta Chen Peter Chang, Irman Forghani, Alana Grajewski, Rosario Isasi, Byron Lam, Roy Levitt, Xue Zhong Liu, Jacob McCauley, Ralph Sacco, Mario Saporta, Judy Schaechter, Mustafa Tekin, Fred Telischi, Willa Thorson, Stephan Zuchner, Heather A. Colley, Jyoti G. Dayal, David J. Eckstein, Laurie C. Findley, Donna M. Krasnewich, Laura A. Mamounas, Teri A. Manolio, John J. Mulvihill, Grace L. LaMoure, Madison P. Goldrich, Tiina K. Urv, Argenia L. Doss, Maria T. Acosta, Carsten Bonnenmann, Precilla D’Souza, David D. Draper, Carlos Ferreira, Rena A. Godfrey, Catherine A. Groden, Valerie V. Maduro, Thomas C. Markello, Avi Nath, Donna Novacic, Barbara N. Pusey, Colleen E. Wahl, Eva Baker, Elizabeth A. Burke, David R. Adams, May Christine V. Malicdan, Cynthia J. Tifft, Lynne A. Wolfe, John Yang, Bradley Power, Bernadette Gochuico, Laryssa Huryn, Lea Latham, Joie Davis, Deborah Mosbrook-Davis, Francis Rossignol, Ben Solomon, John MacDowall, Audrey Thurm, Wadih Zein, Muhammad Yousef, Margaret Adam, Laura Amendola, Michael Bamshad, Anita Beck, Jimmy Bennett, Beverly Berg-Rood, Elizabeth Blue, Brenna Boyd, Peter Byers, Sirisak Chanprasert, Michael Cunningham, Katrina Dipple, Daniel Doherty, Dawn Earl, Ian Glass, Katie Golden-Grant, Sihoun Hahn, Anne Hing, Fuki M. Hisama, Martha Horike-Pyne, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Christina Lam, Kenneth Maravilla, Heather Mefford, J. Lawrence Merritt, Ghayda Mirzaa, Deborah Nickerson, Wendy Raskind, Natalie Rosenwasser, C. Ron Scott, Angela Sun, Virginia Sybert, Stephanie Wallace, Mark Wener, Tara Wenger, Euan A. Ashley, Gill Bejerano, Jonathan A. Bernstein, Devon Bonner, Terra R. Coakley, Liliana Fernandez, Paul G. Fisher, Laure Fresard, Jason Hom, Yong Huang, Jennefer N. Kohler, Elijah Kravets, Marta M. Majcherska, Beth A. Martin, Shruti Marwaha, Colleen E. McCormack, Archana N. Raja, Chloe M. Reuter, Maura Ruzhnikov, Jacinda B. Sampson, Kevin S. Smith, Shirley Sutton, Holly K. Tabor, Brianna M. Tucker, Matthew T. Wheeler, Diane B. Zastrow, Chunli Zhao, William E. Byrd, Andrew B. Crouse, Matthew Might, Mariko Nakano-Okuno, Jordan Whitlock, Gabrielle Brown, Manish J. Butte, Esteban C. Dell’Angelica, Naghmeh Dorrani, Emilie D. Douine, Brent L. Fogel, Irma Gutierrez, Alden Huang, Deborah Krakow, Hane Lee, Sandra K. Loo, Bryan C. Mak, Martin G. Martin, Julian A. Martínez-Agosto, Elisabeth McGee, Stanley F. Nelson, Shirley Nieves-Rodriguez, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, Genecee Renteria, Rebecca H. Signer, Janet S. Sinsheimer, Jijun Wan, Lee-kai Wang, Katherine Wesseling Perry, Jeremy D. Woods, Justin Alvey, Ashley Andrews, Jim Bale, John Bohnsack, Lorenzo Botto, John Carey, Laura Pace, Nicola Longo, Gabor Marth, Paolo Moretti, Aaron Quinlan, Matt Velinder, Dave Viskochil, Pinar Bayrak-Toydemir, Rong Mao, Monte Westerfield, Anna Bican, Laura Duncan, Rizwan Hamid, Jennifer Kennedy, Mary Kozuira, John H. Newman, John A. Phillips, Lynette Rives, Amy K. Robertson, Emily Solem, Joy D. Cogan, F. Sessions Cole, Nichole Hayes, Dana Kiley, Kathy Sisco, Jennifer Wambach, Daniel Wegner, Dustin Baldridge, Stephen Pak, Timothy Schedl, Jimann Shin, Lilianna Solnica-Krezel, Quinten Waisfisz, Petra J.G. Zwijnenburg, Alban Ziegler, Magalie Barth, Rosemarie Smith, Sara Ellingwood, Deborah Gaebler-Spira, Somayeh Bakhtiari, Michael C. Kruer, Antoine H.C. van Kampen, Ronald J.A. Wanders, Hans R. Waterham, David Cassiman, and Frédéric M. Vaz
Subjects: Phenotype, Spastic Paraplegia, Hereditary, Correction, Humans, Aldehyde Oxidoreductases, Lipids, Genetics (clinical), Ethers
Abstract: In this study we investigate the disease etiology in 12 patients with de novo variants in FAR1 all resulting in an amino acid change at position 480 (p.Arg480Cys/His/Leu).Following next-generation sequencing and clinical phenotyping, functional characterization was performed in patients' fibroblasts using FAR1 enzyme analysis, FAR1 immunoblotting/immunofluorescence, and lipidomics.All patients had spastic paraparesis and bilateral congenital/juvenile cataracts, in most combined with speech and gross motor developmental delay and truncal hypotonia. FAR1 deficiency caused by biallelic variants results in defective ether lipid synthesis and plasmalogen deficiency. In contrast, patients' fibroblasts with the de novo FAR1 variants showed elevated plasmalogen levels. Further functional studies in fibroblasts showed that these variants cause a disruption of the plasmalogen-dependent feedback regulation of FAR1 protein levels leading to uncontrolled ether lipid production.Heterozygous de novo variants affecting the Arg480 residue of FAR1 lead to an autosomal dominant disorder with a different disease mechanism than that of recessive FAR1 deficiency and a diametrically opposed biochemical phenotype. Our findings show that for patients with spastic paraparesis and bilateral cataracts, FAR1 should be considered as a candidate gene and added to gene panels for hereditary spastic paraplegia, cerebral palsy, and juvenile cataracts.
Published: 2021

23. Documenting a social movement in real time: the Preserve the Baltimore Uprising 2015 archive project

Author: Jessica Douglas
Subjects: History, Media studies, Social movement
Published: 2019

