Author: "Klaus Dieterich" - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"Klaus Dieterich"' showing total 76 results

Start Over Author "Klaus Dieterich"

76 results on '"Klaus Dieterich"'

1. Next generation phenotyping for diagnosis and phenotype–genotype correlations in Kabuki syndrome

Author: Quentin Hennocq, Marjolaine Willems, Jeanne Amiel, Stéphanie Arpin, Tania Attie-Bitach, Thomas Bongibault, Thomas Bouygues, Valérie Cormier-Daire, Pierre Corre, Klaus Dieterich, Maxime Douillet, Jean Feydy, Eva Galliani, Fabienne Giuliano, Stanislas Lyonnet, Arnaud Picard, Thantrira Porntaveetus, Marlène Rio, Flavien Rouxel, Vorasuk Shotelersuk, Annick Toutain, Kevin Yauy, David Geneviève, Roman H. Khonsari, and Nicolas Garcelon
Subjects: Medicine, Science
Abstract: Abstract The field of dysmorphology has been changed by the use Artificial Intelligence (AI) and the development of Next Generation Phenotyping (NGP). The aim of this study was to propose a new NGP model for predicting KS (Kabuki Syndrome) on 2D facial photographs and distinguish KS1 (KS type 1, KMT2D-related) from KS2 (KS type 2, KDM6A-related). We included retrospectively and prospectively, from 1998 to 2023, all frontal and lateral pictures of patients with a molecular confirmation of KS. After automatic preprocessing, we extracted geometric and textural features. After incorporation of age, gender, and ethnicity, we used XGboost (eXtreme Gradient Boosting), a supervised machine learning classifier. The model was tested on an independent validation set. Finally, we compared the performances of our model with DeepGestalt (Face2Gene). The study included 1448 frontal and lateral facial photographs from 6 centers, corresponding to 634 patients (527 controls, 107 KS); 82 (78%) of KS patients had a variation in the KMT2D gene (KS1) and 23 (22%) in the KDM6A gene (KS2). We were able to distinguish KS from controls in the independent validation group with an accuracy of 95.8% (78.9–99.9%, p
Published: 2024
Full Text: View/download PDF

2. Diagnostic work-up and phenotypic characteristics of a family with variable severity of distal arthrogryposis type 2B (Sheldon-Hall syndrome) and TNNT3 pathogenic variant

Author: Ivana Dabaj, Robert Y. Carlier, Klaus Dieterich, Isabelle Desguerre, Julien Faure, Norma B. Romero, Wenting Trang, Susana Quijano-Roy, and Dominique P. Germain
Subjects: Sheldon-hall syndrome, distal arthrogryposis type 2B, DA2B, TNNT3, neurogenic pattern, Genetics, QH426-470
Abstract: Background: Sheldon–Hall syndrome (SHS) or distal arthrogryposis 2B (DA2B) is a rare clinically and genetically heterogeneous multiple congenital contracture syndrome characterized by contractures of the distal joints of the limbs and mild facial involvement, due to pathogenic variants in genes encoding the fast-twitch skeletal muscle contractile myofiber complex (TNNT3, TNNI2, TMP2, and MYH3 genes).Patients and methods: A 16-year-old boy with a history of congenital distal arthrogryposis developed severe kyphoscoliosis and respiratory insufficiency. His mother and younger sister had phenotypes compatible with SHS but to a much lesser extent. Diagnostic work-up included physical examination and whole-body muscular MRI (WBMRI) in all three patients and electroneuromyography (ENMG) and paravertebral muscle biopsy in the proband. DNA sequencing was used to confirm the diagnosis.Results: Physical examination suggested the diagnosis of SHS. No muscle signal abnormalities were found in WBMRI. Large motor unit potentials and reduced recruitment suggestive of neurogenic changes were observed on needle EMG in distal and paravertebral muscles in the proband. DNA sequencing revealed a pathogenic variant in TNNT3 (c.187C>T), which segregated as a dominant trait with the phenotype.Discussion: This is the first report on neurogenic features in a patient with DA2B and a pathogenic variant in TNNT3 encoding the fast-twitch skeletal muscle contractile myofiber complex. A superimposed length-dependent motor nerve involvement was unexpected. Whether developmental disarrangements in number, distribution, or innervation of the motor unit in fetal life might lead to pseudo-neurogenic EMG features warrants further studies, as well as the role of genetic modifiers in SHS variability.
Published: 2023
Full Text: View/download PDF

3. Clinical Utility of a Unique Genome-Wide DNA Methylation Signature for KMT2A-Related Syndrome

Author: Aidin Foroutan, Sadegheh Haghshenas, Pratibha Bhai, Michael A. Levy, Jennifer Kerkhof, Haley McConkey, Marcello Niceta, Andrea Ciolfi, Lucia Pedace, Evelina Miele, David Genevieve, Solveig Heide, Mariëlle Alders, Giuseppe Zampino, Giuseppe Merla, Mélanie Fradin, Eric Bieth, Dominique Bonneau, Klaus Dieterich, Patricia Fergelot, Elise Schaefer, Laurence Faivre, Antonio Vitobello, Silvia Maitz, Rita Fischetto, Cristina Gervasini, Maria Piccione, Ingrid van de Laar, Marco Tartaglia, Bekim Sadikovic, and Anne-Sophie Lebre
Subjects: epigenetics, DNA methylation, episignature, Wiedemann–Steiner syndrome, KMT2A gene, intellectual disability, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract: Wiedemann–Steiner syndrome (WDSTS) is a Mendelian syndromic intellectual disability (ID) condition associated with hypertrichosis cubiti, short stature, and characteristic facies caused by pathogenic variants in the KMT2A gene. Clinical features can be inconclusive in mild and unusual WDSTS presentations with variable ID (mild to severe), facies (typical or not) and other associated malformations (bone, cerebral, renal, cardiac and ophthalmological anomalies). Interpretation and classification of rare KMT2A variants can be challenging. A genome-wide DNA methylation episignature for KMT2A-related syndrome could allow functional classification of variants and provide insights into the pathophysiology of WDSTS. Therefore, we assessed genome-wide DNA methylation profiles in a cohort of 60 patients with clinical diagnosis for WDSTS or Kabuki and identified a unique highly sensitive and specific DNA methylation episignature as a molecular biomarker of WDSTS. WDSTS episignature enabled classification of variants of uncertain significance in the KMT2A gene as well as confirmation of diagnosis in patients with clinical presentation of WDSTS without known genetic variants. The changes in the methylation profile resulting from KMT2A mutations involve global reduction in methylation in various genes, including homeobox gene promoters. These findings provide novel insights into the molecular etiology of WDSTS and explain the broad phenotypic spectrum of the disease.
Published: 2022
Full Text: View/download PDF

4. Identification of biallelic germline variants of SRP68 in a sporadic case with severe congenital neutropenia

Author: Barbara Schmaltz-Panneau, Anne Pagnier, Séverine Clauin, Julien Buratti, Caroline Marty, Odile Fenneteau, Klaus Dieterich, Blandine Beaupain, Jean Donadieu, Isabelle Plo, and Christine Bellanné-Chantelot
Subjects: Diseases of the blood and blood-forming organs, RC633-647.5
Published: 2020
Full Text: View/download PDF

5. Psychiatrie & Psychotherapie für Heilpraktiker: Lehrbuch zur Prüfungsvorbereitung

Author: Klaus Dieterich and Klaus Dieterich
Published: 2019

6. NGS-driven molecular diagnosis of heterogeneous hereditary neurological disorders reveals novel and known variants in disease-causing genes

Author: Ayaz Khan, Shixiong Tian, Muhammad Tariq, Sheraz Khan, Muhammad Safeer, Naimat Ullah, Nazia Akbar, Iram Javed, Mahnoor Asif, Ilyas Ahmad, Shahid Ullah, Humayoon Shafique Satti, Raees Khan, Muhammad Naeem, Mahwish Ali, John Rendu, Julien Fauré, Klaus Dieterich, Xenia Latypova, Shahid Mahmood Baig, Naveed Altaf Malik, Feng Zhang, Tahir Naeem Khan, and Chunyu Liu
Subjects: Exome Sequencing, Homozygote, Mutation, Genetics, Humans, Metalloendopeptidases, Transposases, General Medicine, Nervous System Diseases, Molecular Biology, Pedigree
Abstract: Hereditary neurological disorders (HNDs) are a clinically and genetically heterogeneous group of disorders. These disorders arise from the impaired function of the central or peripheral nervous system due to aberrant electrical impulses. More than 600 various neurological disorders, exhibiting a wide spectrum of overlapping clinical presentations depending on the organ(s) involved, have been documented. Owing to this clinical heterogeneity, diagnosing these disorders has been a challenge for both clinicians and geneticists and a large number of patients are either misdiagnosed or remain entirely undiagnosed. Contribution of genetics to neurological disorders has been recognized since long; however, the complete picture of the underlying molecular bases are under-explored. The aim of this study was to accurately diagnose 11 unrelated Pakistani families with various HNDs deploying NGS as a first step approach. Using exome sequencing and gene panel sequencing, we successfully identified disease-causing genomic variants these families. We report four novel variants, one each in, ECEL1, NALCN, TBR1 and PIGP in four of the pedigrees. In the rest of the seven families, we found five previously reported pathogenic variants in POGZ, FA2H, PLA2G6 and CYP27A1. Of these, three families segregate a homozygous 18 bp in-frame deletion of FA2H, indicating a likely founder mutation segregating in Pakistani population. Genotyping for this mutation can help low-cost population wide screening in the corresponding regions of the country. Our findings not only expand the existing repertoire of mutational spectrum underlying neurological disorders but will also help in genetic testing of individuals with HNDs in other populations.
Published: 2022

7. Diagnostic workup in children with arthrogryposis: description of practices from a single reference centre, comparison with literature and suggestion of recommendations

Author: Pauline Le Tanno, Xenia Latypova, John Rendu, Julien Fauré, Véronique Bourg, Marjolaine Gauthier, Gipsy Billy-Lopez, Pierre-Simon Jouk, and Klaus Dieterich
Subjects: Genetics, Genetics (clinical)
Abstract: IntroductionArthrogryposis multiplex congenita (AMC) refers to a clinical presentation of congenital contractures involving two or more body areas. More than 400 distinct conditions may lead to AMC, making the aetiological diagnosis challenging. The objective of this work was to set up evidence-based recommendations for the diagnosis of AMC by taking advantage of both data from our nation-wide cohort of children with AMC and from the literature.Material and methodsWe conducted a retrospective single-centre observational study. Patients had been evaluated at least once at a paediatric age in the AMC clinic of Grenoble University Hospital between 2007 and 2019. After gathering data about their diagnostic procedure, a literature review was performed for each paraclinical investigation to discuss their relevance.ResultsOne hundred and twenty-five patients were included, 43% had Amyoplasia, 27% had distal arthrogryposis and 30% had other forms. A definitive aetiological diagnosis was available for 66% of cases. We recommend a two-time diagnostic process: first, non-invasive investigations that aim at classifying patients into one of the three groups, and second, selected investigations targeting a subset of patients.ConclusionThe aetiological management for patients with AMC remains arduous. This process will be facilitated by the increasing use of next-generation sequencing combined with detailed phenotyping. Invasive investigations should be avoided because of their limited yield.
Published: 2021

8. Clinical and genomic delineation of the new proximal 19p13.3 microduplication syndrome

Author: Guillaume Jouret, Matthieu Egloff, Emilie Landais, Olivier Tassy, Fabienne Giuliano, Houda Karmous‐Benailly, Charles Coutton, Véronique Satre, Françoise Devillard, Klaus Dieterich, Gaëlle Vieville, Paul Kuentz, Cédric le Caignec, Claire Beneteau, Bertrand Isidor, Mathilde Nizon, Patrick Callier, Valentine Marquet, Eric Bieth, Jonathan Lévy, Anne‐Claude Tabet, Stanislas Lyonnet, Geneviève Baujat, Marlène Rio, François Cartault, Sophie Scheidecker, Aurélie Gouronc, Audrey Schalk, Clémence Jacquin, Marta Spodenkiewicz, Chloé Angélini, Perrine Pennamen, Caroline Rooryck, Martine Doco‐Fenzy, and Céline Poirsier
Subjects: Comparative Genomic Hybridization, Genetics, Microcephaly, Humans, Abnormalities, Multiple, Syndrome, Genetics (clinical), Genetic Association Studies
Abstract: A small but growing body of scientific literature is emerging about clinical findings in patients with 19p13.3 microdeletion or duplication. Recently, a proximal 19p13.3 microduplication syndrome was described, associated with growth delay, microcephaly, psychomotor delay and dysmorphic features. The aim of our study was to better characterize the syndrome associated with duplications in the proximal 19p13.3 region (prox 19p13.3 dup), and to propose a comprehensive analysis of the underlying genomic mechanism. We report the largest cohort of patients with prox 19p13.3 dup through a collaborative study. We collected 24 new patients with terminal or interstitial 19p13.3 duplication characterized by array-based Comparative Genomic Hybridization (aCGH). We performed mapping, phenotype-genotype correlations analysis, critical region delineation and explored three-dimensional chromatin interactions by analyzing Topologically Associating Domains (TADs). We define a new 377 kb critical region (CR 1) in chr19: 3,116,922-3,494,377, GRCh37, different from the previously described critical region (CR 2). The new 377 kb CR 1 includes a TAD boundary and two enhancers whose common target is PIAS4. We hypothesize that duplications of CR 1 are responsible for tridimensional structural abnormalities by TAD disruption and misregulation of genes essentials for the control of head circumference during development, by breaking down the interactions between enhancers and the corresponding targeted gene.
Published: 2022

9. Common data elements and minimum data sets in cerebral palsy: Start small to grow big

Author: Klaus Dieterich
Subjects: Common Data Elements, Developmental Neuroscience, Cerebral Palsy, Pediatrics, Perinatology and Child Health, Activities of Daily Living, Humans, Neurology (clinical)
Published: 2022

10. OTX2 duplications: a recurrent cause of oculo-auriculo-vertebral spectrum

Author: Tristan Celse, Angèle Tingaud-Sequeira, Klaus Dieterich, Geraldine Siegfried, Cédric Lecaignec, Laurence Bouneau, Madeleine Fannemel, Gaelle Salaun, Fanny Laffargue, Guillaume Martinez, Véronique Satre, Gaelle Vieville, Marie Bidart, Cecilia Soussi Zander, Ann-Charlotte Turesson, Miranda Splitt, Dorothee Reboul, Jean Chiesa, Philippe Khau Van Kien, Manon Godin, Nicolas Gruchy, Himanshu Goel, Elizabeth Palmer, Kalliope Demetriou, Carolyn Shalhoub, Caroline Rooryck, and Charles Coutton
Subjects: Genetics, Genetics (clinical)
Abstract: BackgroundOculo-auriculo-vertebral spectrum (OAVS) is the second most common cause of head and neck malformations in children after orofacial clefts. OAVS is clinically heterogeneous and characterised by a broad range of clinical features including ear anomalies with or without hearing loss, hemifacial microsomia, orofacial clefts, ocular defects and vertebral abnormalities. Various genetic causes were associated with OAVS and copy number variations represent a recurrent cause of OAVS, but the responsible gene often remains elusive.MethodsWe described an international cohort of 17 patients, including 10 probands and 7 affected relatives, presenting with OAVS and carrying a 14q22.3 microduplication detected using chromosomal microarray analysis. For each patient, clinical data were collected using a detailed questionnaire addressed to the referring clinicians. We subsequently studied the effects ofOTX2overexpression in a zebrafish model.ResultsWe defined a 272 kb minimal common region that only overlaps with theOTX2gene. Head and face defects with a predominance of ear malformations were present in 100% of patients. The variability in expressivity was significant, ranging from simple chondromas to severe microtia, even between intrafamilial cases. Heterologous overexpression ofOTX2in zebrafish embryos showed significant effects on early development with alterations in craniofacial development.ConclusionsOur results indicate that properOTX2dosage seems to be critical for the normal development of the first and second branchial arches. Overall, we demonstrated thatOTX2genomic duplications are a recurrent cause of OAVS marked by auricular malformations of variable severity.
Published: 2022