24. De novoloss of function mutations inKIAA2022are associated with epilepsy and neurodevelopmental delay in females

Author: Catherine Nowak, Megan T. Cho, Francisca Millan, Gerald V. Raymond, Aurora Pujol, Kyle Retterer, Amber Begtrup, Rachel Webster, Jessica Douglas, Orrin Devinsky, Wendy K. Chung, Dianalee McKnight, Ayesha Ahmad, and Maria R. Johnson
Subjects: 0301 basic medicine, Genetics, education.field_of_study, Population, Biology, medicine.disease, Phenotype, 03 medical and health sciences, Epilepsy, 030104 developmental biology, 0302 clinical medicine, Intellectual disability, medicine, Autism, education, 030217 neurology & neurosurgery, Genetics (clinical), Exome sequencing, Loss function, X chromosome
Abstract: Intellectual disability (ID) affects about 3% of the population and has a male gender bias. Of at least 700 genes currently linked to ID, more than 100 have been identified on the X chromosome, including KIAA2022. KIAA2022 is located on Xq13.3 and is expressed in the developing brain. The protein product of KIAA2022, X‐linked Intellectual Disability Protein Related to Neurite Extension (XPN), is developmentally regulated and is involved in neuronal migration and cell adhesion. The clinical manifestations of loss‐of‐function KIAA2022 mutations have been described previously in 15 males, born from unaffected carrier mothers, but few females. Using whole‐exome sequencing, we identified a cohort of five unrelated female patients with de novo probably gene damaging variants in KIAA2022 and core phenotypic features of ID, developmental delay, epilepsy refractory to treatment, and impaired language, of similar severity as reported for male counterparts. This study supports KIAA2022 as a novel cause of X‐linked dominant ID, and broadens the phenotype for KIAA2022 mutations.
Published: 2016

25. Is one diagnosis the whole story? patients with double diagnoses

Author: Zohar Levi, Dov Tiosano, Catherine Nowak, Nina Ekhilevich, Lior Cohen, Adi Mory, Monika Weisz Hubshman, Hagit N. Baris, Inbal Kedar, Jessica Douglas, Daphna Marom, Alina Kurolap, Wen-Hann Tan, and Naama Orenstein
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_specialty, Adolescent, media_common.quotation_subject, Clinical Decision-Making, 030105 genetics & heredity, Diagnostic evaluation, Young Adult, 03 medical and health sciences, Presentation, Risk Factors, Chromosome Duplication, Genetics, Humans, Medicine, Genetic Testing, Medical diagnosis, Child, Set (psychology), Intensive care medicine, Genetic Association Studies, Genetics (clinical), media_common, business.industry, Genetic Diseases, Inborn, Infant, Newborn, Genetic Variation, Infant, Middle Aged, Aneuploidy, Natural history, Child, Preschool, Genetics clinic, Female, Chromosome Deletion, Genetic diagnosis, business
Abstract: One of the goals of evaluating a patient in the genetics clinic is to find the diagnosis that would explain his or her clinical presentation. Sometimes the patient's diagnosis remains undefined or does not explain all of the clinical findings. As clinicians are often guided by a "single disorder" paradigm, diagnosing multiple genetic conditions in the same patient requires a heightened sense of awareness. Over the last few years, we evaluated several patients (n = 14) who were found to have more than one genetic diagnosis. In this paper, we will describe their natural history and diagnoses, and draw on the lessons learned from this phenomenon, which we expect to grow in this era of next-generation diagnostic technologies. To our knowledge, this is by far the largest series of patients with double diagnoses. Based on our findings, we strongly recommend that physicians question every diagnosis to determine whether it indeed explains all of the patients' symptoms, and consider whether they should continue the diagnostic evaluation to look for a more accurate and complete set of diagnoses. © 2016 Wiley Periodicals, Inc.
Published: 2016

26. Mutations in TKT Are the Cause of a Syndrome Including Short Stature, Developmental Delay, and Congenital Heart Defects

Author: Nancy Kramer, Melissa Andrew, Birthe Roos, Vivian Hwa, Mirjam M.C. Wamelink, Kristin G. Monaghan, Jessica Douglas, Lia Boyle, Sulagna C. Saitta, Amber Begtrup, Andrew Dauber, Wendy K. Chung, Julia Wynn, Gajja S. Salomons, Ana Pop, Megan T. Cho, Murray Feingold, Kyle Retterer, Laboratory Medicine, and Amsterdam Neuroscience - Cellular & Molecular Mechanisms
Subjects: 0301 basic medicine, Adult, Heart Defects, Congenital, Male, neurodevelopmental disability, Developmental Disabilities, pentose phosphate pathway, Dwarfism, 030204 cardiovascular system & hematology, Biology, Transketolase, Compound heterozygosity, medicine.disease_cause, Short stature, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Cataracts, Report, medicine, Genetics, Missense mutation, Humans, Genetics(clinical), Child, Genetics (clinical), Mutation, Syndrome, transketolase deficiency, medicine.disease, Glutathione, congenital heart disease, Pedigree, TKT, 030104 developmental biology, Child, Preschool, Transketolase activity, Female, medicine.symptom, NADP
Abstract: Whole-exome sequencing (WES) is increasingly being utilized to diagnose individuals with undiagnosed disorders. Developmental delay and short stature are common clinical indications for WES. We performed WES in three families, using proband-parent trios and two additional affected siblings. We identified a syndrome due to an autosomal-recessively inherited deficiency of transketolase, encoded by TKT, on chromosome 3p21. Our series includes three families with a total of five affected individuals, ranging in age from 4 to 25 years. Two families of Ashkenazi Jewish ancestry were homozygous for an 18 base pair in-frame insertion in TKT. The third family was compound heterozygous for nonsense and missense variants in TKT. All affected individuals had short stature and were developmentally delayed. Congenital heart defects were noted in four of the five affected individuals, and there was a history of chronic diarrhea and cataracts in the older individuals with the homozygous 18 base pair insertion. Enzymatic testing confirmed significantly reduced transketolase activity. Elevated urinary excretion of erythritol, arabitol, ribitol, and pent(ul)ose-5-phosphates was detected, as well as elevated amounts of erythritol, arabitol, and ribitol in the plasma of affected individuals. Transketolase deficiency reduces NADPH synthesis and nucleic acid synthesis and cell division and could explain the problems with growth. NADPH is also critical for maintaining cerebral glutathione, which might contribute to the neurodevelopmental delays. Transketolase deficiency is one of a growing list of inborn errors of metabolism in the non-oxidative part of the pentose phosphate pathway.
Published: 2016
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27. Molecular Analysis of Central Nervous System Disease Spectrum in Childhood Acute Lymphoblastic Leukemia

Author: Ritika Ramani, Jitsuda Sitthi-Amorn, Cynthia W. Karlson, Vani Vijayakumar, James Chipeta, Lucio Miele, Gail Megason, Chindo Hicks, and Jessica Douglas
Subjects: 0301 basic medicine, Microarray, Central nervous system, Disease, acute lymphoblastic leukemia, Bioinformatics, lcsh:RC254-282, Central nervous system disease, 03 medical and health sciences, 0302 clinical medicine, medicine, Childhood Acute Lymphoblastic Leukemia, Original Research, business.industry, Wnt signaling pathway, Cancer, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 030104 developmental biology, medicine.anatomical_structure, Oncology, central nervous disease spectrum, 030220 oncology & carcinogenesis, gene expression, Signal transduction, business
Abstract: Treatment of the central nervous system (CNS) is an essential therapeutic component in childhood acute lymphoblastic leukemia (ALL). The goal of this study was to identify molecular signatures distinguishing patients with CNS disease from those without the disease in pediatric patients with ALL. We analyzed gene expression data from 207 pediatric patients with ALL. Patients without CNS were classified as CNS1, while those with mild and advanced CNS disease were classified as CNS2 and CNS3, respectively. We compared gene expression levels among the three disease classes. We identified gene signatures distinguishing the three disease classes. Pathway analysis revealed molecular networks and biological pathways dysregulated in response to CNS disease involvement. The identified pathways included the ILK, WNT, B-cell receptor, AMPK, ERK5, and JAK signaling pathways. The results demonstrate that transcription profiling could be used to stratify patients to guide therapeutic decision-making in pediatric ALL.
Published: 2016

28. Severe neurocognitive and growth disorders due to variation in THOC2, an essential component of nuclear mRNA export machinery

Author: Raman Kumar, Heather C Mefford, Tracy Dudding-Byth, Michael Field, Mark A. Tarnopolsky, Gail E. Herman, Simon Sadedin, Elizabeth E. Palmer, Catherine Nowak, Evelyn Douglas, Broad Cmg, Lauren Brady, Gretchen Parsons, Tim M. Strom, Hermann-Josef Lüdecke, Irene Madrigal, Paul R. Mark, Jozef Gecz, Raquel Rabionet, Jessica Douglas, Naoko Ishihara, Laura Domenech Salgado, Alison Gardner, Hiroki Kurahashi, Hidehito Inagaki, Meredith K. Gillespie, Zornitza Stark, Claire C. Homan, Lourdes Loidi, Jesús Eiris, Dagmar Wieczorek, Theresa Mihalic Mosher, Kumar, Raman, Gardner, Alison, Homan, Claire C, Douglas, Evelyn, Gecz, Jozef, and Broad CMG
Subjects: 0301 basic medicine, Male, Protein subunit, Mutation, Missense, Medizin, Growth disorders, Biology, RNA Transport, Article, 03 medical and health sciences, Neurologia, Intellectual Disability, Genotype, Trastorns del creixement, Genetics, medicine, Missense mutation, Humans, Protein Isoforms, RNA, Messenger, Child, Gene, Genetics (clinical), Growth Disorders, mRNA export, Messenger RNA, Epilepsy, XLID, RNA-Binding Proteins, Exons, Phenotype, THOC2, Cell nucleus, 030104 developmental biology, medicine.anatomical_structure, HEK293 Cells, Neurology, protein stability, Cytoplasm, Child, Preschool, Female, partial loss-of-function variants, HeLa Cells
Abstract: Highly conserved TREX-mediated mRNA export is emerging as a key pathway in neuronal development and differentiation. TREX subunit variants cause neurodevelopmental disorders (NDDs) by interfering with mRNA export from the cell nucleus to the cytoplasm. Previously we implicated four missense variants in the X-linked THOC2 gene in intellectual disability (ID). We now report an additional six affected individuals from five unrelated families with two de novo and three maternally inherited pathogenic or likely pathogenic variants in THOC2 extending the genotypic and phenotypic spectrum. These comprise three rare missense THOC2 variants that affect evolutionarily conserved amino acid residues and reduce protein stability and two with canonical splice-site THOC2 variants that result in C-terminally truncated THOC2 proteins. We present detailed clinical assessment and functional studies on a de novo variant in a female with an epileptic encephalopathy and discuss an additional four families with rare variants in THOC2 with supportive evidence for pathogenicity. Severe neurocognitive features, including movement and seizure disorders, were observed in this cohort. Taken together our data show that even subtle alterations to the canonical molecular pathways such as mRNA export, otherwise essential for cellular life, can be compatible with life, but lead to NDDs in humans. Refereed/Peer-reviewed
Published: 2018

29. Abstract TP198: Reducing Stroke Readmissions

Author: Kelly Venters, Amber Parker, Jessica Douglas, and Heather Ramsey
Subjects: Advanced and Specialized Nursing, medicine.medical_specialty, business.industry, medicine.medical_treatment, medicine.disease, Emergency medicine, Health care, medicine, Neurology (clinical), Medical emergency, Cardiology and Cardiovascular Medicine, business, Stroke recovery, Stroke, Medicaid
Abstract: Background and Purpose: Hospital readmissions have become a priority focus for healthcare organizations. According to the Centers for Medicare and Medicaid, 20% of all patients who are discharged from a hospital will be readmitted within thirty days (CMS, 2015). This not only has a negative impact for the patient, but also imposes a financial impact on the healthcare organization. Baseline data from 2014 at Lake Cumberland Regional Hospital (LCRH) showed a stroke readmission rate of 9.6%. The purpose was to decrease stroke readmissions through development of a discharge call process that targets risk factors for readmission and ensures transition from hospital care to post-discharge follow-up. Methods: The discharge call process was implemented in June 2014. Calls were conducted by the facility’s stroke educator. All stroke program participants excluding discharges to nursing homes, rehabilitation center, or hospice were included in the discharge call process. Minimally, 3 attempts per patient were made to conduct the phone call within 3 days of discharge. In addition, the Lake Cumberland Area Stroke Support Group was established in May 2016 for stroke survivors and their caregivers. Results: Stroke readmission rates at LCRH decreased to 7.9% in 2015 and further declined to 1.6% as of 2nd quarter 2016. Interventions completed as a result of the discharge phone call process include: expediting follow-up appointments, collaborating with primary care practitioner for needed prescriptions, clarifying discharge instructions, reinforcing stroke education, and scheduling additional follow-up calls to provide assistance when needed. Conclusions: Stroke readmission rates decreased from 9.6% in 2014 to 1.6% through second quarter of 2016. Multiple opportunities were discovered to close the communication gap between hospital care and primary care follow-up. Maintaining contact post-discharge is needed to transition from the hospital to home care.
Published: 2017