11. Clinical phenotype and loss of the slow skeletal muscle troponin T in three new patients with recessive TNNT1 nemaline myopathy

Author: A. Madelaine, Julie Brocard, Mireille Cossée, Isabelle Marty, Anne-Cécile Coville, Michel Koenig, Christine Ioos, C. Thèze, John Rendu, Klaus Dieterich, Aurore Siegfried, Julien Fauré, Claude Cances, Henri Pegeot, Eloïse Baudou, Pascale Marcorelle, Norma B. Romero, Emmanuelle Lacène, Emmanuelle Uro Coste, Murielle Dobrzynski, Raul Juntas Morales, Justine Géraud, Neurologie générale et maladies inflammatoires du système nerveux [Toulouse], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Groupe d'imagerie neurofonctionnelle (GIN), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CHRU Brest, Pôle de Biologie Pathologie (CHU - BREST - Biologie pathologie), Hôpital Raymond Poincaré [AP-HP], Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Institut des Neurosciences de Montpellier (INM)
Subjects: 0301 basic medicine, Pathology, medicine.medical_specialty, diagnosis, [SDV]Life Sciences [q-bio], Biopsy, Nonsense mutation, neuromuscular diseases, Slow skeletal muscle troponin T, Myopathies, Nemaline, 03 medical and health sciences, Exon, 0302 clinical medicine, Nemaline myopathy, Troponin T, Genetics, medicine, Humans, Genetic Predisposition to Disease, Diagnostics, Genetics (clinical), Genetic Association Studies, Sequence Deletion, business.industry, Homozygote, Skeletal muscle, Muscle weakness, Computational Biology, High-Throughput Nucleotide Sequencing, Infant, Sequence Analysis, DNA, medicine.disease, musculoskeletal system, Immunohistochemistry, Hypotonia, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Phenotype, Child, Preschool, Mutation, Female, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: BackgroundCongenital nemaline myopathies are rare pathologies characterised by muscle weakness and rod-shaped inclusions in the muscle fibres.MethodsUsing next-generation sequencing, we identified three patients with pathogenic variants in the Troponin T type 1 (TNNT1) gene, coding for the troponin T (TNT) skeletal muscle isoform.ResultsThe clinical phenotype was similar in all patients, associating hypotonia, orthopaedic deformities and progressive chronic respiratory failure, leading to early death. The anatomopathological phenotype was characterised by a disproportion in the muscle fibre size, endomysial fibrosis and nemaline rods. Molecular analyses of TNNT1 revealed a homozygous deletion of exons 8 and 9 in patient 1; a heterozygous nonsense mutation in exon 9 and retention of part of intron 4 in muscle transcripts in patient 2; and a homozygous, very early nonsense mutation in patient 3.Western blot analyses confirmed the absence of the TNT protein resulting from these mutations.DiscussionThe clinical and anatomopathological presentations of our patients reinforce the homogeneous character of the phenotype associated with recessive TNNT1 mutations. Previous studies revealed an impact of recessive variants on the tropomyosin-binding affinity of TNT. We report in our patients a complete loss of TNT protein due to open reading frame disruption or to post-translational degradation of TNT.
Published: 2020

12. Exome sequencing efficacy and phenotypic expansions involving esophageal atresia/tracheoesophageal fistula plus

Author: Mary R. Sy, Jaynee Chauhan, Katrina Prescott, Aliza Imam, Alison Kraus, Ana Beleza, Lee Salkeld, Saraswati Hosdurga, Michael Parker, Pradeep Vasudevan, Lily Islam, Himanshu Goel, Nicole Bain, Soo‐Mi Park, Shehla Mohammed, Klaus Dieterich, Charles Coutton, Véronique Satre, Gaëlle Vieville, Alan Donaldson, Claire Beneteau, Jamal Ghoumid, Kris Van Den Bogaert, Anneleen Boogaerts, Elise Boudry, Clémence Vanlerberghe, Florence Petit, Laura Bernardini, Barbara Torres, Teresa Mattina, Diana Carli, Giorgia Mandrile, Michele Pinelli, Nicola Brunetti‐Pierri, Katherine Neas, Rachel Beddow, Pernille M. Tørring, Flavio Faletra, Beatrice Spedicati, Paolo Gasparini, Alessandro Mussa, Giovanni Battista Ferrero, Anne Lampe, Wayne Lam, Weimin Bi, Carlos A. Bacino, Akela Kuwahara, Jeffrey O. Bush, Xiaonan Zhao, Pamela N. Luna, Chad A. Shaw, Jill A. Rosenfeld, Daryl A. Scott, Sy, Mary R, Chauhan, Jaynee, Prescott, Katrina, Imam, Aliza, Kraus, Alison, Beleza, Ana, Salkeld, Lee, Hosdurga, Saraswati, Parker, Michael, Vasudevan, Pradeep, Islam, Lily, Goel, Himanshu, Bain, Nicole, Park, Soo-Mi, Mohammed, Shehla, Dieterich, Klau, Coutton, Charle, Satre, Véronique, Vieville, Gaëlle, Donaldson, Alan, Beneteau, Claire, Ghoumid, Jamal, Van Den Bogaert, Kri, Boogaerts, Anneleen, Boudry, Elise, Vanlerberghe, Clémence, Petit, Florence, Bernardini, Laura, Torres, Barbara, Mattina, Teresa, Carli, Diana, Mandrile, Giorgia, Pinelli, Michele, Brunetti-Pierri, Nicola, Neas, Katherine, Beddow, Rachel, Tørring, Pernille M, Faletra, Flavio, Spedicati, Beatrice, Gasparini, Paolo, Mussa, Alessandro, Ferrero, Giovanni Battista, Lampe, Anne, Lam, Wayne, Bi, Weimin, Bacino, Carlos A, Kuwahara, Akela, Bush, Jeffrey O, Zhao, Xiaonan, Luna, Pamela N, Shaw, Chad A, Rosenfeld, Jill A, and Scott, Daryl A
Subjects: tracheoesophageal fistula, NRXN1, Fanconi anemia, Genetics, Humans, TCF4, esophageal atresia, exome sequencing, Exome, Genetics (clinical)
Abstract: Esophageal atresia/tracheoesophageal fistula (EA/TEF) is a life-threatening birth defect that often occurs with other major birth defects (EA/TEF+). Despite advances in genetic testing, a molecular diagnosis can only be made in a minority of EA/TEF+ cases. Here, we analyzed clinical exome sequencing data and data from the DECIPHER database to determine the efficacy of exome sequencing in cases of EA/TEF+ and to identify phenotypic expansions involving EA/TEF. Among 67 individuals with EA/TEF+ referred for clinical exome sequencing, a definitive or probable diagnosis was made in 11 cases for an efficacy rate of 16% (11/67). This efficacy rate is significantly lower than that reported for other major birth defects, suggesting that polygenic, multifactorial, epigenetic, and/or environmental factors may play a particularly important role in EA/TEF pathogenesis. Our cohort included individuals with pathogenic or likely pathogenic variants that affect TCF4 and its downstream target NRXN1, and FANCA, FANCB, and FANCC, which are associated with Fanconi anemia. These cases, previously published case reports, and comparisons to other EA/TEF genes made using a machine learning algorithm, provide evidence in support of a potential pathogenic role for these genes in the development of EA/TEF.
Published: 2022

13. Phenotypic spectrum and genomics of undiagnosed arthrogryposis multiplex congenital

Author: Ivo Gut, Sarah Grotto, Céline Bellesme, Arnold Munnich, Cyril Gitiaux, Jeanne Amiel, Chloé Quélin, Annie Laquerrière, Suonavy Khung, Hanitra Ranjatoelina-Randrianaivo, Luc Rigonnot, Christine Francannet, Loic Quevarec, Jérôme Bouligand, Fabienne Prieur, Alexandra Benachi, Valérie Cormier-Daire, Laurence Perrin, Judith Melki, Pierre-Simon Jouk, Flora Nolent, Tania Attié-Bitach, Delphine Héron, Marie-Line Jacquemont, Claire Beneteau, Fabien Guimiot, Laetitia Lambert, Sandra Mercier, Valérie Biancalana, Fanny Laffargue, Elise Boucher, Jean-Louis Bessereau, P. Landrieu, Annick Toutain, Alain Verloes, Alice Goldenberg, Philippe Latour, Dominique Martin-Coignard, Anne Guiochon-Mantel, Dan Mejlachowicz, Damien Sternberg, Haluk Topaloglu, Bruno Eymard, Géraldine Viot, Catherine Fallet-Bianco, Julien Saada, Isabelle Desguerre, Marie-Hélène Saint-Frison, Catherine Vincent-Delorme, Sophie Blesson, Radka Stoeva, Alexandre J. Vivanti, Martine Bucourt, Pascaline Letard, Jérome Maluenda, Laurence Loeuillet, Lionel Van Maldergem, Didier Lacombe, Marcel Tawk, Michèle Granier, Stanislas Lyonnet, Anne-Lise Delezoide, Andrée Delahaye-Duriez, André Mégarbané, Marie Gonzales, Florence Petit, Juliette Piard, Laurence Faivre, Helene Verhelst, Bettina Bessières, Sabine Sigaudy, Sandra Whalen, Valérie Layet, Yline Capri, Fanny Pelluard, Emanuela Abiusi, Klaus Dieterich, Marie Vincent, Marine Legendre, Dana Jaber, Romulus Grigorescu, Florent Marguet, Eric Bieth, Helge Amthor, Christine Barnerias, Estelle Colin, Laetitia Trestard, Mathilde Nizon, Jelena Martinovic, Daniel Amram, and Nicoletta Resta
Subjects: musculoskeletal diseases, Artrogriposi múltiple congènita, Settore BIO/18 - GENETICA, human genetics, neuromuscular diseases, Genomics, Biology, CONTRACTURES, CLASSIFICATION, diseases, symbols.namesake, Diagnòstic, Gene mapping, arthrogryposis multiplex congenita, Exome Sequencing, OF-FUNCTION MUTATIONS, Genetics, Medicine and Health Sciences, genomics, Humans, Genetics (clinical), Exome sequencing, Arthrogryposis, Sanger sequencing, Arthrogryposis multiplex congenita, Genetic heterogeneity, SPINAL MUSCULAR-ATROPHY, Proteins, nervous system malformations, DYSTROPHY, Disease gene identification, GENE, Human genetics, Pedigree, ETIOLOGY, Phenotype, symbols, neuromuscular, Genètica, Transcription Factors
Abstract: BackgroundArthrogryposis multiplex congenita (AMC) is characterised by congenital joint contractures in two or more body areas. AMC exhibits wide phenotypic and genetic heterogeneity. Our goals were to improve the genetic diagnosis rates of AMC, to evaluate the added value of whole exome sequencing (WES) compared with targeted exome sequencing (TES) and to identify new genes in 315 unrelated undiagnosed AMC families.MethodsSeveral genomic approaches were used including genetic mapping of disease loci in multiplex or consanguineous families, TES then WES. Sanger sequencing was performed to identify or validate variants.ResultsWe achieved disease gene identification in 52.7% of AMC index patients including nine recently identified genes (CNTNAP1, MAGEL2, ADGRG6, ADCY6, GLDN, LGI4, LMOD3, UNC50 and SCN1A). Moreover, we identified pathogenic variants in ASXL3 and STAC3 expanding the phenotypes associated with these genes. The most frequent cause of AMC was a primary involvement of skeletal muscle (40%) followed by brain (22%). The most frequent mode of inheritance is autosomal recessive (66.3% of patients). In sporadic patients born to non-consanguineous parents (n=60), de novo dominant autosomal or X linked variants were observed in 30 of them (50%).ConclusionNew genes recently identified in AMC represent 21% of causing genes in our cohort. A high proportion of de novo variants were observed indicating that this mechanism plays a prominent part in this developmental disease. Our data showed the added value of WES when compared with TES due to the larger clinical spectrum of some disease genes than initially described and the identification of novel genes.
Published: 2022

14. Clinical Utility of a Unique Genome-Wide DNA Methylation Signature for

Author: Aidin, Foroutan, Sadegheh, Haghshenas, Pratibha, Bhai, Michael A, Levy, Jennifer, Kerkhof, Haley, McConkey, Marcello, Niceta, Andrea, Ciolfi, Lucia, Pedace, Evelina, Miele, David, Genevieve, Solveig, Heide, Mariëlle, Alders, Giuseppe, Zampino, Giuseppe, Merla, Mélanie, Fradin, Eric, Bieth, Dominique, Bonneau, Klaus, Dieterich, Patricia, Fergelot, Elise, Schaefer, Laurence, Faivre, Antonio, Vitobello, Silvia, Maitz, Rita, Fischetto, Cristina, Gervasini, Maria, Piccione, Ingrid, van de Laar, Marco, Tartaglia, Bekim, Sadikovic, and Anne-Sophie, Lebre
Subjects: Craniofacial Abnormalities, Phenotype, Intellectual Disability, Hypertrichosis, Facies, Humans, Abnormalities, Multiple, DNA, Syndrome, DNA Methylation, Growth Disorders
Abstract: Wiedemann-Steiner syndrome (WDSTS) is a Mendelian syndromic intellectual disability (ID) condition associated with hypertrichosis cubiti, short stature, and characteristic facies caused by pathogenic variants in the
Published: 2021

15. The Clinical and Genotypic Spectrum of Scoliosis in Multiple Pterygium Syndrome: A Case Series on 12 Children

Author: Noémi Dahan-Oliel, Reggie C. Hamdy, Klaus Dieterich, Frank Rauch, Taylor N. Blondell, Kamran Shazand, Anxhela Gjyshi Gustafson, Harold J.P. van Bosse, Philip F Giampietro, Xenia Latypova, and Ghalib Bardai
Subjects: Male, Pediatrics, medicine.medical_specialty, Heterozygote, CHRNG, Adolescent, MYH3, Scoliosis, QH426-470, Article, Young Adult, multiple pterygium syndrome, Genotype, Genetics, Medicine, Humans, Abnormalities, Multiple, Prospective Studies, Child, Exome, Genetics (clinical), Retrospective Studies, scoliosis, Arthrogryposis multiplex congenita, business.industry, Genetic heterogeneity, distal arthrogryposis type 8, Infant, medicine.disease, Cytoskeletal Proteins, Phenotype, Escobar, Child, Preschool, Fetal movement, Orthopedic surgery, Skin Abnormalities, Female, Multiple pterygium syndrome, business, Malignant Hyperthermia
Abstract: Background: Multiple pterygium syndrome (MPS) is a genetically heterogeneous rare form of arthrogryposis multiplex congenita characterized by joint contractures and webbing or pterygia, as well as distinctive facial features related to diminished fetal movement. It is divided into prenatally lethal (LMPS, MIM253290) and nonlethal (Escobar variant MPS, MIM 265000) types. Developmental spine deformities are common, may present early and progress rapidly, requiring regular fo llow-up and orthopedic management. Methods: Retrospective chart review and prospective data collection were conducted at three hospital centers. Molecular diagnosis was confirmed with whole exome or whole genome sequencing. Results: This case series describes the clinical features and scoliosis treatment on 12 patients from 11 unrelated families. A molecular diagnosis was confirmed in seven, two with MYH3 variants and five with CHRNG. Scoliosis was present in all but our youngest patient. The remaining 11 patients spanned the spectrum between mild (curve ≤ 25°) and malignant scoliosis (≥50° curve before 4 years of age), the two patients with MYH3 mutations presented with malignant scoliosis. Bracing and serial spine casting appear to be beneficial for a few years, non-fusion spinal instrumentation may be needed to modulate more severe curves during growth and spontaneous spine fusions may occur in those cases. Conclusions: Molecular diagnosis and careful monitoring of the spine is needed in children with MPS.
Published: 2021
Full Text: View/download PDF