30. De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder

Author: Jill A. Rosenfeld, Dominique Bonneau, Deborah Barbouth, Stephen Sanders, Kimberly Nugent, Kimberly Glaser, Ignacio Briceño, Kyle Retterer, Sylvain Simon, Weimin Bi, Yaping Yang, Holly A.F. Stessman, Kristin G. Monaghan, Pawel Stankiewicz, Caroline Rooryck, Sébastien Küry, James R. Lupski, Xenia Latypova, Carlos A. Bacino, Stephanie Sacharow, Sandra Mercier, Evan E. Eichler, Marie Vincent, Elizabeth Roeder, Sébastien Schmitt, Thomas Besnard, Alberto Gómez, Ankita Patel, Brigitte Gilbert-Dussardier, Valérie Malan, Mathilde Nizon, Jessica Douglas, Annick Toutain, Peter-Michael Kloetzel, Anne-Sophie Denommé-Pichon, Frédéric Ebstein, Fan Xia, Laurent Pasquier, Megan T. Cho, Mathilde Pacault, Laurence Perrin-Sabourin, James B. Gibson, Bertrand Isidor, William J. Craigen, Bo Yuan, Stéphane Bézieau, Chad A. Shaw, Richard Redon, Janice L. Smith, Benjamin Cogné, Eric Bieth, Wallid Deb, Kamal Khan, Sylvie Odent, Andrea Lehmann, Tahir N. Khan, Philippe Parent, Christelle Golzio, Nicholas Katsanis, Marie-Line Jacquemont, Tomasz Gambin, Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Boston Children's Hospital, Department of Medicine, Karolinska Institutet [Stockholm], Service de Génétique [Purpan], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Department of Pediatrics, The University of Texas at San Antonio (UTSA), LabEX IGO Immunothérapie Grand Ouest, Service de Cancéro-Dermatologie, Centre hospitalier universitaire de Nantes (CHU Nantes), Anti-tumor immunosurveillances and immunotherapy (CRCINA - Département INCIT - Equipe 3), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers (CRCINA), 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 de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-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 de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Mitochondrie : Régulations et Pathologie, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Génétique Médicale, Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Centre de Référence Anomalies du Développement Ouest, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de génétique clinique [Rennes], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-Hôpital Sud, CHU Pontchaillou [Rennes], Service de génétique [Tours], Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Imagerie et cerveau, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Laboratoire Histologie Embryologie Cytogénétique [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Instituto de Genetica Humana, Pontificia Universidad Javeriana, Universitad de la Sabana, Baylor College of Medicine (BCM), Baylor University, 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), Center for Human Disease Modeling, Duke University [Durham], National Heart, Lung, and Blood Institute, Wellcome Trust, French Ministry of Health, HUGODIMS, 2013, RC14_0107, Health Regional Agency from Poitou-Charentes, U54HG006542, US National Human Genome Research Institute, 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), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Duke University Medical Center, Warsaw University of Technology [Warsaw], University of California [San Francisco] (UC San Francisco), University of California (UC), University of Miami, Service Génétique Médicale [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Hôpital Robert Debré, GeneDx [Gaithersburg, MD, USA], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Nantes Université (Nantes Univ), Anti-Tumor Immunosurveillance and Immunotherapy (CRCINA-ÉQUIPE 3), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-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)-Université d'Angers (UA)-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), Laboratoire de Biologie Neurovasculaire Intégrée [Angers] (CNRS UMR6214 - INSERM U771), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Pontificia Universidad Javeriana (PUJ), University of Washington [Seattle], Howard Hughes Medical Institute [Seattle], Howard Hughes Medical Institute (HHMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Jonchère, Laurent, Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Centre Hospitalier Universitaire de La Réunion ( CHU La Réunion ), The University of Texas at San Antonio ( UTSA ), Centre hospitalier universitaire de Nantes ( CHU Nantes ), Anti-tumor immunosurveillances and immunotherapy ( CRCINA - Département INCIT - Equipe 3 ), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers ( CRCINA ), Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Université d'Angers ( UA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université d'Angers ( UA ) -CHU Angers, Centre hospitalier universitaire de Poitiers ( CHU Poitiers ) -Centre de Référence Anomalies du Développement Ouest, Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -CHU Pontchaillou [Rennes]-Hôpital Sud, Hôpital Bretonneau-CHRU Tours, Université de Tours-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Universidad de la Sabana, Baylor College of Medicine ( BCM ), Baylor College of Medicine, unité de recherche de l'institut du thorax UMR1087 UMR6291 ( ITX ), Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), and Duke university [Durham]
Subjects: Male, 0301 basic medicine, Microcephaly, Intellectual disability, [SDV.GEN] Life Sciences [q-bio]/Genetics, 030105 genetics & heredity, 0302 clinical medicine, Neurodevelopmental disorder, Ubiquitin, PSMD12, Syndromic neurodevelopmental disorder, Child, Zebrafish, Genetics (clinical), Genetics, Proteasome 26S, Phenotype, proteasome 26S, intellectual disability, Child, Preschool, Female, Proteasome Endopeptidase Complex, Adolescent, DNA Copy Number Variations, syndromic neurodevelopmental disorder, Protein subunit, Down-Regulation, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Report, RPN5, ubiquitin, medicine, Animals, Humans, [SDV.GEN]Life Sciences [q-bio]/Genetics, Point mutation, Infant, Correction, biology.organism_classification, medicine.disease, Human genetics, Disease Models, Animal, 030104 developmental biology, Proteasome, Neurodevelopmental Disorders, biology.protein, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Gene Deletion, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery
Abstract: 12 páginas Trichosporon asahii es un hongo patógeno emergente reportado en la literatura médica principalmente en pacientes inmunocomprometidos. No obstante, el presente caso es inusual debido a que se trata de un paciente adulto joven inmunocompetente que presentó fungemia por T. asahii y al mismo tiempo desarrolló insuficiencia respiratoria aguda por bronquiolitis respiratoria y neumonía descamativa, la cual resolvió posterior al tratamiento antimicótico instaurado, soporte ventilatorio y vigilancia en Unidad de Cuidado Intesivo (UCI). Degradation of proteins by the ubiquitin-proteasome system (UPS) is an essential biological process in the development of eukaryotic organisms. Dysregulation of this mechanism leads to numerous human neurodegenerative or neurodevelopmental disorders. Through a multi-center collaboration, we identified six de novo genomic deletions and four de novo point mutations involving PSMD12, encoding the non-ATPase subunit PSMD12 (aka RPN5) of the 19S regulator of 26S proteasome complex, in unrelated individuals with intellectual disability, congenital malformations, ophthalmologic anomalies, feeding difficulties, deafness, and subtle dysmorphic facial features. We observed reduced PSMD12 levels and an accumulation of ubiquitinated proteins without any impairment of proteasome catalytic activity. Our PSMD12 loss-of-function zebrafish CRISPR/Cas9 model exhibited microcephaly, decreased convolution of the renal tubules, and abnormal craniofacial morphology. Our data support the biological importance of PSMD12 as a scaffolding subunit in proteasome function during development and neurogenesis in particular; they enable the definition of a neurodevelopmental disorder due to PSMD12 variants, expanding the phenotypic spectrum of UPS-dependent disorders.
Published: 2017

31. Clinical Characterization of Patients With Autosomal Dominant Short Stature due to Aggrecan Mutations

Author: Pedro A. Sanchez-Lara, Alexander A. L. Jorge, Andrew Dauber, Lenka Elblova, Evan Los, Jeffrey Baron, Nancy Dunbar, Ariadna Gonzalez Del Angel, Karen E. Heath, Emma Segerlund, Jan Fairchild, Melissa K. Crocker, Mariana F A Funari, Ola Nilsson, Yuezhen Lin, Jessica Douglas, Sinhue Diaz Cuellar, Eva-Lena Stattin, Catherine Nowak, Leah Tyzinski, Marwan Shinawi, Melissa Andrew, Lucia Sentchordi, Hidekazu Hosono, Alexandra Gkourogianni, Vivian Hwa, Jadranka Popovic, Tracey Kurtzman, Jose Bernardo Quintos, Micah L. Olson, Stepanka Pruhova, Stephen H. LaFranchi, Seema R. Lalani, Dorothee Newbern, Jan Lebl, and Jonathan M. Swartz
Subjects: 0301 basic medicine, Male, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, DNA Mutational Analysis, Growth, Intervertebral Disc Degeneration, medicine.disease_cause, Biochemistry, 0302 clinical medicine, Endocrinology, Aggrecans, Child, Sanger sequencing, Genetics, Aged, 80 and over, Mutation, Anthropometry, Brachydactyly, Middle Aged, musculoskeletal system, Phenotype, Osteochondritis Dissecans, Pedigree, Child, Preschool, symbols, Female, medicine.symptom, Intervertebral Disc Displacement, musculoskeletal diseases, Adult, medicine.medical_specialty, Heterozygote, Adolescent, 030209 endocrinology & metabolism, Context (language use), Dwarfism, Biology, ESTATURA, Short stature, DNA sequencing, 03 medical and health sciences, symbols.namesake, Young Adult, Internal medicine, medicine, Humans, Clinical Research Articles, Aged, Biochemistry (medical), Infant, Heterozygote advantage, Bone age, 030104 developmental biology, Growth Hormone
Abstract: Context: Heterozygous mutations in the aggrecan gene (ACAN) cause autosomal dominant short stature with accelerated skeletal maturation. Objective: We sought to characterize the phenotypic spectrum and response to growth-promoting therapies. Patients and Methods: One hundred three individuals (57 females, 46 males) from 20 families with autosomal dominant short stature and heterozygous ACAN mutations were identified and confirmed using whole-exome sequencing, targeted next-generation sequencing, and/or Sanger sequencing. Clinical information was collected from the medical records. Results: Identified ACAN variants showed perfect cosegregation with phenotype. Adult individuals had mildly disproportionate short stature [median height, −2.8 standard deviation score (SDS); range, −5.9 to −0.9] and a history of early growth cessation. The condition was frequently associated with early-onset osteoarthritis (12 families) and intervertebral disc disease (9 families). No apparent genotype–phenotype correlation was found between the type of ACAN mutation and the presence of joint complaints. Childhood height was less affected (median height, −2.0 SDS; range, −4.2 to −0.6). Most children with ACAN mutations had advanced bone age (bone age − chronologic age; median, +1.3 years; range, +0.0 to +3.7 years). Nineteen individuals had received growth hormone therapy with some evidence of increased growth velocity. Conclusions: Heterozygous ACAN mutations result in a phenotypic spectrum ranging from mild and proportionate short stature to a mild skeletal dysplasia with disproportionate short stature and brachydactyly. Many affected individuals developed early-onset osteoarthritis and degenerative disc disease, suggesting dysfunction of the articular cartilage and intervertebral disc cartilage. Additional studies are needed to determine the optimal treatment strategy for these patients.
Published: 2017

32. Genetic Counselors’ Views and Experiences with the Clinical Integration of Genome Sequencing

Author: Jessica Douglas, Judith Tsipis, Kate Kramer, Kalotina Machini, and Alicia Braxton
Subjects: medicine.medical_specialty, Medical education, Attitude of Health Personnel, Genome, Human, business.industry, Public health, Genetic counseling, Professional development, MEDLINE, Genetic Counseling, Bioethics, Bioinformatics, Health care, medicine, Humans, Medical genetics, business, Genetics (clinical), Exome sequencing
Abstract: In recent years, new sequencing technologies known as next generation sequencing (NGS) have provided scientists the ability to rapidly sequence all known coding as well as non-coding sequences in the human genome. As the two emerging approaches, whole exome (WES) and whole genome (WGS) sequencing, have started to be integrated in the clinical arena, we sought to survey health care professionals who are likely to be involved in the implementation process now and/or in the future (e.g., genetic counselors, geneticists and nurse practitioners). Two hundred twenty-one genetic counselors- one third of whom currently offer WES/WGS-participated in an anonymous online survey. The aims of the survey were first, to identify barriers to the implementation of WES/WGS, as perceived by survey participants; second, to provide the first systematic report of current practices regarding the integration of WES/WGS in clinic and/or research across the US and Canada and to illuminate the roles and challenges of genetic counselors participating in this process; and third to evaluate the impact of WES/WGS on patient care. Our results showed that genetic counseling practices with respect to WES/WGS are consistent with the criteria set forth in the ACMG 2012 policy statement, which highlights indications for testing, reporting, and pre/post test considerations. Our respondents described challenges related to offering WES/WGS, which included billing issues, the duration and content of the consent process, result interpretation and disclosure of incidental findings and variants of unknown significance. In addition, respondents indicated that specialty area (i.e., prenatal and cancer), lack of clinical utility of WES/WGS and concerns about interpretation of test results were factors that prevented them from offering this technology to patients. Finally, study participants identified the aspects of their professional training which have been most beneficial in aiding with the integration of WES/WGS into the clinical setting (molecular/clinical genetics, counseling and bioethics) and suggested that counseling aids (to assist them when explaining aspects of these tests to patients) and webinars focused on WES/WGS (for genetic counselors and other health care professionals) would be useful educational tools. Future research should permit us to further enhance our knowledge of pitfalls and benefits associated with the introduction of these powerful technologies in patient care and to further explore the roles and opportunities for genetic counselors in this rapidly evolving field.
Published: 2014

33. Autosomal-Recessive Mutations in AP3B2, Adaptor-Related Protein Complex 3 Beta 2 Subunit, Cause an Early-Onset Epileptic Encephalopathy with Optic Atrophy

Author: Catherine Nowak, Kamiar Mireskandari, Masano Amamoto, Jean-Baptiste Rivière, Amber Begtrup, Thibaud Jouan, Laurence Faivre, Aline Saunier, Nicolas Chatron, Noriko Miyake, Mitsuhiro Kato, Dorothée Ville, Jessica Douglas, Stéphane Auvin, Bertrand Isidor, Guylène Lemeur, Stylianos E. Antonarakis, Naomichi Matsumoto, Mathieu Milh, Philippe Jonveaux, Hanan Hamamy, Neal Sondheimer, Mirna Assoum, Paolo Milani, Mitsuko Nakashima, Amira Masri, Gaetan Lesca, Julien Thevenon, Yannis Duffourd, Laurence Perrin, Caroline Paris, Christel Thauvin-Robinet, Christophe Philippe, Periklis Makrythanasis, Génétique des Anomalies du Développement ( GAD ), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne ( UB ), Nutrition-Génétique et Exposition aux Risques Environnementaux ( NGERE ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lorraine ( UL ), Centre hospitalier universitaire de Nantes ( CHU Nantes ), Service de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP), University of Geneva, Division of Clinical and Metabolic Genetics [Toronto], The Hospital for sick children [Toronto] ( SickKids ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ), Boston Children's Hospital, Centre de recherche en neurosciences de Lyon ( CRNL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] ( UJM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Lyon, Service de Génétique Médicale [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), GeneDx, Service de Neurologie Pédiatrique [CHU Lyon], Hôpital Femme Mère Enfant [CHU - HCL] ( HFME ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Service de Neurologie Pédiatrique, HFME, Bron, France, Service d'ophtalmologie [Nantes], Hôtel-Dieu, Service de pédiatrie et neurologie pédiatrique, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Génétique Médicale et Génomique Fonctionnelle ( GMGF ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Pediatric Emergency Centre, Kitakyushu Municipal Yahata Hospital, Yokohama City University School of Medecine ( YCUSM ), University School of Medecine, University of Amman, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Regional Council of Burgundy Dijon University Hospital Association Française du Syndrome de Rett, Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre hospitalier universitaire de Nantes (CHU Nantes), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), The Hospital for sick children [Toronto] (SickKids), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), GeneDx [Gaithersburg, MD, USA], Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Yokohama City University School of Medecine (YCUSM), Yokohama University School of Medecine, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), and Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Male, Microcephaly, Developmental Disabilities, Postnatal microcephaly, copper-metabolism, Epilepsy, 0302 clinical medicine, expansion, hermansky-pudlak-syndrome, ddc:576.5, Age of Onset, Child, disorders, Genetics (clinical), seizures, Genetics, MEDNIK syndrome, Syndrome, 3. Good health, Pedigree, intellectual disability, Child, Preschool, mednik syndrome, Female, Developmental regression, Adaptor Protein Complex 3, Genes, Recessive, Biology, AP3B1, 03 medical and health sciences, Atrophy, Report, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, medicine, Humans, Adaptor Protein Complex beta Subunits, mouse, disease, ap-4 deficiency, Infant, Newborn, Infant, medicine.disease, Optic Atrophy, 030104 developmental biology, Mutation, Hermansky–Pudlak syndrome, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Early-onset epileptic encephalopathy (EOEE) represents a heterogeneous group of severe disorders characterized by seizures, interictal epileptiform activity with a disorganized electroencephalography background, developmental regression or retardation, and onset before 1 year of age. Among a cohort of 57 individuals with epileptic encephalopathy, we ascertained two unrelated affected individuals with EOEE associated with developmental impairment and autosomal-recessive variants in AP3B2 by means of whole-exome sequencing. The targeted sequencing of AP3B2 in 86 unrelated individuals with EOEE led to the identification of an additional family. We gathered five additional families with eight affected individuals through the Matchmaker Exchange initiative by matching autosomal- recessive mutations in AP3B2. Reverse phenotyping of 12 affected individuals from eight families revealed a homogeneous EOEE phenotype characterized by severe developmental delay, poor visual contact with optic atrophy, and postnatal microcephaly. No spasticity, albinism, or hematological symptoms were reported. AP3B2 encodes the neuron-specific subunit of the AP-3 complex. Autosomal-recessive variations of AP3B1, the ubiquitous isoform, cause Hermansky-Pudlak syndrome type 2. The only isoform for the delta subunit of the AP-3 complex is encoded by AP3D1. Autosomal-recessive mutations in AP3D1 cause a severe disorder cumulating the symptoms of the AP3B1 and AP3B2 defects.
Published: 2016