16. A Genomic Approach to Delineating the Occurrence of Scoliosis in Arthrogryposis Multiplex Congenita

Author: Philip F Giampietro, Harold J.P. van Bosse, Stefan Giovanni Creadore, Steven W. Hwang, Noémi Dahan-Oliel, Tanya Bedard, Kamran Shazand, Klaus Dieterich, Xenia Latypova, and Anxhela Gjyshi Gustafson
Subjects: Genetic Markers, musculoskeletal diseases, DNA Copy Number Variations, DA (distal arthrogryposis), Genomics, Computational biology, Scoliosis, QH426-470, Biology, Article, 03 medical and health sciences, Genetics, medicine, Humans, Copy-number variation, Human phenotype, Gene, CNV (copy number variant), Genetics (clinical), 030304 developmental biology, Arthrogryposis, 0303 health sciences, Amyoplasia, scoliosis, Arthrogryposis multiplex congenita, Gene Expression Profiling, 030305 genetics & heredity, DECIPHER (DatabasE of genomiC variation and Phenotype in Humans using Ensemble Resources), IGF2, medicine.disease, Pathway analysis, HPO (human phenotype ontology), Phenotype, Gene Expression Regulation, akinesia, MYOD, IPA (ingenuity pathway analysis)
Abstract: Arthrogryposis multiplex congenita (AMC) describes a group of conditions characterized by the presence of non-progressive congenital contractures in multiple body areas. Scoliosis, defined as a coronal plane spine curvature of ≥10 degrees as measured radiographically, has been reported to occur in approximately 20% of children with AMC. To identify genes that are associated with both scoliosis as a clinical outcome and AMC, we first queried the DECIPHER database for copy number variations (CNVs). Upon query, we identified only two patients with both AMC and scoliosis (AMC-SC). The first patient contained CNVs in three genes (FBN2, MGF10, and PITX1), while the second case had a CNV in ZC4H2. Looking into small variants, using a combination of Human Phenotype Ontogeny and literature searching, 908 genes linked with scoliosis and 444 genes linked with AMC were identified. From these lists, 227 genes were associated with AMC-SC. Ingenuity Pathway Analysis (IPA) was performed on the final gene list to gain insight into the functional interactions of genes and various categories. To summarize, this group of genes encompasses a diverse group of cellular functions including transcription regulation, transmembrane receptor, growth factor, and ion channels. These results provide a focal point for further research using genomics and animal models to facilitate the identification of prognostic factors and therapeutic targets for AMC.
Published: 2021
Full Text: View/download PDF

17. Development and Validation of a New Risk Prediction Score for Life-Threatening Ventricular Tachyarrhythmias in Laminopathies

Author: Mélanie Fradin, Nicolas Sadoul, Xavier Waintraub, Didier Klug, Albert Hagège, Pascal Sabouraud, Arnaud Isapof, Julien Durigneux, Olivier Lascols, Pascal Laforêt, Armelle Magot, Ivana Dabaj, Eloi Marijon, Camille Vatier, Pascal Cintas, Emmanuelle Salort, Bénédicte Gaborit, Antoine Muchir, Xavier Ferrer, Pascale Richard, Corinne Metay, Stéphane Boulé, Sarah Leonard-Louis, Philippe Mabo, V. Tiffreau, Caroline Stalens, Jitendra K. Vohra, Stéphane Schaeffer, Khadija Chikhaoui, Eric Bieth, Sandra Mercier, Pierre Ambrosi, Aleksandra Nadaj-Pakleza, Michèle Mayer, Katja Zeppenfeld, Gisèle Bonne, Véronique Manel, Jean-Marc Davy, Guilhem Sole, Ghassan Moubarak, Nicolas Lamblin, Klaus Dieterich, Christophe Meune, Abdallah Fayssoil, Arnaud Lazarus, Philippe Maury, Karim Wahbi, Philippe Petiot, Isabelle Jéru, Annick Toutain, Corinne Vigouroux, Ana Ferreiro, Maud Michaud, H.M. Bécane, Bruno Eymard, Thomas D. Gossios, Marie-Christine Vantyghem, Saurabh Kumar, Estelle Gandjbakhch, Yann Péréon, T. Thompson, Marie-Christine Minot-Myhié, Anthony Behin, Frédéric Sacher, Philippe Charron, Nicolas Combes, Julien Praline, Dominique Babuty, Emmanuelle Lagrue, Usha B. Tedrow, Jean-Marc Sellal, Florence Petit, Perry M. Elliott, Frédéric Anselme, Philippe Chevalier, Frederic Taithe, Christine Barnerias, Vincent Laugel, Andoni Echaniz-Laguna, Raphaël P. Martins, Alexander F.A. Androulakis, Rabah Ben Yaou, Franck Boccara, Ulrike Walther-Louvier, Tanya Stojkovic, Françoise Bouhour, Annachiara De Sandre-Giovannoli, Susana Quijano-Roy, Françoise Chapon, Jean-Noël Trochu, Céline Tard, Anne Rollin, Jean-Marie Cuisset, Denis Duboc, Raphaël Porcher, Catherine Sarret, Jonathan M. Kalman, Florence Demurger, Damien Bonnet, Christine Francannet, Neal K. Lakdawala, Romain Eschalier, Fabien Labombarda, Kostantinos Savvatis, Raul Juntas Morales, Isabelle Desguerre, Nicolas Lévy, Anne-Claire Brehin, Service de Cardiologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Rouen, Normandie Université (NU), St Bartholomew's Hospital (London), Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Association française contre les myopathies (AFM-Téléthon), IHU-LIRYC, Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux], Service de Cardiologie B, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Hôpital Ambroise Paré [AP-HP], William Harvey Research Institute, Barts and the London Medical School, Biostatistique et épidemiologie clinique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de cardiologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Filière Neuromusculaire (FILNEMUS), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Université de Caen Normandie (UNICAEN), Laboratoire d'Informatique Scientifique et Industrielle (LISI), Université de Poitiers-Ecole Nationale Supérieure de Mécanique et d'Aérotechnique [Poitiers] (ISAE-ENSMA), Hôpital Raymond Poincaré [AP-HP], CHU Lille, Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Aix Marseille Université (AMU), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Institut de cardiologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de cardiologie et maladies vasculaires [Rennes] = Cardiac, Thoracic, and Vascular Surgery [Rennes], CHU Pontchaillou [Rennes], Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Clinique Pasteur [Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Imagerie Adaptative Diagnostique et Interventionnelle (IADI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), The Royal Melbourne Hospital, Leiden University Medical Center (LUMC), Universiteit Leiden, Service de neurologie pédiatrique [CHU Necker], Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Saint-Antoine [AP-HP], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Necker - Enfants Malades [AP-HP], Hôpital Privé Le Bois Ramsay Santé [Lille], Service de génétique [Rouen], Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Hôpital Côte de Nacre [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Mobilités : Vieillissement, Pathologie, Santé (COMETE), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Roger Salengro [Lille], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de ressources biologiques Tissus ADN Cellules [Hôpital de la Timone - APHM] (CRB TAC), 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)-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), Service de Cytogénétique et de Biologie Cellulaire, Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Centre Hospitalier Universitaire [Grenoble] (CHU), [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Les Hôpitaux Universitaires de Strasbourg (HUS), CHU Clermont-Ferrand, Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de neurologie [Bordeaux], Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de chirurgie cadiovasculaire et thoracique [Rouen], Hôpital Charles Nicolle [Rouen], Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Service de cardiologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CHU Trousseau [APHP], Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Strasbourg, Clinique Ambroise Paré [Centres Médico-Chirurgicaux Ambroise Pré, Pierre Cherest, Hartmann], Hôpital Cochin [AP-HP], Hospices Civils de Lyon (HCL), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Université de Lorraine (UL), Service de neurologie [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), Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Centre Hospitalier Universitaire de Reims (CHU Reims), Institut Pascal (IP), SIGMA Clermont (SIGMA Clermont)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de Neurologie [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Laboratoire d'étude de la motricité humaine - EA 3608 (LEMH), Université de Lille, Droit et Santé, Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Physiopathologie et thérapie du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Montréal (UdeM), Laboratoire Génie des procédés papetiers (LGP2 ), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS), The Heart Hospital [London], University College of London [London] (UCL), This study was funded by grants from the AFM-Téléthon (French Alliance against Myopathies), which was not involved in the design and conduct of the study, collection, management, analysis, and interpretation of the data, preparation, review, or approval of the manuscript, and decision to submit the manuscript for publication. Some of this work was undertaken at University College London (United Kingdom) and St. Bartholomew’s Hospital (London, United Kingdom), which received a portion of funding from the United Kingdom Department of Health’s National Institute for Health Research Biomedical Research Centres funding scheme., Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], Centre de recherche en myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP], CHU Bordeaux [Bordeaux]-Université Bordeaux Segalen - Bordeaux 2, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-CHU Trousseau [APHP], 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), Service de cardiologie et maladies vasculaires, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], CHU Pitié-Salpêtrière [APHP], Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Unit of Neuromuscular Morphology [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [APHP]-Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de référence des maladies rares neuromusculaires Aquitaine-Grand Sud Ouest, CHU Bordeaux [Bordeaux], Laboratoire d'Informatique Scientifique et Industrielle (LISI / ENSMA), LISI-ENSMA, Service de Biochimie-Génétique [Béclère], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Thérapie des maladies du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Cardiologie A, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'Endocrinologie et Métabolisme, Unité de Cardiologie et Soins Intensifs, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse], CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Service de Génétique [Purpan], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], Centre de Référence M3C Malformations Cardiaques Congénitales Complexes, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité-CHU Necker - Enfants Malades [AP-HP], Hôpital neurologique, Centre Hospitalier Universitaire de Lille (CHU de Lille), Service Neurologie Pédiatrique, Service de Neuropédiatrie, INSERM U836, équipe 4, Muscles et pathologies, Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Département de Neurologie, Hôpital Civil de Strasbourg, Groupe Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique médicale, CHU - HÔTEL-DIEU Clermont-Ferrand, CLAD Ouest, Centre Hospitalier Universitaire [Rennes], Centre recherche en CardioVasculaire et Nutrition (C2VN), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service de Neuropédiatrie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie et cerveau, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement (Inserm U1167 - RID-AGE - Institut Pasteur), Clinique Ambroise Paré, CHU Cochin [AP-HP], Epilepsie, sommeil et explorations fonctionnelles neuropédiatriques, Hospices Civils de Lyon (HCL)-Hopital Neurologique-Hôpital Femme Mère Enfant, Department of Medicine, Columbia University [New York]-College of Physicians and Surgeons, Service de neurologie, Hospices Civils de Lyon (HCL)-Hôpital de la Croix-Rousse [CHU - HCL], Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U837 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, Hôpital de Rangueil, Institut Pascal - Clermont Auvergne (IP), Sigma CLERMONT (Sigma CLERMONT)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), laboratoire d'étude de la motricité humaine (LEMH EA3608), Université de Montréal - UdeM (CANADA), Laboratoire Génie des procédés papetiers (LGP2), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche en Myologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité-CHU Necker - Enfants Malades [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Sorbonne Université, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), European Genomic Institute for Diabetes - FR 3508 (EGID), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Hôpital Purpan [Toulouse], Hôpital Charles Nicolle [Rouen]-CHU Rouen, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Hôpital Gui de Chauliac [Montpellier]-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), SIGMA Clermont (SIGMA Clermont)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut de Myologie, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)
Subjects: Adult, Male, Tachycardia, medicine.medical_specialty, implantable, Accurate estimation, Ventricular Tachyarrhythmias, Validation Studies as Topic, 030204 cardiovascular system & hematology, tachycardia, Sudden death, LMNA, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, death, Physiology (medical), Internal medicine, defibrillators, medicine, Humans, In patient, 030212 general & internal medicine, sudden, [SDV.GEN]Life Sciences [q-bio]/Genetics, Prediction score, business.industry, Defibrillators, Implantable, ventricular, Tachycardia, Ventricular, Cardiology, Female, medicine.symptom, Cardiomyopathies, Cardiology and Cardiovascular Medicine, business
Abstract: Background: An accurate estimation of the risk of life-threatening (LT) ventricular tachyarrhythmia (VTA) in patients with LMNA mutations is crucial to select candidates for implantable cardioverter-defibrillator implantation. Methods: We included 839 adult patients with LMNA mutations, including 660 from a French nationwide registry in the development sample, and 179 from other countries, referred to 5 tertiary centers for cardiomyopathies, in the validation sample. LTVTA was defined as (1) sudden cardiac death or (2) implantable cardioverter defibrillator–treated or hemodynamically unstable VTA. The prognostic model was derived using the Fine-Gray regression model. The net reclassification was compared with current clinical practice guidelines. The results are presented as means (SD) or medians [interquartile range]. Results: We included 444 patients, 40.6 (14.1) years of age, in the derivation sample and 145 patients, 38.2 (15.0) years, in the validation sample, of whom 86 (19.3%) and 34 (23.4%) experienced LTVTA over 3.6 [1.0–7.2] and 5.1 [2.0–9.3] years of follow-up, respectively. Predictors of LTVTA in the derivation sample were: male sex, nonmissense LMNA mutation, first degree and higher atrioventricular block, nonsustained ventricular tachycardia, and left ventricular ejection fraction (https://lmna-risk-vta.fr). In the derivation sample, C-index (95% CI) of the model was 0.776 (0.711–0.842), and the calibration slope 0.827. In the external validation sample, the C-index was 0.800 (0.642–0.959), and the calibration slope was 1.082 (95% CI, 0.643–1.522). A 5-year estimated risk threshold ≥7% predicted 96.2% of LTVTA and net reclassified 28.8% of patients with LTVTA in comparison with the guidelines-based approach. Conclusions: In comparison with the current standard of care, this risk prediction model for LTVTA in laminopathies significantly facilitated the choice of candidates for implantable cardioverter defibrillators. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03058185.
Published: 2019

18. International multidisciplinary collaboration toward an annotated definition of arthrogryposis multiplex congenita

Author: Harold J.P. van Bosse, Ann Marie Davison, Maureen Donohoe, Alicja Fąfara, Reggie C. Hamdy, Igor A. Komolkin, Judith G. Hall, Eva Kimber, Tanya Bedard, Sarah Cachecho, Klaus Dieterich, Eva Pontén, Ruth Lester, Naimisha S. Hoffman, Noémi Dahan-Oliel, Helgi Thor Hjartarson, and Douglas Barnes
Subjects: 0301 basic medicine, Process (engineering), Computer science, 030105 genetics & heredity, Field (computer science), Terminology, 03 medical and health sciences, Annotation, arthrogryposis multiplex congenita, Health care, Genetics, Humans, definition, Intersectoral Collaboration, Research Articles, Genetics (clinical), Arthrogryposis, Arthrogryposis multiplex congenita, business.industry, Data science, collaboration, expert opinion, 030104 developmental biology, annotation, Paragraph, business, Sentence, Research Article
Abstract: Arthrogryposis multiplex congenita (AMC) has been described and defined in thousands of articles, but the terminology used has been inconsistent in clinical and research communities. A definition of AMC was recently developed using a modified Delphi consensus method involving 25 experts in the field of AMC from 8 countries. Participants included health care professionals, researchers, and individuals with AMC. An annotation of the definition provides more in‐depth explanations of the different sentences of the AMC definition and is useful to complement the proposed definition. The aim of this study was to provide an annotation of the proposed consensus‐based AMC definition. For the annotation process, 17 experts in AMC representing 10 disciplines across 7 countries participated. A paragraph was developed for each sentence of the definition using an iterative process involving multiple authors with varied and complementary expertise, ensuring all points of view were taken into consideration. The annotated definition provides an overview of the different topics related to AMC and is intended for all stakeholders, including youth and adults with AMC, their families, and clinicians and researchers, with the hopes of unifying the understanding of AMC in the international community.
Published: 2019

19. Xq22.3q23 microdeletion harboring TMEM164 and AMMECR1 genes: Two case reports confirming a recognizable phenotype with short stature, midface hypoplasia, intellectual delay, and elliptocytosis

Author: Renaud Touraine, Véronique Adouard, Pierre-Simon Jouk, Véronique Satre, Radu Harbuz, Claire Vettier, Claire Barro, Charles Coutton, Francis Ramond, Julien Thevenon, Brice Poreau, and Klaus Dieterich
Subjects: Male, Nephritis, Hereditary, Short stature, Contiguous gene syndrome, Craniofacial Abnormalities, Elliptocytosis, Intellectual Disability, Intellectual disability, Genetics, medicine, Humans, Alport syndrome, Child, Genetics (clinical), Exome sequencing, Chromosomes, Human, X, business.industry, Elliptocytosis, Hereditary, Membrane Proteins, Proteins, Genetic Diseases, X-Linked, AMMECR1, Prognosis, medicine.disease, Chromosome Deletion, medicine.symptom, business, Haploinsufficiency
Abstract: The AMME syndrome defined as the combination of Alport syndrome, intellectual disability, midface hypoplasia, and elliptocytosis (AMME) is known to be a contiguous gene syndrome associated with microdeletions in the region Xq22.3q23. Recently, using exome sequencing, missense pathogenic variants in AMMECR1 have been associated with intellectual disability, midface hypoplasia, and elliptocytosis. In these cases, AMMECR1 gene appears to be responsible for most of the clinical features of the AMME syndrome except for Alport syndrome. In this article, we present two unrelated male patients with short stature, mild intellectual disability or neurodevelopmental delay, sensorineural hearing loss, and elliptocytosis harboring small microdeletions identified by array-CGH involving TMEM164 and AMMECR1 genes and SNORD96B small nucleolar RNA for one patient, inherited from their mothers. These original cases further confirm that most specific AMME features are ascribed to AMMECR1 haploinsufficiency. These cases reporting the smallest microdeletions encompassing AMMECR1 gene provide new evidence for involvement of AMMECR1 in the AMME phenotype and permit to discuss a phenotype related to AMMECR1 haploinsufficiency: developmental delay/intellectual deficiency, midface hypoplasia, midline defect, deafness, and short stature.
Published: 2019

20. Spinal muscular atrophy with respiratory distress type 1: A multicenter retrospective study

Author: Maryse Magen, Susana Quijano-Roy, Domitille Gras, Mathilde Nizon, Corinne Magdelaine, Catherine Vanhulle, Fabienne Giuliano, Eric Bieth, Véronique Manel, Damien Haye, Pascal Cintas, Florence Petit, Klaus Dieterich, Agnès Viguier, S. Peudenier, Valérie Lauwers-Cances, Mélanie Fradin, Claude Cances, Isabelle Desguerre, Arnaud Isapof, Michèle Mathieu-Dramard, and Michaël Jokic
Subjects: Male, 0301 basic medicine, Artificial ventilation, Pediatrics, medicine.medical_specialty, medicine.medical_treatment, Diaphragmatic breathing, Muscular Atrophy, Spinal, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Respiratory system, Genetics (clinical), Retrospective Studies, Respiratory Distress Syndrome, Newborn, Palsy, Respiratory distress, business.industry, Infant, Newborn, Infant, Retrospective cohort study, Spinal muscular atrophy, Prognosis, medicine.disease, Respiration, Artificial, Hypotonia, DNA-Binding Proteins, Phenotype, 030104 developmental biology, Neurology, Child, Preschool, Mutation, Pediatrics, Perinatology and Child Health, Disease Progression, Female, France, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery, Transcription Factors
Abstract: Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a rare autosomal recessive neuromuscular disorder characterized by progressive motor and respiratory decline during the first year of life. Early and late-onset cases have recently been reported, although not meeting the established diagnostic criteria, these cases have been genotyped. We thus conducted a national multicenter observational retrospective study to determine the prognosis of children with SMARD1 according to their phenotype. We recorded all known French pediatric cases with mutations identified on the immunoglobulin μ-binding protein 2 gene and the presence of respiratory symptoms. Thirty centers provided 22 observations. A diaphragmatic palsy was diagnosed 1.5 months (p = 0.02) after first respiratory symptoms, and hypotonia preceded areflexia by 4 months (p = 0.02). Early onset of symptoms leading to specialist consultation before the age of 3 months was associated with a significantly worse prognosis (p
Published: 2019

21. Review for 'Bi-allelic loss of ERGIC1 causes relatively mild arthrogryposis'

Author: klaus dieterich
Subjects: Genetics, Arthrogryposis, medicine, Biology, medicine.symptom, Allelic loss
Published: 2021

22. Using deep-neural-network-driven facial recognition to identify distinct Kabuki syndrome 1 and 2 gestalt

Author: Didier Lacombe, Claire Duflos, David Geneviève, Jeanne Amiel, Elodie Sanchez, Yline Capri, Damien Sanlaville, Marlène Rio, Alexandra Afenjar, Fabienne Giuliano, Elise Brischoux-Boucher, Mathilde Nizon, Stanislas Lyonnet, Sébastien Moutton, Vincent Gatinois, Stéphanie Arpin, Annick Toutain, Mouna Barat-Houari, Guilaine Boursier, Flavien Rouxel, Sophie Julia, Klaus Dieterich, Aurélia Jacquette, Boris Keren, Kevin Yauy, Patricia Blanchet, Marie-Line Jacquemont, Damien Haye, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), 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), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Tours], 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), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Université de Lausanne (UNIL), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pitié-Salpêtrière [AP-HP], Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), CHU Necker - Enfants Malades [AP-HP], [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), CHU Grenoble, Centre de génétique humaine [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC), CHU Toulouse [Toulouse], Centre hospitalier universitaire de Nantes (CHU Nantes), GRC ConCer-LD, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Maison de Santé Protestante Bagatelle, Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), and Hospices Civils de Lyon (HCL)
Subjects: Image Series, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Biology, [INFO.INFO-NE]Computer Science [cs]/Neural and Evolutionary Computing [cs.NE], Facial recognition system, Article, Genetics, medicine, Humans, Abnormalities, Multiple, Genetics (clinical), [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Artificial neural network, Receiver operating characteristic, business.industry, Significant difference, Genetic disorder, [INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], Pattern recognition, medicine.disease, Hematologic Diseases, Vestibular Diseases, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Face, Mutation, Gestalt psychology, Artificial intelligence, business, Kabuki syndrome, Facial Recognition
Abstract: International audience; Kabuki syndrome (KS) is a rare genetic disorder caused by mutations in two major genes, KMT2D and KDM6A, that are responsible for Kabuki syndrome 1 (KS1, OMIM147920) and Kabuki syndrome 2 (KS2, OMIM300867), respectively. We lack a description of clinical signs to distinguish KS1 and KS2. We used facial morphology analysis to detect any facial morphological differences between the two KS types. We used a facial-recognition algorithm to explore any facial morphologic differences between the two types of KS. We compared several image series of KS1 and KS2 individuals, then compared images of those of Caucasian origin only (12 individuals for each gene) because this was the main ethnicity in this series. We also collected 32 images from the literature to amass a large series. We externally validated results obtained by the algorithm with evaluations by trained clinical geneticists using the same set of pictures. Use of the algorithm revealed a statistically significant difference between each group for our series of images, demonstrating a different facial morphotype between KS1 and KS2 individuals (mean area under the receiver operating characteristic curve = 0.85 [p = 0.027] between KS1 and KS2). The algorithm was better at discriminating between the two types of KS with images from our series than those from the literature (p = 0.0007). Clinical geneticists trained to distinguished KS1 and KS2 significantly recognised a unique facial morphotype, which validated algorithm findings (p = 1.6e-11). Our deep-neural-network-driven facial-recognition algorithm can reveal specific composite gestalt images for KS1 and KS2 individuals.
Published: 2021

23. Identification of biallelic germline variants of SRP68 in a sporadic case with severe congenital neutropenia

Author: Barbara, Schmaltz-Panneau, Anne, Pagnier, Séverine, Clauin, Julien, Buratti, Caroline, Marty, Odile, Fenneteau, Klaus, Dieterich, Blandine, Beaupain, Jean, Donadieu, Isabelle, Plo, Christine, Bellanné-Chantelot, Gestionnaire, Hal Sorbonne Université, Institut Gustave Roussy (IGR), Centre Hospitalier Universitaire [Grenoble] (CHU), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Dynamique moléculaire de la transformation hématopoïétique (Dynamo), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Service d'Hématologie Biologique [Hôpital Robert Debré, Paris], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau]
Subjects: [SDV] Life Sciences [q-bio], Germ Cells, Neutropenia, [SDV]Life Sciences [q-bio], Congenital Bone Marrow Failure Syndromes, Humans, Case Reports, Signal Recognition Particle, Germ-Line Mutation, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2021

24. DOORS syndrome and a recurrent truncating ATP6V1B2 variant

Author: Marzena Wisniewska, Sirinart Molidperee, Juliet M. Taylor, Philippe M. Campeau, Tabib Dabir, Eliane Beauregard-Lacroix, Maria Vittoria Camurri, Jessica Tardif, Yolande van Bever, Sanjay M. Sisodiya, Klaus Dieterich, Pernille Mathiesen Tørring, Guillermo Pacheco-Cuellar, Ed Blair, Alexandre Dionne-Laporte, Dina Vind-Kezunovic, Dénes Zádori, Claudia Castiglioni, Norbert F. Ajeawung, Lisbeth Tranebjærg, Susan M. White, Raoul C.M. Hennekam, General Paediatrics, APH - Quality of Care, and Clinical Genetics
Subjects: Sanger sequencing, Pediatrics, medicine.medical_specialty, business.industry, 03.01. Általános orvostudomány, medicine.disease, Human genetics, TBC1D24 gene, Epilepsy, symbols.namesake, ATP6V1B2 gene, DOOR syndrome, DOORS syndrome, Onychodystrophy, Intellectual disability, symbols, DDOD syndrome, Medicine, exome sequencing, business, Exome, Genetics (clinical), Exome sequencing
Abstract: Purpose: Biallelic variants in TBC1D24, which encodes a protein that regulates vesicular transport, are frequently identified in patients with DOORS (deafness, onychodystrophy, osteodystrophy, intellectual disability [previously referred to as mental retardation], and seizures) syndrome. The aim of the study was to identify a genetic cause in families with DOORS syndrome and without a TBC1D24 variant. Methods: Exome or Sanger sequencing was performed in individuals with a clinical diagnosis of DOORS syndrome without TBC1D24 variants. Results: We identified the same truncating variant in ATP6V1B2 (NM_001693.4:c.1516C>T; p.Arg506*) in nine individuals from eight unrelated families with DOORS syndrome. This variant was already reported in individuals with dominant deafness onychodystrophy (DDOD) syndrome. Deafness was present in all individuals, along with onychodystrophy and abnormal fingers and/or toes. All families but one had developmental delay or intellectual disability and five individuals had epilepsy. We also describe two additional families with DDOD syndrome in whom the same variant was found. Conclusion: We expand the phenotype associated with ATP6V1B2 and propose another causal gene for DOORS syndrome. This finding suggests that DDOD and DOORS syndromes might lie on a spectrum of clinically and molecularly related conditions.
Published: 2021

25. Mutations in MYLPF Cause a Novel Segmental Amyoplasia that Manifests as Distal Arthrogryposis

Author: Arthur S. Aylsworth, Kathryn M. Shively, Kati J. Buckingham, Mariam Al-Mulla, Paul M.L. Janssen, Periyasamy Radhakrishnan, Julien Fauré, Klaus Dieterich, Deborah A. Nickerson, Tawfeg Ben-Omran, Francesca Inzana, Emily M Teets, Yline Capri, Xenia Latypova, David M. Warshaw, Tamar Harel, Brit L. Martin, Ulrich A. Schatz, Katta M. Girisha, Sharon L. Amacher, Michael J. Bamshad, Reem Saadeh-Haddad, John Rendu, Hagar Mor-Shaked, Colby T. Marvin, Anju Shukla, Shalini S. Nayak, Samantha Beck Previs, Jessica X. Chong, Fatima Almusafri, and Jared C. Talbot
Subjects: Male, 0301 basic medicine, medicine.medical_specialty, Contracture, Myosin Light Chains, Myosin light-chain kinase, Adolescent, Myosins, Biology, Short stature, Article, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Myosin, Genetics, medicine, Paralysis, Animals, Humans, Amino Acid Sequence, Child, Muscle, Skeletal, Letter to the Editor, Zebrafish, Genetics (clinical), Exome sequencing, 030304 developmental biology, Arthrogryposis, 0303 health sciences, Amyoplasia, Muscle weakness, Skeletal muscle, Extremities, medicine.disease, Musculoskeletal Abnormalities, Pedigree, 030104 developmental biology, medicine.anatomical_structure, Endocrinology, Mutation, Female, medicine.symptom, 030217 neurology & neurosurgery
Abstract: We identified ten persons in six consanguineous families with Distal Arthrogryposis (DA) who had congenital contractures, scoliosis, and short stature. Exome sequencing revealed that each affected person was homozygous for one of two different rare variants (c.470G>T, p.(Cys157Phe) or c.469T>C, p.(Cys157Arg)) affecting the same residue ofmyosin light chain, phosphorylatable, fast skeletal muscle(MYLPF). In a seventh family, a c.487G>A, p.(Gly163Ser) variant inMYLPFarosede novoin a father, who transmitted it to his son. In an eighth family comprised of seven individuals with dominantly-inherited DA, a c.98C>T, p.(Ala33Val) variant segregated in all four persons tested. Variants inMYLPFunderlie both dominant and recessively inherited DA. Mylpf protein models suggest that the residues associated with dominant DA interact with myosin whereas the residues altered in families with recessive DA only indirectly impair this interaction. Pathological and histological exam of a foot amputated from an affected child revealed complete absence of skeletal muscle (i.e., segmental amyoplasia). To investigate the mechanism for this finding, we generated an animal model for partial MYLPF impairment by knocking out zebrafishmylpfa. Themylpfamutant had reduced trunk contractile force and complete pectoral fin paralysis, demonstrating thatmylpfimpairment most severely affects limb movement.mylpfamutant muscle weakness was most pronounced in an appendicular muscle and was explained by reduced myosin activity and fiber degeneration. Collectively, our findings demonstrate that partial loss of MYLPF function can lead to congenital contractures, likely as a result of degeneration of skeletal muscle in the distal limb.
Published: 2020

26. Primrose syndrome: a phenotypic comparison of patients with a ZBTB20 missense variant versus a 3q13.31 microdeletion including ZBTB20