34. Abstract TP385: Decreasing Door-to-Needle Times for Acute Ischemic Stroke Patients

Author: Kelly Venters, Amber Parker, and Jessica Douglas
Subjects: Advanced and Specialized Nursing, business.industry, medicine.medical_treatment, Certification, Thrombolysis, Emergency department, Baseline data, medicine.disease, Door to needle time, medicine, Neurology (clinical), Medical emergency, Cardiology and Cardiovascular Medicine, business, Stroke, Acute ischemic stroke, Educational program
Abstract: Background and Purpose: The Joint Commission recommendation is to meet door-to-needle (DTN) times of less than 60 minutes in 50% of tPA recipients. Lake Cumberland Regional Hospital is a certified primary stroke center by The Joint Commission and has strived to develop a process that drives DTN times to less than 60 minutes for acute ischemic stroke patients being treated with tissue plasminogen activator (tPA). Baseline data from 2014 showed tPA compliance was 27% (n=15). In 2015, pre-implementation tPA compliance was 0% (n=3). Methods: Guided by a process map outlining time frames for all steps in the tPA administration process, findings were utilized to identify barriers, inefficiencies, and solutions. An educational program was developed and centered on identified barriers. Educational sessions were completed for all emergency department staff. DTN times were analyzed before and after implementation of educational program. A timekeeper role was implemented in the emergency department to increase awareness during cases of tPA administration. Results: 100% of Emergency Department staff was educated on process map, Joint Commission recommendations, and role of timekeeper. Since completion of educational sessions and implementation of timekeeper role, Lake Cumberland Regional Hospital has met The Joint Commission DTN recommendation in 78% (n=9) of patients treated with tPA. As of August 11 th , overall DTN compliance for 2015 at Lake Cumberland Regional Hospital was 54%. Conclusions: Average DTN treatment times were decreased and compliance with The Joint Commission standard of meeting DTN times of less than 60 minutes in 50% of tPA cases was improved. For continued identification of performance improvement initiatives, debriefings are conducted after each tPA case with all staff involved to discuss strengths, barriers, and opportunities for improvement.
Published: 2016

35. De novo pathogenic variants in CHAMP1 are associated with global developmental delay, intellectual disability, and dysmorphic facial features

Author: Kyle Retterer, Aida Telegrafi, Yong-hui Jiang, Akemi J. Tanaka, Omar A. Rahman, Wendy K. Chung, Julie Kaylor, Julie R. Jones, G. Bradley Schaefer, Allyn McConkie-Rosell, Catherine Nowak, Bethany Friedman, Megan T. Cho, Ganka Douglas, Kristin G. Monaghan, and Jessica Douglas
Subjects: Genetics, Zinc finger, Research Report, Microcephaly, Cell division, Chromosome, General Medicine, medicine.disease, Intellectual disability, medicine, Global developmental delay, congenital microcephaly, Psychology, intellectual disability, severe, Metaphase, Mitosis, severe global developmental delay
Abstract: We identified five unrelated individuals with significant global developmental delay and intellectual disability (ID), dysmorphic facial features and frequent microcephaly, and de novo predicted loss-of-function variants in chromosome alignment maintaining phosphoprotein 1 (CHAMP1). Our findings are consistent with recently reported de novo mutations in CHAMP1 in five other individuals with similar features. CHAMP1 is a zinc finger protein involved in kinetochore–microtubule attachment and is required for regulating the proper alignment of chromosomes during metaphase in mitosis. Mutations in CHAMP1 may affect cell division and hence brain development and function, resulting in developmental delay and ID.
Published: 2016

36. Assessing the effects of surface-bound humic acid on the phototoxicity of anatase and rutile TiO₂ nanoparticles in vitro

Author: Xiaojia, He, Sabrieon, Sanders, Winfred G, Aker, Yunfeng, Lin, Jessica, Douglas, and Huey-Min, Hwang
Subjects: Titanium, Escherichia coli, Metal Nanoparticles, Reactive Oxygen Species, Humic Substances
Abstract: In this study, the cytotoxicity of two different crystal phases of TiO2 nanoparticles, with surface modification by humic acid (HA), to Escherichia coli, was assessed. The physicochemical properties of TiO2 nanoparticles were thoroughly characterized. Three different initial concentrations, namely 50, 100, and 200 ppm, of HA were used for synthesis of HA coated TiO2 nanoparticles (denoted as A/RHA50, A/RHA100, and A/RHA200, respectively). Results indicate that rutile (LC50 (concentration that causes 50% mortality compared the control group)=6.5) was more toxic than anatase (LC50=278.8) under simulated sunlight (SSL) irradiation, possibly due to an extremely narrow band gap. It is noted that HA coating increased the toxicity of anatase, but decreased that of rutile. Additionally, AHA50 and RHA50 had the biggest differences compared to uncoated anatase and rutile with LC50 of 201.9 and 21.6, respectively. We then investigated the formation of reactive oxygen species (ROS) by TiO2 nanoparticles in terms of hydroxyl radicals (·OH) and superoxide anions (O2(·-)). Data suggested that O2(·-) was the main ROS that accounted for the higher toxicity of rutile upon SSL irradiation. We also observed that HA coating decreased the generation of ·OH and O2(·-) on rutile, but increased O2(·-) formation on anatase. Results from TEM analysis also indicated that HA coated rutile tended to be attached to the surface of E. coli more than anatase.
Published: 2015