Author: Anne-Sophie Denommé-Pichon, Laetitia Gouas, Martin Chevarin, Marlène Rio, Elodie Gautier, Sonia Bouquillon, Nolwenn Jean-Marçais, Jennifer Fabre-Teste, Dominique Martin, Elise Schaefer, Fabienne Giuliano, Didier Lacombe, Sophie Nambot, Gaëlle Vieville, Sophie Blesson, Paul Kuentz, Christine Francannet, Yannis Duffourd, Aurélien Juven, Alice Masurel, Patrick Callier, Arnold Munnich, Salima El Chehadeh, Sophie Rondeau, Christophe Philippe, Amélie Piton, Fanny Laffargue, Catherine Vincent Delorme, Marie Vincent, Olivier Pichon, Bénédicte Gérard, Anne-Laure Mosca-Boidron, Bertrand Isidor, Christel Thauvin-Robinet, Laurence Perrin-Sabourin, Nathalie Marle, Cédric Le Caignec, Laurence Faivre, Hubert Journel, Klaus Dieterich, 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), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de génétique, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratoire de cytogénétique (CHU de Dijon), Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe GAD (LNC - U1231), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut cellule souche et cerveau (U846 Inserm - UCBL1), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance Publique-Hôpitaux de Paris, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Service de Génétique Médicale, Hôpital Civil, Strasbourg, DGA Maîtrise de l'information (DGA.MI), Direction générale de l'Armement (DGA), Institut de Génétique Médicale [CHRU Lille], Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, CHU Clermont-Ferrand, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Hôpital l'Archet, Service de Génétique Médicale, Génétique médicale [Centre Hospitalier de Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), 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), Laboratoire de biochimie et génétique moléculaire, CHU Grenoble, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Département de Biochimie et 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), FHU TRANSLAD (CHU de Dijon), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), 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-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, Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Institut cellule souche et cerveau (SBRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Groupe d'imagerie neurofonctionnelle (GIN), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), and Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)
Subjects: Adolescent, Hearing loss, [SDV]Life Sciences [q-bio], Mutation, Missense, Nerve Tissue Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, Bioinformatics, Article, Corpus Callosum, 03 medical and health sciences, Ectopic calcification, Ptosis, Intellectual Disability, Genetics, Medicine, Missense mutation, Humans, Abnormalities, Multiple, Child, Ear Diseases, Wasting, Genetics (clinical), Muscle contracture, 0303 health sciences, business.industry, 030305 genetics & heredity, Macrocephaly, Calcinosis, medicine.disease, Primrose syndrome, Muscular Atrophy, Phenotype, Child, Preschool, Chromosomes, Human, Pair 3, medicine.symptom, Chromosome Deletion, business, Transcription Factors
Abstract: International audience; Primrose syndrome is characterized by variable intellectual deficiency, behavior disorders, facial features with macrocephaly, and a progressive phenotype with hearing loss and ectopic calcifications, distal muscle wasting, and contractures. In 2014, ZBTB20 variants were identified as responsible for this syndrome. Indeed, ZBTB20 plays an important role in cognition, memory, learning processes, and has a transcription repressive effect on numerous genes. A more severe phenotype was discussed in patients with missense single nucleotide variants than in those with large deletions. Here, we report on the clinical and molecular results of 14 patients: 6 carrying ZBTB20 missense SNVs, 1 carrying an early truncating indel, and 7 carrying 3q13.31 deletions, recruited through the AnDDI-Rares network. We compared their phenotypes and reviewed the data of the literature, in order to establish more powerful phenotype-genotype correlations. All 57 patients presented mild-to-severe ID and/or a psychomotor delay. Facial features were similar with macrocephaly, prominent forehead, downslanting palpebral fissures, ptosis, and large ears. Hearing loss was far more frequent in patients with missense SNVs (p = 0.002), ectopic calcification, progressive muscular wasting, and contractures were observed only in patients with missense SNVs (p nonsignificant). Corpus callosum dysgenesis (p = 0.00004), hypothyroidism (p = 0.047), and diabetes were also more frequent in this group. However, the median age was 9.4 years in patients with deletions and truncating variant compared with 15.1 years in those with missense SNVs. Longer follow-up will be necessary to determine whether the phenotype of patients with deletions is also progressive.
Published: 2020

27. Liste des auteurs

Author: Kariman Abelin-genevois, Philippe Beaudet, Benjamin Blondel, Véronique Bourg, Emeline Bourgeois, Bertrand Boyer, Jean Brilhault, Adeline Cambon-binder, Céline Cazorla, Jean-michel Cognet, Olivier Cornu, Vincent Crenn, Klaus Dieterich, Alice Fassier, Stéphane Fuentes, Jeannot Gaudias, Louis-Etienne Gayet, Loïc Geffroy, Jacques Griffet, Denis Huten, Dragan Jeremic, Jean-Christophe Lambotte, François Lintz, Julie Manon, Olivier Mares, Julien Maximen, Pierre Métais, Didier Moukoko, Xavier Ohl, Didier Ollat, Régis Pailhé, Sébastien Pesenti, Solène Prost, Dan Putineanu, Gérard Richardi, Charles Rivière, Mickaël Ropars, Renaud Siboni, Karim Tribak, Alexandre Tronchot, Patrick Tropiano, Tanguy Vendeuvre, Pascal-André Vendittoli, and Loic Villet
Published: 2020

28. Further delineation of the clinical spectrum of KAT6B disorders and allelic series of pathogenic variants

Author: Jennifer Tarpinian, Alberto Fernández-Jaén, Deborah A. Nickerson, Michael J. Bamshad, Kosuke Izumi, Giovanni Battista Ferrero, Emma Bedoukian, Marcello Niceta, Brendan Lee, A. Micheil Innes, Yuri A. Zarate, Katherine A. Bosanko, Annie Laquerrière, Jennifer A. Bassetti, David Mowat, Beth Keena, Carolina Galaz-Montoya, Claudia Gonzaga-Jauregui, Boris Keren, Reid Sutton, Elaine H. Zackai, James R. Lupski, Constance F. Wells, Francesca Clementina Radio, Natalie Hauser, Dong Li, Grace U Ediae, Marco Tartaglia, Xiang-Jiao Yang, Para Chottil Soumya, Elizabeth J. Bhoj, Christine Coubes, Kinattinkara R. Subbaraman, Alain Verloes, Klaus Dieterich, John C. Carey, Mary K. Kukolich, Francisco Cammarata-Scalisi, Alper Gezdirici, Jessica X. Chong, Sirinart Molidperee, Amelle Shillington, Sarah L. Sawyer, David S. Liu, Ana Bracho, Li Xin Zhang, Richard A. Gibbs, Sheela Nampoothiri, Ingrid A. Holm, Philip M. Boone, Alyssa Ritter, Charlotte Dubucs, Philippe M. Campeau, Gabrielle Lemire, Maria Lisa Dentici, Jacqueline Aziza, Frank J. Probst, Karippoth Mohandas Nair, Millan S. Patel, and Chester W. Brown
Subjects: 0301 basic medicine, Say–Barber–Biesecker–Young–Simpson syndrome, 030105 genetics & heredity, Blepharophimosis, Bioinformatics, KAT6B, Article, 03 medical and health sciences, genitopatellar syndrome, KAT6B disorders, SBBYSS, Intellectual Disability, Genotype, Medicine, Humans, Allele, Increased nuchal translucency, Genetics (clinical), Histone Acetyltransferases, Optic nerve hypoplasia, Polydactyly, business.industry, Enfermedades genéticas congénitas, Pediatría, Embriología, Cystic hygroma, Exons, medicine.disease, Genética, 030104 developmental biology, Intestinal malrotation, Mutation, Genitopatellar syndrome, business
Abstract: Purpose :Genitopatellar syndrome and Say–Barber–Biesecker–Young–Simpson syndrome are caused by variants in the KAT6B gene and are part of a broad clinical spectrum called KAT6B disorders, whose variable expressivity is increasingly being recognized. Methods: We herein present the phenotypes of 32 previously unreported individuals with a molecularly confirmed diagnosis of a KAT6B disorder, report 24 new pathogenic KAT6B variants, and review phenotypic information available on all published individuals with this condition. We also suggest a classification of clinical subtypes within the KAT6B disorder spectrum. Results: We demonstrate that cerebral anomalies, optic nerve hypoplasia, neurobehavioral difficulties, and distal limb anomalies other than long thumbs and great toes, such as polydactyly, are more frequently observed than initially reported. Intestinal malrotation and its serious consequences can be present in affected individuals. Additionally, we identified four children with Pierre Robin sequence, four individuals who had increased nuchal translucency/cystic hygroma prenatally, and two fetuses with severe renal anomalies leading to renal failure. We also report an individual in which a pathogenic variant was inherited from a mildly affected parent. Conclusión: Our work provides a comprehensive review and expansion of the genotypic and phenotypic spectrum of KAT6B disorders that will assist clinicians in the assessment, counseling, and management of affected individuals. Sin financiación 8.822 JCR(2020) Q1, 15/176 Genetics & Heredity 3.509 SJR (2020) Q1, 7/96 Genetics (clinical) No data IDR 2020 UEM
Published: 2020

29. Disability in adults with arthrogryposis is severe, partly invisible, and varies by genotype

Author: Shenhao Dai, Marie Jaeger, Klaus Dieterich, Bernard Wuyam, Dominic Pérennou, and Pierre-Simon Jouk
Subjects: musculoskeletal diseases, Arthrogryposis, 030222 orthopedics, Pediatrics, medicine.medical_specialty, Amyoplasia, Arthrogryposis multiplex congenita, business.industry, Retrospective cohort study, medicine.disease, Invisible disability, 03 medical and health sciences, 0302 clinical medicine, International Classification of Functioning, Disability and Health, Cohort, medicine, Anxiety, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: ObjectiveTo understand the disability of adults with arthrogryposis multiplex congenita (AMC), a rare disease spectrum characterized by at least 2 joint contractures at birth in different body areas.MethodsThis is a retrospective analysis of data for unselected persons with AMC referred to the French center for adults with AMC from 2010 to 2016. All underwent a pluriprofessional systematic and comprehensive investigation of deficits, activity limitation, and participation restriction according to the International Classification of Functioning, Disability and Health and genetic analysis when indicated. Participants were divided by amyoplasia and other AMC types.ResultsMean (SD) age of the 43 participants (27 female) was 33.2 (13.4) years; 28 had amyoplasia and 15 other types of AMC. Beyond joint stiffness, deformities, and muscle weakness, the well-known core symptoms that we quantified and for which first-line treatment involved technical aids, other less visible disorders that could contribute to severe participation restriction were particularly pain and psychological problems including anxiety, fatigue, difficulty in sexual life, altered self-esteem, and feelings of solitude. Severe respiratory disorders were infrequent and were linked toPIEZO2mutations. Gait disorders were not due to respiratory impairment but to skeletal problems and were always associated with amyoplasia when severe. Functional independence was worse but respiratory and swallowing capacities were better with amyoplasia than other AMC types.ConclusionThis study describes disability patterns of a cohort of adults with AMC by genotype. The disability of adults with AMC is influenced by genotype, with important invisible disability.
Published: 2018

30. Response to Hall et al

Author: Tawfeg Ben-Omran, Xenia Latypova, Jared C. Talbot, Reem Saadeh-Haddad, Julien Fauré, Mariam Al-Mulla, Jessica X. Chong, Arthur S. Aylsworth, Kati J. Buckingham, John Rendu, Fatima Almusafri, Yline Capri, Brit L. Martin, Deborah A. Nickerson, Emily M Teets, Francesca Inzana, Paul M.L. Janssen, Shalini S. Nayak, Sharon L. Amacher, Klaus Dieterich, David M. Warshaw, Katta M. Girisha, Colby T. Marvin, Periyasamy Radhakrishnan, Kathryn M. Shively, Ulrich A. Schatz, Tamar Harel, Hagar Mor-Shaked, Michael J. Bamshad, Anju Shukla, and Samantha Beck Previs
Subjects: Genetics, Arthrogryposis, business.industry, Mutation (genetic algorithm), MEDLINE, Medicine, medicine.symptom, business, Genetics (clinical)
Published: 2020

31. Neurofibromatose de type 1 : survenue de deux tumeurs avant l’âge de 5 ans

Author: C. Piolat, Klaus Dieterich, C. Durand, M. Remillieux, F. Hameury, H. Sartelet, E. Bourgeois, C. Perret, P. Pommier, and D. Vidaud
Subjects: 0301 basic medicine, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, Pediatrics, Perinatology and Child Health
Abstract: Resume La neurofibromatose de type 1 (NF1) est une maladie genetique predisposant au developpement de tumeurs malignes et benignes. La mutation du gene NF1 entraine une deregulation de la voie de signalisation RAS-MAP-kinase aboutissant a un dysfonctionnement du controle de la proliferation cellulaire et a la proliferation tumorale. L’epidemiologie des cancers chez les enfants atteints de neurofibromatose est tres differente de celle de la population pediatrique generale, imposant une surveillance specifique et rapprochee. Le neurofibrome est la tumeur benigne la plus frequente. Elle peut etre tres invalidante selon sa localisation et sa taille. Il n’existe actuellement pas de traitement specifique pour ces tumeurs. Les tumeurs malignes les plus frequentes sont les leucemies, les rhabdomyosarcomes, les gliomes et les tumeurs malignes des nerfs peripheriques. La prise en charge therapeutique doit prendre en compte le risque de developpement de tumeurs secondaires aux traitements. Nous rapportons le cas d’un enfant ayant developpe avant l’âge de 5 ans deux tumeurs.
Published: 2017

32. PBX1haploinsufficiency leads to syndromic congenital anomalies of the kidney and urinary tract (CAKUT) in humans

Author: Françoise Devillard, Marie Bidart, Véronique Satre, Pierre-Simon Jouk, Pauline Le Tanno, Frédérique Béna, Pierre F. Ray, Klaus Dieterich, Ida Vogel, Julie Breton, Maria Antonietta Pisanti, Charles Coutton, Hervé Sartelet, Luisa Mackenroth, Siv Fokstuen, M. C. Digilio, Fitsum Guebre-Egziabher, Alexia Apostolou, Karl Hackmann, C Bosson, Rikke Christensen, Sylvie Odent, Antonio Novelli, Radu Harbuz, Rachel Beddow, Gemma Poke, Laura Bernardini, Sylvie Jaillard, Gaëlle Vieville, and Florence Amblard
Subjects: 0301 basic medicine, Genetics, Fetus, Pregnancy, Pathology, medicine.medical_specialty, Kidney, Microarray analysis techniques, Urinary system, Genetic counseling, 030105 genetics & heredity, Biology, medicine.disease, 03 medical and health sciences, 030104 developmental biology, medicine.anatomical_structure, Journal Article, medicine, Copy-number variation, Haploinsufficiency, Genetics (clinical)
Abstract: BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) represent a significant healthcare burden since it is the primary cause of chronic kidney in children. CNVs represent a recurrent molecular cause of CAKUT but the culprit gene remains often elusive. Our study aimed to define the gene responsible for CAKUT in patients with an 1q23.3q24.1 microdeletion.METHODS: We describe eight patients presenting with CAKUT carrying an 1q23.3q24.1 microdeletion as identified by chromosomal microarray analysis (CMA). Clinical features were collected, especially the renal and urinary tract phenotype, and extrarenal features. We characterised PBX1 expression and localisation in fetal and adult kidneys using quantitative RT-PCR and immunohistochemistry.RESULTS: We defined a 276-kb minimal common region (MCR) that only overlaps with the PBX1 gene. All eight patients presented with syndromic CAKUT. CAKUT were mostly bilateral renal hypoplasia (75%). The most frequent extrarenal symptoms were developmental delay and ear malformations. We demonstrate that PBX1 is strongly expressed in fetal kidneys and brain and expression levels decreased in adult samples. In control fetal kidneys, PBX1 was localised in nuclei of medullary, interstitial and mesenchymal cells, whereas it was present in endothelial cells in adult kidneys.CONCLUSIONS: Our results indicate that PBX1 haploinsufficiency leads to syndromic CAKUT as supported by the Pbx1-null mice model. Correct PBX1 dosage appears to be critical for normal nephrogenesis and seems important for brain development in humans. CMA should be recommended in cases of fetal renal anomalies to improve genetic counselling and pregnancy management.
Published: 2017

33. Xq28 duplication includingMECP2in six unreported affected females: what can we learn for diagnosis and genetic counselling?