37. Further supporting evidence for the SATB2-associated syndrome found through whole exome sequencing

Author: Murray Feingold, Yue Si, Ophir D. Klein, Kyle Retterer, Michael C. Kruer, Mariam Almureikhi, Kirk Simmons, Federica Gibellini, Rong Mao, Elizabeth A. Sellars, Hazel Perry, Jessica Douglas, Quinn Stein, Tawfeg Ben-Omran, Anne Slavotinek, Dianalee McKnight, Jennifer L. Fish, and Yuri A. Zarate
Subjects: Adult, Male, Craniofacial abnormality, Nonsense mutation, Biology, Bioinformatics, Frameshift mutation, Craniofacial Abnormalities, Intellectual Disability, Intellectual disability, Genetics, medicine, Humans, Exome, Language Development Disorders, Child, Frameshift Mutation, Genetics (clinical), Exome sequencing, Point mutation, High-Throughput Nucleotide Sequencing, Matrix Attachment Region Binding Proteins, medicine.disease, Phenotype, Cleft Palate, Codon, Nonsense, Child, Preschool, Chromosomes, Human, Pair 2, Female, Transcription Factors
Abstract: The SATB2-associated syndrome (SAS) was recently proposed as a clinically recognizable syndrome that results from deleterious alterations of the SATB2 gene in humans. Although interstitial deletions at 2q33 encompassing SATB2, either alone or contiguously with other genes, have been reported before, there is limited literature regarding intragenic mutations of this gene and the resulting phenotype. We describe five patients in whom whole exome sequencing identified five unique de novo mutations in the SATB2 gene (one splice site, one frameshift, and three nonsense mutations). The five patients had overlapping features that support the characteristic features of the SAS: intellectual disability with limited speech development and craniofacial abnormalities including cleft palate, dysmorphic features, and dental abnormalities. Furthermore, Patient 1 also had features not previously described that represent an expansion of the phenotype. Osteopenia was seen in two of the patients, suggesting that this finding could be added to the list of distinctive findings. We provide supporting evidence that analysis for deletions or point mutations in SATB2 should be considered in children with intellectual disability and severely impaired speech, cleft or high palate, teeth abnormalities, and osteopenia.
Published: 2014

38. Reporting Incidental Findings in Clinical Whole Exome Sequencing: Incorporation of the 2013 ACMG Recommendations into Current Practices of Genetic Counseling

Author: Jessica Douglas, Kate Kramer, Lacey A. Smith, and Alicia Braxton
Subjects: Adult, Male, medicine.medical_specialty, Attitude of Health Personnel, Genetic counseling, MEDLINE, Alternative medicine, Genetic Counseling, Pregnancy, Surveys and Questionnaires, medicine, Medical Records, Problem-Oriented, Humans, Exome, Genetic Testing, Child, Genetics (clinical), Exome sequencing, Genetic testing, Incidental Findings, medicine.diagnostic_test, business.industry, Public health, Medical record, Infant, Newborn, Family medicine, Medical genetics, Female, Guideline Adherence, business, Sequence Analysis, Genome-Wide Association Study
Abstract: The purpose of this study was to investigate how the American College of Medical Genetics and Genomics (ACMG) March 2013 recommendations for reporting incidental findings (IFs) have influenced current practices of genetic counselors involved in utilizing whole exome sequencing (WES) for clinical diagnosis. An online survey was sent to all members of the National Society of Genetic Counselors; members were eligible to participate if they currently offered WES for clinical diagnosis. Forty-six respondents completed the survey of whom 34 were in practice prior to the March 2013 ACMG recommendations. Half of respondents (N = 19, 54.9 %) in practice prior to March 2013 reported that the ACMG recommendations have had a significant impact on the content of their counseling sessions. Approximately half of respondents (N = 21, 45.5 %) report all IFs, regardless of patient age, while one third (N = 14, 30.4 %) consider factors such as age and parent preference in reporting IFs. Approximately 40 % (N = 18) of respondents reported that the testing laboratory’s policy for returning IFs has an influence on their choice of laboratory; of those, 72.2 % (N = 13) reported that the option to opt out of receiving reports of IFs has a significant influence on their choice of laboratory. A majority of respondents (N = 43, 93.5 %) found that most patients want to receive reports of IFs. However, respondents report there are patients who wish to decline receiving this information. This study querying genetic counselors identified benefits and challenges that the 2013 ACMG recommendations elicited. Some challenges, such as not having the option to opt out of IFs, have been addressed by the ACMG’s most recent updates to their recommendations. Further investigation into larger and more inclusive provider populations as well as patient populations will be valuable for the ongoing discussion surrounding IFs in WES.
Published: 2014

39. Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer

Author: Emma Ramsay, Elise Ruark, Angela F. Brady, Ilirjana Bajrami, Manuel A. Rivas, Peter Humburg, Panos Deloukas, Rachel Brough, Chey Loveday, Mary Porteous, Alexander Renwick, Anne Murray, Jessica Douglas, Lorna Gregory, D. Gareth Evans, Patrick J. Morrison, Alan Ashworth, Jonathan Berg, Nazneen Rahman, Daniel Nava Rodrigues, Christopher J. Lord, Diana Eccles, John A. Todd, Anna Zachariou, Margaret Warren-Perry, Louise Izatt, Silvana Del Vecchio Duarte, Alex Henderson, Sandra Hanks, Fiona Douglas, Julian Adlard, Mark I. McCarthy, Lynn Greenhalgh, Caron Chapman, Katie Snape, Martin Gore, Jackie Cook, Andrew J. Rimmer, Tsun-Po Yang, Julian Barwell, Matthew A. Brown, Mark J. Caufield, Peter Donnelly, Naser Ansari Pour, Ajith Kumar, Sheila Seal, Jorge S. Reis-Filho, Mark T. Rogers, Carole Brewer, Antonis C. Antoniou, R. Davidson, Fiona Lalloo, Zosia Miedzybrodzka, G Brice, Adriana Campion-Flora, Joan Paterson, Lisa Walker, Neil Walker, Alan Donaldson, Susan Shanley, Richard S. Houlston, and Clare Turnbull
Subjects: Breast Neoplasms, Biology, medicine.disease_cause, Article, Exon, Breast cancer, Genetic variation, medicine, Genetic predisposition, Phosphoprotein Phosphatases, Cluster Analysis, Humans, Genetic Predisposition to Disease, Lymphocytes, Allele, Gene, Alleles, Genetics, Ovarian Neoplasms, Mutation, Multidisciplinary, Mosaicism, Exons, Sequence Analysis, DNA, medicine.disease, Protein Phosphatase 2C, Isoenzymes, Female, Tumor Suppressor Protein p53, Ovarian cancer
Abstract: Improved sequencing technologies offer unprecedented opportunities for investigating the role of rare genetic variation in common disease. However, there are considerable challenges with respect to study design, data analysis and replication. Using pooled next-generation sequencing of 507 genes implicated in the repair of DNA in 1,150 samples, an analytical strategy focused on protein-truncating variants (PTVs) and a large-scale sequencing case-control replication experiment in 13,642 individuals, here we show that rare PTVs in the p53-inducible protein phosphatase PPM1D are associated with predisposition to breast cancer and ovarian cancer. PPM1D PTV mutations were present in 25 out of 7,781 cases versus 1 out of 5,861 controls (P = 1.12 × 10(-5)), including 18 mutations in 6,912 individuals with breast cancer (P = 2.42 × 10(-4)) and 12 mutations in 1,121 individuals with ovarian cancer (P = 3.10 × 10(-9)). Notably, all of the identified PPM1D PTVs were mosaic in lymphocyte DNA and clustered within a 370-base-pair region in the final exon of the gene, carboxy-terminal to the phosphatase catalytic domain. Functional studies demonstrate that the mutations result in enhanced suppression of p53 in response to ionizing radiation exposure, suggesting that the mutant alleles encode hyperactive PPM1D isoforms. Thus, although the mutations cause premature protein truncation, they do not result in the simple loss-of-function effect typically associated with this class of variant, but instead probably have a gain-of-function effect. Our results have implications for the detection and management of breast and ovarian cancer risk. More generally, these data provide new insights into the role of rare and of mosaic genetic variants in common conditions, and the use of sequencing in their identification.
Published: 2013