Author: Sophie Rondeau, Charles Coutton, Pierre-Simon Jouk, Lydie Burglen, Alice Goldenberg, Bérénice Doray, Nathalie Marle, Séverine Drunat, Pascal Chambon, P. Callier, Thierry Bienvenu, F. Devillard, M.-L. Moutard, Danielle Martinet, Bernard Aral, Pascale Saugier-Veber, Nathalie Perreton, Marie-Claude Addor, Marguerite Miguet, Martine Doco-Fenzy, N. Le Meur, Anne-Marie Guerrot, J.-L. Alessandri, C. Thauvin-Robinet, R. Touraine, Anne-Claude Tabet, Anne-Laure Mosca-Boidron, S. El Chehadeh, D. Devys, Sébastien Lebon, Alexandra Afenjar, Sandra Chantot-Bastaraud, Laurence Faivre, Emilie Landais, Cathy Philippe, Klaus Dieterich, Valérie Kremer, Julien Thevenon, Véronique Satre, V. des Portes, Francine Mugneret, Willie Reardon, and Fabienne Prieur
Subjects: 0301 basic medicine, Genetics, Pediatrics, medicine.medical_specialty, Genetic counseling, MECP2 duplication syndrome, 030105 genetics & heredity, Biology, medicine.disease, X-inactivation, 3. Good health, Xq28, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Gene duplication, medicine, Asymptomatic carrier, Skewed X-inactivation, 030217 neurology & neurosurgery, Genetics (clinical)
Abstract: Duplication of the Xq28 region, involving MECP2 (dupMECP2), has been primarily described in males with severe developmental delay, spasticity, epilepsy, stereotyped movements and recurrent infections. Carrier mothers are usually asymptomatic with an extremely skewed X chromosome inactivation (XCI) pattern. We report a series of six novel symptomatic females carrying a de novo interstitial dupMECP2, and review the 14 symptomatic females reported to date, with the aim to further delineate their phenotype and give clues for genetic counselling. One patient was adopted and among the other 19 patients, seven (37%) had inherited their duplication from their mother, including three mildly (XCI: 70/30, 63/37, 100/0 in blood and random in saliva), one moderately (XCI: random) and three severely (XCI: uninformative and 88/12) affected patients. After combining our data with data from the literature, we could not show a correlation between XCI in the blood or duplication size and the severity of the phenotype, or explain the presence of a phenotype in these females. These findings confirm that an abnormal phenotype, even severe, can be a rare event in females born to asymptomatic carrier mothers, making genetic counselling difficult in couples at risk in terms of prognosis, in particular in prenatal cases.
Published: 2017

34. Correction: Variants in MED12L, encoding a subunit of the Mediator kinase module, are responsible for intellectual disability associated with transcriptional defect

Author: Mathilde Nizon, Vincent Laugel, Kevin M. Flanigan, Matthew Pastore, Megan A. Waldrop, Jill A. Rosenfeld, Ronit Marom, Rui Xiao, Amanda Gerard, Olivier Pichon, Cédric Le Caignec, Marion Gérard, Klaus Dieterich, Megan Truitt Cho, Kirsty McWalter, Susan Hiatt, Michelle L. Thompson, Stéphane Bézieau, Alexandrea Wadley, Klaas J. Wierenga, Jean-Marc Egly, Bertrand Isidor, Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital de Hautepierre [Strasbourg], Baylor College of Medicine (BCM), Baylor University, Gatonero SA, Centre hospitalier universitaire de Nantes (CHU Nantes), 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), INSERM U836, équipe 4, Muscles et pathologies, Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Service de Génétique, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Nationwide Children's Hospital, Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Normandie Université (NU)-Normandie Université (NU), Pôle Couple-Enfant, Département de Génétique et Procréation, GeneDx [Gaithersburg, MD, USA], HudsonAlpha Genome Sequencing Center, University of Alabama in Huntsville (UAH), University of Oklahoma (OU), Mayo Clinic [Jacksonville], Richard, Nicolas, Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)
Subjects: MED12L, corpus callosum, [SDV.GEN]Life Sciences [q-bio]/Genetics, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, intellectual disability, transcriptional defect, [SDV.GEN] Life Sciences [q-bio]/Genetics, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Article, mediator complex, Genetics (clinical)
Abstract: Purpose Mediator is a multiprotein complex that allows the transfer of genetic information from DNA binding proteins to the RNA polymerase II during transcription initiation. MED12L is a subunit of the kinase module, which is one of the four sub-complexes of the mediator complex. Other subunits of the kinase module have been already implicated in intellectual disability, namely MED12, MED13L, MED13 and CDK19. Methods We describe an international cohort of seven affected individuals harboring variants involving MED12L identified by array CGH, exome or genome sequencing. Results All affected individuals presented with intellectual disability and/or developmental delay, including speech impairment. Other features included autism spectrum disorder, aggressive behavior, corpus callosum abnormality and mild facial morphological features. Three individuals had a MED12L deletion or duplication. The other four individuals harbored single nucleotide variants (one nonsense, one frameshift and two splicing variants). Functional analysis confirmed a moderate and significant alteration of RNA synthesis in two individuals. Conclusion Overall data suggest that MED12L haploinsufficiency is responsible for intellectual disability and transcriptional defect. Our findings confirm that the integrity of this kinase module is a critical factor for neurological development.
Published: 2019

35. Author Correction: A framework to identify contributing genes in patients with Phelan-McDermid syndrome

Author: Stephan Kemeny, Sandrine Passemard, Sandra Chantot-Bastaraud, Chloé Quélin, Laurence Perrin, Julien Buratti, Patrick Edery, Céline Dupont, Chantal Missirian, Philippe Vago, Alexandra Afenjar, Marie-Laure Vuillaume, Yline Capri, Klaus Dieterich, Laila El Khattabi, Charles Coutton, Françoise Devillard, Annick Toutain, Alain Verloes, Nicole Philip, Hubert Journel, Véronique Satre, Marie Ducloy, Delphine Héron, Richard Delorme, Cédric Le Caignec, Anne-Claude Tabet, Damien Sanlaville, Isabelle Marey, Laurence Faivre, Christèle Dubourg, Anne-Laure Mosca-Boidron, Laetitia Gouas, Abdelamdjid Benmansour, Jean Chiesa, Séverine Drunat, Cyril Mignot, Aurélia Jacquette, Boris Keren, Claire S. Leblond, Claire Beneteau, Brigitte Benzacken, Vincent Gatinois, Olivier Pichon, Damien Haye, Roberto Toro, Sandra Whalen, Dominique Martin, Thomas Rolland, Thomas Bourgeron, Albert David, Alexandre Mathieu, Mélanie Fradin, Frédérique Amsellem, Bertrand Isidor, James Lespinasse, Caroline Rooryck, Jacques Puechberty, Eva Pipiras, Lucile Pinson, Didier Lacombe, Jonathan M. Levy, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), 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), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service Histologie-embryologie-cytogénétique, Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Jean Verdier [AP-HP], CHU Trousseau [APHP], Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, 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, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Cytogénétique Constitutionnelle [Hospices civils de Lyon], Hospices Civils de Lyon (HCL), CHU de Lyon, Centre Hospitalier Universitaire [Grenoble] (CHU), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier de Chambéry (C.H.de Chambéry), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Génétique médicale [Centre Hospitalier de Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Centre Hospitalier Le Mans (CH Le Mans), AP-HP Hôpital universitaire Robert-Debré [Paris], Service Psychiatrie de l'Enfant et de l'Adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, UF de Cytogénétique, Institut Pasteur [Paris], Université de Bordeaux (UB), École normale supérieure - Rennes (ENS Rennes), Unité de Mathématique, Informatique et Génome (MIG), Institut National de la Recherche Agronomique (INRA), Laboratoire Interdisciplinaire Carnot de Bourgogne (LICB), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service de génétique clinique [Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, Service de Génétique, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de génétique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Service de génétique, cytogénétique, embryologie [Pitié-Salpétrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Jean Verdier [Bondy], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service de Génétique et d'Embryologie Médicale, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Gatonero SA, Hôtel-Dieu de Nantes, Physiopathologie et thérapie du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique Médicale, CHU Clermont-Ferrand-Hôpital d'Estaing, Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de génétique chromosomique [Hôpital de la Timone - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE), Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de référence des anomalies du développement [Lyon], UF de Biochimie et Génétique Moléculaire (BGM), CHU Grenoble, Dynamique Cellulaire et Tissulaire- Interdisciplinarité, Modèles & Microscopies (TIMC-IMAG-DyCTiM), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), IMAXIO, Maladies rares, génétique et métabolisme / Rare Diseases, Genetics and Metabolism, École de sage femme - Groupe hospitalier Pellegrin - CHU de Bordeaux-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Universitaire Carémeau [Nîmes], Département de Génétique Chromosomique, Bâtiment Hôtel Dieu - Centre Hospitalier de Chambéry, 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, CLAD Ouest, Centre Hospitalier Universitaire [Rennes], Centre Hospitalier Bretagne Atlantique [Vannes], Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de génétique, cytogénétique, embryologie [CHU Pitié-Salpétrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and Rolland, Thomas
Subjects: medicine.medical_specialty, lcsh:QH426-470, lcsh:Medicine, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Article, 03 medical and health sciences, 0302 clinical medicine, Phelan-McDermid syndrome, Genetics, medicine, 0501 psychology and cognitive sciences, In patient, Clinical genetics, Author Correction, Psychiatry, Molecular Biology, Genetics (clinical), business.industry, lcsh:R, Neurodevelopmental disorders, 05 social sciences, lcsh:Genetics, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Medical genetics, business, 030217 neurology & neurosurgery, 050104 developmental & child psychology
Abstract: Phelan-McDermid syndrome (PMS) is characterized by a variety of clinical symptoms with heterogeneous degrees of severity, including intellectual disability (ID), absent or delayed speech, and autism spectrum disorders (ASD). It results from a deletion of the distal part of chromosome 22q13 that in most cases includes the SHANK3 gene. SHANK3 is considered a major gene for PMS, but the factors that modulate the severity of the syndrome remain largely unknown. In this study, we investigated 85 patients with different 22q13 rearrangements (78 deletions and 7 duplications). We first explored the clinical features associated with PMS, and provide evidence for frequent corpus callosum abnormalities in 28% of 35 patients with brain imaging data. We then mapped several candidate genomic regions at the 22q13 region associated with high risk of clinical features, and suggest a second locus at 22q13 associated with absence of speech. Finally, in some cases, we identified additional clinically relevant copy-number variants (CNVs) at loci associated with ASD, such as 16p11.2 and 15q11q13, which could modulate the severity of the syndrome. We also report an inherited SHANK3 deletion transmitted to five affected daughters by a mother without ID nor ASD, suggesting that some individuals could compensate for such mutations. In summary, we shed light on the genotype-phenotype relationship of patients with PMS, a step towards the identification of compensatory mechanisms for a better prognosis and possibly treatments of patients with neurodevelopmental disorders., The underlying genetics of Phelan-McDermid syndrome Multiple chromosomal changes may impact the severity of symptoms in people with Phelan-McDermid syndrome (PMS). Thomas Bourgeron of the Institut Pasteur and colleagues in France conducted genomic analyses and explored the clinical features of 85 people with PMS, a condition caused by a deletion in the long arm of chromosome 22. It is often associated with severe symptoms such as intellectual disability, autism, and seizures. The chromosomal changes in 65% of those studied were not inherited. MRI brain scans showed visible abnormalities in 23 of 35 patients imaged. The size of the chromosomal deletion varied. Patients with small deletions were more likely to have autistic symptoms while those with large deletions were more likely to be unable to talk. The team also identified genes in chromosome 22 and in other regions of the genome that could modify the severity of PMS symptoms.
Published: 2019

36. The diagnostic workup in a patient with AMC: Overview of the clinical evaluation and paraclinical analyses with review of the literature

Author: Eva Kimber, Pierre-Simon Jouk, Klaus Dieterich, Judith G. Hall, Pauline Le Tanno, and Philip F Giampietro
Subjects: musculoskeletal diseases, 0301 basic medicine, Pediatrics, medicine.medical_specialty, 030105 genetics & heredity, 03 medical and health sciences, Intellectual Disability, Intellectual disability, Genetics, medicine, Humans, Joint Contracture, Exome, Genetics (clinical), Arthrogryposis, Muscle biopsy, Arthrogryposis multiplex congenita, medicine.diagnostic_test, business.industry, medicine.disease, 030104 developmental biology, Fetal movement, Congenital contracture, business, Clinical evaluation, Genome-Wide Association Study
Abstract: Arthrogryposis multiplex congenita, or AMC, is a clinical sign defined as congenital contractures of at least two joint levels. These joint contractures are always secondary to diminished fetal movement which can have numerous causes that affect any part of the anatomical structures implicated in movement: the central nervous system, the anterior horn cell, the nerve, the neuromuscular junction, the muscle, or the joint itself. Make a precise diagnosis of the cause in a patient with multiple joint contractures is therefore challenging. The aim of this article is to summarize the use and diagnostic value of common examinations and analyses performed postnatally in patients affected by AMC from a literature review. We also compare this data with results from our clinical practice. Even though it is difficult to give precise guidelines today, it appears that genetic studies, such as whole exome or genome analysis in all patients and chromosomal microarray analysis in patients with intellectual disability and AMC should be preferred as first tier investigations over EMG and muscle biopsy.
Published: 2019

37. Central nervous system involvement in arthrogryposis multiplex congenita: Overview of causes, diagnosis, and care

Author: Klaus Dieterich, Judith G. Hall, and Eva Kimber
Subjects: musculoskeletal diseases, 0301 basic medicine, medicine.medical_specialty, Genetic counseling, Central nervous system, 030105 genetics & heredity, Bioinformatics, 03 medical and health sciences, Intellectual Disability, Intellectual disability, Genetics, medicine, Humans, Exome, Genetics (clinical), Arthrogryposis, Arthrogryposis multiplex congenita, business.industry, Brain, Electroencephalography, medicine.disease, Magnetic Resonance Imaging, 030104 developmental biology, medicine.anatomical_structure, Blood chemistry, Spinal Cord, Medical genetics, medicine.symptom, business
Abstract: Arthrogryposis or AMC, arthrogryposis multiplex congenita, is defined as multiple congenital joint contractures in more than two joints and in different body areas. The common cause of all AMC is lack of movement in utero, which in turn can have different causes, one of which is CNS involvement. Intellectual disability/CNS involvement is found in approximately 25% of all AMC. AMC with CNS involvement includes a large number of genetic syndromes. So far, more than 400 genes have been identified as linked to AMC, with and without CNS involvement. A number of neonatally lethal syndromes and syndromes resulting in severe disability due to CNS malfunction belong to this group of syndromes. There are several X-linked disorders with AMC, which are primarily related to intellectual disability. A number of neuromuscular disorders may include AMC and CNS/brain involvement. Careful clinical evaluation by a geneticist and a pediatrician/pediatric neurologist is the first step in making a specific diagnosis. Further investigations may include MRI of the brain and spinal cord, electroencephalogram, blood chemistry for muscle enzymes, other organ investigations (ophtalmology, cardiology, gastrointestinal, and genitourinary systems). Nerve conduction studies, electromyogram, and muscle pathology may be of help when there is associated peripheral nervous system involvement. But most importantly, genetic investigations with targeted or rather whole exome or genome sequencing should be performed. A correct diagnosis is important in planning adequate treatment, in genetic counselling and also for future understanding of pathogenic mechanisms and possible new treatments. A multidiciplinary team is needed both in investigation and treatment.
Published: 2019

38. Classification of arthrogryposis

Author: Eva Kimber, Klaus Dieterich, and Judith G. Hall
Subjects: Arthrogryposis, medicine.medical_specialty, business.industry, Genetics, Medicine, Humans, medicine.symptom, business, Intensive care medicine, Genetics (clinical)
Abstract: There is a need for a system to classify various forms of arthrogryposis. None is satisfactory or complete. Nevertheless, several have been developed to meet the needs of clinicians, prenatal diagnosticians, researchers, and basic scientists. They all await more insight into basic mechanisms.
Published: 2019

39. Author response: Disability in adults with arthrogryposis is severe, partly invisible, and varies by genotype

Author: Pierre-Simon Jouk, Bernard Wuyam, Marie Jaeger, Dominic Pérennou, Klaus Dieterich, and Shenhao Dai
Subjects: Arthrogryposis, Adult, Genotype, education, MEDLINE, Subject (documents), Negative attitude, Medical writing, Standard language, 03 medical and health sciences, 0302 clinical medicine, Phenotype, International Classification of Functioning, Disability and Health, medicine, Humans, Disabled Persons, 030212 general & internal medicine, Neurology (clinical), medicine.symptom, Psychology, 030217 neurology & neurosurgery, Allegation, Clinical psychology
Abstract: In their comment on our article,1 Drs. Sawatzky and Hall discuss how to positively or negatively describe a handicap, in terms of either ability or disability, and how to inform patients. We refer to the International Classification of Functioning, Disability and Health,2 edited with the aim to provide a unified and standard language for describing health and health-related states. Medical writing is also subject to international recommendations to ensure clear, ethical, and unbiased reporting of scientific findings,3 and this is also true for rare diseases. We followed these recommendations and reject any allegation of a negative attitude in our article.1
Published: 2019

40. LRSAM1 variants and founder effect in French families with ataxic form of Charcot-Marie-Tooth type 2

Author: Klaus Dieterich, Sarah Leonard-Louis, Corinne Magdelaine, Martial Mallaret, Philippe Latour, Eric LeGuern, Alessia Peretti, Didier Vincent, Cyril Goizet, Guilhem Solé, Laurent Magy, Raul Juntas-Morales, Anne-Sophie Lia, Bruno Francou, Maud Perie, Adeline Not, Tanya Stojkovic, Françoise Bouhour, Sylvain Nollet, Fanny Duval, Centre de référence des maladies rares neuromusculaires, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), University of Verona (UNIVR), CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand, Service d'Electroneuromyographie et Service de Neurologie C [Hôpital Pierre Wertheimer - HCL], Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre Hospitalier Universitaire [Grenoble] (CHU), CHU Bordeaux [Bordeaux], Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Neurologie [CHU Limoges], CHU Limoges, Centre de référence national neuropathies périphériques rares [CHU Limoges], CHU de Bordeaux Pellegrin [Bordeaux], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service de Neuroradiologie [CHU de Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Maintenance Myélinique et Neuropathies Périphériques (MMNP), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), and Hospices Civils de Lyon (HCL)
Subjects: Biopsy, Ubiquitin-Protein Ligases, [SDV]Life Sciences [q-bio], Cell Cycle Proteins, Biology, Article, 03 medical and health sciences, Charcot-Marie-Tooth disease (CMT), LRSAM1-related neuropathies, neuropathic pain, novel variants, Sensory ataxia, Charcot-Marie-Tooth Disease, Gene duplication, Genetic variation, Genetics, medicine, Humans, Family, Amino Acid Sequence, Genetic Testing, Allele, Gene, Genetics (clinical), Alleles, Genetic testing, Adaptor Proteins, Signal Transducing, 0303 health sciences, medicine.diagnostic_test, 030305 genetics & heredity, Haplotype, Genetic Variation, Nuclear Proteins, Founder Effect, 3. Good health, Pedigree, Phenotype, France, medicine.symptom, Founder effect
Abstract: International audience; Currently only 25-30% of patients with axonal forms of Charcot-Marie-Tooth disease (CMT) receive a genetic diagnosis. We aimed to identify the causative gene of CMT type 2 in 8 non-related French families with a distinct clinical phenotype. We collected clinical, electrophysiological, and laboratory findings and performed genetic analyses in four different French laboratories. Seventy-two patients with autosomal dominant inheritance were identified. The disease usually started in the fourth decade and the clinical picture was dominated by sensory ataxia (80%), neuropathic pain (38%), and length-dependent sensory loss to all modalities. Electrophysiological studies showed a primarily axonal neuropathy, with possible isolated sensory involvement in milder phenotypes. Disease severity varied greatly but the clinical course was generally mild. We identified 2 novel variants in LRSAM1 gene: a deletion of 4 amino acids, p.(Gln698_Gln701del), was found in 7 families and a duplication of a neighboring region of 10 amino acids, p.(Pro702_Gln711dup), in the remaining family. A common haplotype of ~450 kb suggesting a founder effect was noted around LRSAM1 in 4 families carrying the first variant. LRSAM1 gene encodes for an E3 ubiquitin ligase important for neural functioning. Our results confirm the localization of variants in its catalytic C-terminal RING domain and broaden the phenotypic spectrum of LRSAM1-related neuropathies, including painful and predominantly sensory ataxic forms.
Published: 2019

41. Variants in MED12L, encoding a subunit of the mediator kinase module, are responsible for intellectual disability associated with transcriptional defect

Author: Kirsty McWalter, Susan M. Hiatt, Vincent Laugel, Megan A. Waldrop, Jean-Marc Egly, Ronit Marom, Cédric Le Caignec, Klaas J. Wierenga, Olivier Pichon, Jill A. Rosenfeld, Amanda Gerard, Michelle L. Thompson, Bertrand Isidor, Mathilde Nizon, Stéphane Bézieau, Marion Gérard, Megan T. Cho, Alexandrea Wadley, Klaus Dieterich, Kevin M. Flanigan, Matthew Pastore, Rui Xiao, gerard, marion, Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital de Hautepierre [Strasbourg], Baylor College of Medicine (BCM), Baylor University, Gatonero SA, INSERM U836, équipe 4, Muscles et pathologies, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique, Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), and Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, 0301 basic medicine, MED12L, Adolescent, Autism Spectrum Disorder, Developmental Disabilities, Protein subunit, macromolecular substances, 030105 genetics & heredity, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, corpus callosum, Young Adult, 03 medical and health sciences, Mediator, Intellectual disability, medicine, Humans, Encoding (semiotics), Exome, Child, Frameshift Mutation, Genetics (clinical), Sequence Deletion, Genetics, Kinase, transcriptional defect, medicine.disease, Human genetics, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, intellectual disability, Child, Preschool, Mutation, Female, Psychology, mediator complex, Transcription Factors
Abstract: Mediator is a multiprotein complex that allows the transfer of genetic information from DNA binding proteins to the RNA polymerase II during transcription initiation. MED12L is a subunit of the kinase module, which is one of the four subcomplexes of the mediator complex. Other subunits of the kinase module have been already implicated in intellectual disability, namely MED12, MED13L, MED13, and CDK19.We describe an international cohort of seven affected individuals harboring variants involving MED12L identified by array CGH, exome or genome sequencing.All affected individuals presented with intellectual disability and/or developmental delay, including speech impairment. Other features included autism spectrum disorder, aggressive behavior, corpus callosum abnormality, and mild facial morphological features. Three individuals had a MED12L deletion or duplication. The other four individuals harbored single-nucleotide variants (one nonsense, one frameshift, and two splicing variants). Functional analysis confirmed a moderate and significant alteration of RNA synthesis in two individuals.Overall data suggest that MED12L haploinsufficiency is responsible for intellectual disability and transcriptional defect. Our findings confirm that the integrity of this kinase module is a critical factor for neurological development.
Published: 2019

42. CHRNG-related nonlethal multiple pterygium syndrome: Muscle imaging pattern and clinical, histopathological, and molecular genetic findings

Author: Emili Inarejos, Robert Carlier, Susana Quijano-Roy, Chantal Durand, Cecilia Jimenez-Mallebrera, Klaus Dieterich, Jaume Colomer, Andrés Nascimento, Daniel Natera-de Benito, Monica Roldan, Laura Carrera-García, Adrien Felter, Cristina Jou, Marta G G de la Banda, Francesc Palau, Jessica Expósito-Escudero, Jordi Pijuan, Carlos Ortez, Anna Codina, Janet Hoenicka, Hanns Lochmüller, and Frédérique Nugues
Subjects: 0301 basic medicine, Male, Models, Molecular, Pathology, Protein Conformation, Biopsy, 030105 genetics & heredity, Receptors, Nicotinic, Escobar syndrome, multiple pterygium syndrome, Whole Body Imaging, CHRNG, Genetics (clinical), Arthrogryposis, arthrogryposis, medicine.diagnostic_test, Clinical course, Phenotype, Magnetic Resonance Imaging, medicine.anatomical_structure, Echocardiography, Child, Preschool, whole-body MRI, Female, Multiple pterygium syndrome, medicine.symptom, medicine.medical_specialty, Adolescent, Genotype, Neuromuscular junction, 03 medical and health sciences, Structure-Activity Relationship, Genetics, medicine, Humans, Abnormalities, Multiple, Genetic Predisposition to Disease, Genetic Testing, Muscle, Skeletal, Alleles, Genetic Association Studies, Muscle biopsy, business.industry, Magnetic resonance imaging, medicine.disease, Pterygium, 030104 developmental biology, Amino Acid Substitution, Mutation, Skin Abnormalities, business, Malignant Hyperthermia
Abstract: Mutations in the CHRNG gene cause autosomal recessive multiple pterygium syndrome (MPS). Herein we present a long-term follow-up of seven patients with CHRNG-related nonlethal MPS and we compare them with the 57 previously published patients. The objective is defining not only the clinical, histopathological, and molecular genetic characteristics, but also the type and degree of muscle involvement on whole-body magnetic resonance imaging (WBMRI). CHRNG mutations lead to a distinctive phenotype characterized by multiple congenital contractures, pterygium, and facial dysmorphism, with a stable clinical course over the years. Postnatal abnormalities at the neuromuscular junction were observed in the muscle biopsy of these patients. WBMRI showed distinctive features different from other arthrogryposis multiple congenita. A marked muscle bulk reduction is the predominant finding, mostly affecting the spinal erector muscles and gluteus maximus. Fatty infiltration was only observed in deep paravertebral muscles and distal lower limbs. Mutations in CHRNG are mainly located at the extracellular domain of the protein. Our study contributes to further define the phenotypic spectrum of CHRNG-related nonlethal MPS, including muscle imaging features, which may be useful in distinguishing it from other diffuse arthrogryposis entities.
Published: 2018

43. Amyoplasia and distal arthrogryposis

Author: Klaus Dieterich, Véronique Bourg, Jacques Griffet, and E. Bourgeois
Subjects: medicine.medical_specialty, Contracture, Context (language use), Walking, Upper Extremity, 03 medical and health sciences, 0302 clinical medicine, Physical medicine and rehabilitation, Humans, Medicine, Orthopedics and Sports Medicine, Joint Contracture, Arthrogryposis, 030222 orthopedics, Amyoplasia, Arthrogryposis multiplex congenita, business.industry, 030229 sport sciences, medicine.disease, Surgery, medicine.anatomical_structure, Lower Extremity, Orthopedic surgery, Upper limb, Congenital contracture, medicine.symptom, business
Abstract: Arthrogryposis multiplex congenita (AMC) consists of congenital joint contractures that affect at least two joints. There are two types: in the first, arthrogryposis is an additional sign in the context of various pathologies (neuromuscular diseases); in the second, it is the main and constant symptom. In the first type, the progression of the causal underlying disease must be considered. In the second type, there are two specific forms: Amyoplasia corresponds to a significant congenital absence of muscles (epigenetic disease or vascular origin) while distal arthrogryposis has a genetic component and is transmissible. The orthopedic surgeon's purpose, which is usually to enhance movement, is not appropriate for an arthrogryposis patient. One must keep in mind that without muscle, movement is impossible. The goal differs between the upper and lower limbs: for the upper limb, it is to allow grasping, and, if possible, to bring the hand to the mouth; for the lower limb, it is to ensure ambulation with plantigrade support, and the knees extended, which is the only stable position possible with little to no muscles. The rehabilitation, orthoses and/or surgical techniques are chosen to achieve this singular aim. While it may appear modest, it is crucial for patients. The goal is to achieve useful mobility, not maximum mobility. This multidisciplinary treatment, which evolves over time, must be explained to the family to get its adherence.
Published: 2021

44. Correction: DOORS syndrome and a recurrent truncating ATP6V1B2 variant

Author: Alexandre Dionne-Laporte, Marzena Wisniewska, Raoul C.M. Hennekam, Susan M. White, Ed Blair, Sirinart Molidperee, Dina Vind-Kezunovic, Lisbeth Tranebjærg, Guillermo Pacheco-Cuellar, Jessica Tardif, Klaus Dieterich, Eliane Beauregard-Lacroix, Maria Vittoria Camurri, Claudia Castiglioni, Pernille Mathiesen Tørring, Juliet M. Taylor, Tabib Dabir, Yolande van Bever, Norbert F. Ajeawung, Philippe M. Campeau, Sanjay M. Sisodiya, and Dénes Zádori
Subjects: Pediatrics, medicine.medical_specialty, business.industry, DOOR syndrome, Published Erratum, MEDLINE, Medicine, business, medicine.disease, Genetics (clinical), Human genetics
Published: 2021

45. Microdeletion del(22)(q12.1) excluding theMN1gene in a patient with craniofacial anomalies

Author: Françoise Devillard, Pierre-Simon Jouk, Gaëlle Vieville, Florence Amblard, Fanny Dubois-Teklali, Klaus Dieterich, Sophie Brouillet, Béatrice Morand, Joris Andrieux, Charles Coutton, Véronique Satre, Pierre F. Ray, C Bosson, Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Département de génétique et procréation, Université Joseph Fourier - Grenoble 1 (UJF)-Hôpital Couple-Enfant, AGeing and IMagery (AGIM), Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Joseph Fourier - Grenoble 1 (UJF)-Université Pierre Mendès France - Grenoble 2 (UPMF), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Paediatric Department, CHU Grenoble, Laboratoire de biochimie et génétique moléculaire, Laboratoire de Génétique Médicale, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Dynamique Cellulaire et Tissulaire- Interdisciplinarité, Modèles & Microscopies (TIMC-IMAG-DyCTiM), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), and Dynamiques Cellulaire et Tissulaire - Interdisciplinarité, Modélisation & Microscopie (TIMC-IMAG-DyCTiM2)
Subjects: Adult, Male, 0301 basic medicine, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Craniofacial abnormality, MESH: Chromosome Deletion, Chromosomes, Human, Pair 22, 030105 genetics & heredity, Biology, MESH: Phenotype, Craniofacial Abnormalities, 03 medical and health sciences, Genetics, medicine, MESH: Craniofacial Abnormalities, Humans, MESH: Tumor Suppressor Proteins, Global developmental delay, MESH: Chromosomes, Human, Pair 22, Craniofacial, Gene, Genetics (clinical), craniofacial anomalies, Comparative Genomic Hybridization, MESH: Humans, MESH: Middle Aged, MN1, deletion 22q12.1, Tumor Suppressor Proteins, MESH: Child, Preschool, Chromosome, MESH: Adult, Middle Aged, medicine.disease, Phenotype, MESH: Male, MESH: Comparative Genomic Hybridization, NF2, Child, Preschool, Trans-Activators, Female, Chromosome Deletion, Haploinsufficiency, MESH: Female, Comparative genomic hybridization
Abstract: International audience; Several studies have recently reported that 22q12.1 deletions encompassing the MN1 gene are associated with craniofacial anomalies. These observations are consistent with the hypothesis that MN1 haploinsufficiency may be solely responsible for craniofacial anomalies and/or cleft palate. We report here the case of a 4-year-old boy presenting with global developmental delay and craniofacial anomalies including severe maxillary protrusion and retromicrognathia. Array-CGH detected a 2.4 Mb de novo deletion of chromosome 22q12.1 which did not encompass the MN1 gene thought to be the main pathological candidate in 22q12.1 deletions. This observation, combined with data from other patients from the Database of Chromosomal Imbalance and Phenotype in Humans Using Ensemble Resources (DECIPHER), suggests that other gene(s) in the 22q12.1 region are likely involved in craniofacial anomalies and/or may contribute to the phenotypic variability observed in patients with MN1 deletion.
Published: 2015