40. World of museums

Author: Jessica Douglas‐Home, Paul Berghuis, and Peter Cannon‐Brookes
Subjects: Visual Arts and Performing Arts, Tourism, Leisure and Hospitality Management, Business and International Management
Published: 1993

41. Further molecular and clinical delineation of co-locating 17p13.3 microdeletions and microduplications that show distinctive phenotypes

Author: Edwin Reyniers, Jessica Douglas, Anna Lindstrand, Howard R. Slater, Trijnie Dijkhuizen, Conny M. A. van Ravenswaaij-Arts, Catherine Nowak, Margaret P Adam, Devika Ganesamoorthy, Johanna Lundin, Jacqueline Schoumans, Bregje W.M. van Bon, Bert B.A. de Vries, David J. Amor, Carlos Cardoso, Martin B. Delatycki, Alison Yeung, Irene Stolte-Dijkstra, Birgit Borgström, D L Bruno, Christa Lese Martin, Nathalie Van der Aa, Anders Wallin, Geert Vandeweyer, Rolph Pfundt, Lena Thelin, R. Frank Kooy, Paul A. James, and Britt-Marie Anderlid
Subjects: Male, medicine.medical_specialty, Candidate gene, NUMBER VARIATION, Adolescent, IMPACT, Lissencephaly, Classical Lissencephalies and Subcortical Band Heterotopias, Biology, Craniofacial Abnormalities, Genomic disorders and inherited multi-system disorders [IGMD 3], PAFAH1B1, DIEKER-SYNDROME, Segmental Duplications, Genomic, Intellectual Disability, Molecular genetics, Genetics, medicine, Humans, Child, YWHAE, Genetics (clinical), Oligonucleotide Array Sequence Analysis, Segmental duplication, Chromosome Aberrations, ALU REPEATS, REARRANGEMENTS, Brain, Infant, medicine.disease, GENE, Pedigree, GENOMIC HYBRIDIZATION, DELETIONS, Phenotype, Child, Preschool, ARRAY, Female, Human genome, Human medicine, Chromosome Deletion, Haploinsufficiency, MENTAL-RETARDATION, Chromosomes, Human, Pair 17
Abstract: Contains fulltext : 88561.pdf (Publisher’s version ) (Closed access) BACKGROUND: Chromosome 17p13.3 contains extensive repetitive sequences and is a recognised region of genomic instability. Haploinsufficiency of PAFAH1B1 (encoding LIS1) causes either isolated lissencephaly sequence or Miller-Dieker syndrome, depending on the size of the deletion. More recently, both microdeletions and microduplications mapping to the Miller-Dieker syndrome telomeric critical region have been identified and associated with distinct but overlapping phenotypes. METHODS: Genome-wide microarray screening was performed on 7678 patients referred with unexplained learning difficulties and/or autism, with or without other congenital abnormalities. Eight and five unrelated individuals, respectively, were identified with microdeletions and microduplications in 17p13.3. RESULTS: Comparisons with six previously reported microdeletion cases identified a 258 kb critical region, encompassing six genes including CRK (encoding Crk) and YWHAE (encoding 14-3-3epsilon). Clinical features included growth retardation, facial dysmorphism and developmental delay. Notably, one individual with only subtle facial features and an interstitial deletion involving CRK but not YWHAE suggested that a genomic region spanning 109 kb, encompassing two genes (TUSC5 and YWHAE), is responsible for the main facial dysmorphism phenotype. Only the microduplication phenotype included autism. The microduplication minimal region of overlap for the new and previously reported cases spans 72 kb encompassing a single gene, YWHAE. These genomic rearrangements were not associated with low-copy repeats and are probably due to diverse molecular mechanisms. CONCLUSIONS: The authors further characterise the 17p13.3 microdeletion and microduplication phenotypic spectrum and describe a smaller critical genomic region allowing identification of candidate genes for the distinctive facial dysmorphism (microdeletions) and autism (microduplications) manifestations. 01 mei 2010
Published: 2010

42. World of museums

Author: Corina Sandu, Jessica Douglas‐Home, Lydia Stohrová, Colin Amery, and Donald Moore
Subjects: Visual Arts and Performing Arts, Tourism, Leisure and Hospitality Management, Business and International Management
Published: 1992

43. Acute pancreatitis in Soweto, South Africa: relationship between trypsinogen load, trypsinogen activation, and fibrinolysis

Author: Isidor Segal, Christopher Chaloner, Jessica Douglas, Klaus-Dieter John, Amir Zaidi, Lawrence Cotter, Stefan Appelros, Anders Borgstrom, and Joan M. Braganza
Subjects: Adult, Aged, 80 and over, Male, Fibrin, Hepatology, Pancreatitis, Alcoholic, Fibrinolysis, Gastroenterology, Middle Aged, Severity of Illness Index, South Africa, Acute Disease, Trypsinogen, Humans, Female, Protease Inhibitors, Aged
Abstract: It is not known why acute pancreatitis in Soweto, South Africa, pursues an aggressive course. We sought clues from circulating trypsinogen load at admission as marker of initial acinar injury, trypsinogen activation using the carboxypeptidase B activation peptide as surrogate, proteinase inhibitors, the coagulation-fibrinolysis axis, indicators of inflammation, oxidative stress markers, and antioxidant status. This article reports on the first four aspects.The study involved 24 consecutive patients with a first attack. All of them were admitted within 24 h, and 22 were alcoholic. Urine was analyzed for anionic trypsinogen and the carboxypeptidase B activation peptide. Serum was tested for anionic and cationic trypsinogen, alpha1 proteinase inhibitor and alpha2 macroglobulin. Plasma from a subset was assayed for soluble fibrin, cross-linked fibrin degradation products (surrogates for thrombin and plasmin activity, respectively), and tissue-type plasminogen activator and inhibitor.Soweto controls had higher serum anionic trypsinogen (p = 0.004) and plasminogen activator:inhibitor ratio (p = 0.047) than U.K. controls. The outcome of acute pancreatitis was mild in 17 but severe in seven with three deaths, two on day 2. In mild pancreatitis, intense plasmin activity (p0.001) accompanied the surge in trypsinogen, especially anionic (p0.001), but without increased thrombin activity and in five patients without trypsinogen activation. In severe pancreatitis, further significant increments in plasmin activity and trypsinogens were accompanied by increased thrombin activity (p = 0.013) and trypsinogen activation (p = 0.046). There was no correlation between surrogates of plasmin and thrombin activity, or between either and the carboxypeptidase B activation peptide, which showed a curvilinear relationship to total serum trypsinogen.The aggressive nature of alcoholic acute pancreatitis in Soweto seems to reflect early profound fibrinolysis, which precedes coagulation and is initially independent of trypsin. Subclinical acinar-cell injury and a profibrinolytic diathesis in outwardly healthy Sowetans may predispose to this problem.
Published: 2002

44. Saxon culture in the Siebenbürgen

Author: Jessica Douglas-Home
Subjects: Visual Arts and Performing Arts, Tourism, Leisure and Hospitality Management, Business and International Management
Published: 1993

45. Laogai - The Chinese Gulag

Author: Home, Jessica Douglas
Subjects: Laogai - The Chinese Gulag (Book) -- Book reviews, Books -- Book reviews
Published: 1993

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