46. Further delineation of the MECP2 duplication syndrome phenotype in 59 French male patients, with a particular focus on morphological and neurological features

Author: Sophie Scheidecker, Françoise Devillard, Gaetan Lesca, Maryline Carneiro, Christèle Dubourg, Ganaëlle Remerand, Catherine Badens, Odile Boespflug-Tanguy, Nathalie Marle, Serge Romana, Nadia Bahi-Buisson, Jean-Paul Bonnefont, Hubert Journel, Bénédicte Duban-Bedu, Brigitte Gilbert-Dussardier, Mathilde Nizon, Nathalie Perreton, Sophie Julia, Cyril Goizet, Delphine Héron, Véronique Satre, Marguerite Miguet, Joris Andrieux, Pierre-Simon Jouk, Laurence Perrin, Renaud Touraine, Ghislaine Plessis, Dominique Martin-Coignard, Caroline Rooryck, Catherine Vincent-Delorme, Laurence Faivre, Salima El Chehadeh, Thierry Bienvenu, Jean-Luc Alessandri, Anne-Claude Tabet, Laurent Pasquier, Martine Raynaud, Réseau AChro-Puce, Marjolaine Willems, Bruno Leheup, Marianne Till, Jeanne Amiel, Jacqueline Vigneron, Nicole Philip, Valérie Kremer, Massimiliano Rossi, Boris Keren, Annick Toutain, Fabienne Prieur, Bertrand Isidor, Séverine Drunat, Marilyn Lackmy-Port-Lis, Albert David, Christel Thauvin-Robinet, Damien Sanlaville, Laetitia Lambert, Lydie Burglen, Klaus Dieterich, Catherine Sarret, Anne Moncla, Didier Lacombe, Fanny Laffargue, Kim Maincent, Marlène Rio, Clarisse Baumann, Mathilde Lefebvre, Sabine Sigaudy, Laurent Guibaud, Adeline Vigouroux, Valérie Malan, Patrick Callier, Chantal Missirian, Christophe Philippe, Christine Francannet, Anne-Laure Mosca-Boidron, Valérie Cormier-Daire, Cédric Le Caignec, Vincent des Portes, Charles Coutton, Alexandra Afenjar, Sandrine Chantot-Bastaraud, Julien Thevenon, Mylène Béri-Dexheimer, Hilde Van Esch, Bernard Echenne, Jean-Marie Cuisset, Jean-Michel Pedespan, 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), FHU TRANSLAD (CHU de Dijon), Service de Génétique Médicale [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Génétique Clinique (CHU de Saint-Etienne), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Service de Génétique Clinique [CHU Rennes] (Réseau de Génétique et Génomique Médicale), Hôpitaux Universitaires du Grand Ouest, Laboratoire de Génétique Moléculaire & Génomique [CHU Rennes], CHU Pontchaillou [Rennes], Service de génétique médicale [Toulouse], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Image Guided Clinical Neurosciences and Connectomics (IGCNC), Université d'Auvergne - Clermont-Ferrand I (UdA), Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Service de neuropédiatrie et maladies métaboliques [CHU Robert-Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Génétique Médicale [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Laboratoire de Génétique Médicale (CHU de Nancy), Centre hospitalier universitaire de Nantes (CHU Nantes), Service de neuro-pédiatrie (CHRU de Lille), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire de Génétique Médicale, Hopital Jeanne de Flandre, 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), Service de génétique [Tours], Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service de Radiologie [Hôpital Femme Mère Enfant - HCL], Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service de génétique clinique [CHU Necker], Département de neurologie pédiatrique [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Génétique médicale [Centre Hospitalier de Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Service de génétique et embryologie médicales [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Biochimie et biologie moléculaire, Hôpital Cochin [AP-HP], Service de génétique clinique [Debré], Dynamique Cellulaire et Tissulaire- Interdisciplinarité, Modèles & Microscopies (TIMC-IMAG-DyCTiM), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Maladies rares, génétique et métabolisme / Rare Diseases, Genetics and Metabolism, Institut National de la Santé et de la Recherche Médicale (INSERM)-École de sage femme - Groupe hospitalier Pellegrin - CHU de Bordeaux, Service de Génétique Médicale du CHU de Bordeaux, Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de génétique chromosomique [Hôpital de la Timone - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE), Laboratoire de Biologie Moléculaire (MARSEILLE - Biolo Moléculaire), Assistance Publique - Hôpitaux de Marseille (APHM), CIC 1407, Hospices Civils de Lyon (HCL), Service de neurologie pédiatrique [CHU de Bordeaux], CHU de Bordeaux Pellegrin [Bordeaux], Clinique de Génétique médicale Guy Fontaine [CHRU LIlle], Centre de Génétique Chromosomique [Hôpital Saint Vincent de Paul], GHICL-Hôpital Saint Vincent de Paul, Service de Neuropédiatrie [CHU Necker - Enfants Malades], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Laboratoire de génétique médicale et cytogénétique [Le Mans], Centre Hospitalier Le Mans (CH Le Mans), Service de Génétique [HCL Groupement Hospitalier Est], Groupement hospitalier Lyon-Est, 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), Laboratoire de Génétique Moléculaire [CHU Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Laboratoire de Génétique Chromosomique et Moléculaire [CHU Dijon], Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), 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)-Université Bretagne Loire (UBL), Laboratoire de Cytogénétique Constitutionnelle [Hospices civils de Lyon], Service de Neurologie Pédiatrique [CHU Lyon], Service Génétique Médicale [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Centre for Human Genetics, University Hospitals Leuven [Leuven], Institut des Sciences cognitives Marc Jeannerod - Laboratoire sur le langage, le cerveau et la cognition (L2C2), École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Centre de référence des déficiences intellectuelles de causes rares (Hospices Civils de Lyon), Hospices civils de Lyon (HCL), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Laboratoire de génétique moléculaire et génomique médicale [CHU Rennes], 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), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Dynamiques Cellulaire et Tissulaire - Interdisciplinarité, Modélisation & Microscopie (TIMC-IMAG-DyCTiM2), Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Groupement Hospitalier Lyon-Est (GHE), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-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), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), 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, and Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS)
Subjects: 0301 basic medicine, Pediatrics, medicine.medical_specialty, MECP2 duplication syndrome, MECP2gene, Scoliosis, MECP2duplication syndrome, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Gene duplication, Genetics, medicine, Spasticity, Genetics (clinical), X-linked, Vasomotor, business.industry, facial dysmorphism, medicine.disease, Gait, Hypotonia, 3. Good health, 030104 developmental biology, Xq28 duplication, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, medicine.symptom, business, 030217 neurology & neurosurgery, genetic counselling
Abstract: The Xq28 duplication involving theMECP2gene (MECP2duplication) has been mainly described in male patients with severe developmental delay (DD) associated with spasticity, stereotypic movements and recurrent infections. Nevertheless, only a few series have been published. We aimed to better describe the phenotype of this condition, with a focus on morphological and neurological features. Through a national collaborative study, we report a large French series of 59 affected males with interstitialMECP2duplication. Most of the patients (93%) shared similar facial features, which evolved with age (midface hypoplasia, narrow and prominent nasal bridge, thick lower lip, large prominent ears), thick hair, livedo of the limbs, tapered fingers, small feet and vasomotor troubles. Early hypotonia and global DD were constant, with 21% of patients unable to walk. In patients able to stand, lower limbs weakness and spasticity led to a singular standing habitus: flexion of the knees, broad-based stance with pseudo-ataxic gait. Scoliosis was frequent (53%), such as divergent strabismus (76%) and hypermetropia (54%), stereotypic movements (89%), without obvious social withdrawal and decreased pain sensitivity (78%). Most of the patients did not develop expressive language, 35% saying few words. Epilepsy was frequent (59%), with a mean onset around 7.4 years of age, and often (62%) drug-resistant. Other medical issues were frequent: constipation (78%), and recurrent infections (89%), mainly lung. We delineate the clinical phenotype ofMECP2duplication syndrome in a large series of 59 males. Pulmonary hypertension appeared as a cause of early death in these patients, advocating its screening early in life.
Published: 2018

47. Parcours scolaire et prise en charge médico-éducative des enfants avec déficience intellectuelle légère

Author: J. Counillon, Pierre-Simon Jouk, C. Prado, Klaus Dieterich, M. David, A. Billette de Villemeur, A. Descotes, F. Devillard, J.-L. Guillon, Christine Cans, and J. Bloch
Subjects: medicine.medical_specialty, Rehabilitation, Intelligence quotient, medicine.medical_treatment, Professional development, Special education, medicine.disease, Family medicine, Pediatrics, Perinatology and Child Health, Severity of illness, Intellectual disability, medicine, Written language, Medical history, Psychology
Abstract: Studies on mild intellectual disability (MID) are scarce. The aim of this study was to describe the educational and medical care trajectories and their determinants in children with MID. The study population concerned children born in 1997 and resident in a French county (Isere) in 2008. MID was defined as an overall IQ score between 50 and 69. For the present study, this definition was adjusted by integrating the IQ confidence intervals so that the risk of IQ measurement relativity and possible score discrepancy could be taken into account. Of the 267 children included, 180 (67%) were identified through an institute that decides upon special education and allowances (MDPH) and 87 (33%) through the educational system. The parents of 181 children (68%) accepted to answer a telephone questionnaire, describing their child's educational and medical history. Children with MID frequently presented clinical signs and comorbidities. Educational trajectories were quite varied: a majority of the children (52.9%) were oriented toward sections with adapted general and professional education (SEGPA) after finishing primary school, a minority (41.3%) were oriented towards specialized schools, such as medical-educational institutions, and a small proportion of children (5.8%) stayed in ordinary school. Children followed the SEGPA orientation more frequently when a relative written language disorder was present, and autism-spectrum disorders or other clinical signs were absent. Concerning follow-up care and rehabilitation, children mostly took part in speech therapy (76.2%) and psychotherapy (55.8%). The French law dating from 2005, ensuring equal opportunity for people with disabilities, has borne fruit in the diversification of educational trajectories.
Published: 2015

48. Neuropathy target esterase impairments cause Oliver–McFarlane and Laurence–Moon syndromes

Author: Henry Houlden, Thomas Jaworek, Yvonne C Anderson, Rudy J. Richardson, Sarah Hull, Louise C. Gregory, Saima Riazuddin, Thomas M. Morgan, Joshua Hersheson, Craig Jefferies, Gavin Arno, Anthony T. Moore, Abi Li, Hélène Dollfus, Corinne Stoetzel, Christi M. Willen, Juan Pedro Martinez-Barbera, Robert A. Sisk, Megana K. Prasad, Mehul T. Dattani, Gregory A. Grabowski, Cynthia A. Prows, Rashmi S. Hegde, Tamas Revesz, John K. Fink, Zubair M. Ahmed, Robert B. Hufnagel, Klaus Dieterich, Vincent Plagnol, Laura Krueger, Taosheng Huang, and Nichole D. Hein
Subjects: Central Nervous System, Retinal degeneration, medicine.medical_specialty, Pathology, Pituitary disorder, Developmental Disabilities, Molecular Sequence Data, Hypertrichosis, Embryonic Development, Dwarfism, Neuropathy target esterase, Biology, Article, Retina, Bardet–Biedl syndrome, Intellectual Disability, Internal medicine, Genetics, medicine, Cerebellar Degeneration, Animals, Blepharoptosis, Humans, Genetic Predisposition to Disease, Amino Acid Sequence, Trichomegaly, Alleles, Zebrafish, Genetics (clinical), Laurence-Moon Syndrome, Gene Expression Regulation, Developmental, medicine.disease, Protein Structure, Tertiary, Phenotype, Endocrinology, Phospholipases, Mutation, Spinocerebellar ataxia, biology.protein, Laurence–Moon syndrome, medicine.symptom, Carboxylic Ester Hydrolases, Retinitis Pigmentosa
Abstract: Background Oliver–McFarlane syndrome is characterised by trichomegaly, congenital hypopituitarism and retinal degeneration with choroidal atrophy. Laurence–Moon syndrome presents similarly, though with progressive spinocerebellar ataxia and spastic paraplegia and without trichomegaly. Both recessively inherited disorders have no known genetic cause. Methods Whole-exome sequencing was performed to identify the genetic causes of these disorders. Mutations were functionally validated in zebrafish pnpla6 morphants. Embryonic expression was evaluated via in situ hybridisation in human embryonic sections. Human neurohistopathology was performed to characterise cerebellar degeneration. Enzymatic activities were measured in patient-derived fibroblast cell lines. Results Eight mutations in six families with Oliver–McFarlane or Laurence–Moon syndrome were identified in the PNPLA6 gene, which encodes neuropathy target esterase (NTE). PNPLA6 expression was found in the developing human eye, pituitary and brain. In zebrafish, the pnpla6 curly-tailed morphant phenotype was fully rescued by wild-type human PNPLA6 mRNA and not by mutation-harbouring mRNAs. NTE enzymatic activity was significantly reduced in fibroblast cells derived from individuals with Oliver–McFarlane syndrome. Intriguingly, adult brain histology from a patient with highly overlapping features of Oliver–McFarlane and Laurence–Moon syndromes revealed extensive cerebellar degeneration and atrophy. Conclusions Previously, PNPLA6 mutations have been associated with spastic paraplegia type 39, Gordon–Holmes syndrome and Boucher–Neuhauser syndromes. Discovery of these additional PNPLA6 -opathies further elucidates a spectrum of neurodevelopmental and neurodegenerative disorders associated with NTE impairment and suggests a unifying mechanism with diagnostic and prognostic importance.
Published: 2014

49. Further delineation of the

Author: Marguerite, Miguet, Laurence, Faivre, Jeanne, Amiel, Mathilde, Nizon, Renaud, Touraine, Fabienne, Prieur, Laurent, Pasquier, Mathilde, Lefebvre, Julien, Thevenon, Christèle, Dubourg, Sophie, Julia, Catherine, Sarret, Ganaëlle, Remerand, Christine, Francannet, Fanny, Laffargue, Odile, Boespflug-Tanguy, Albert, David, Bertrand, Isidor, Jacqueline, Vigneron, Bruno, Leheup, Laetitia, Lambert, Christophe, Philippe, Mylène, Béri-Dexheimer, Jean-Marie, Cuisset, Joris, Andrieux, Ghislaine, Plessis, Annick, Toutain, Laurent, Guibaud, Valérie, Cormier-Daire, Marlene, Rio, Jean-Paul, Bonnefont, Bernard, Echenne, Hubert, Journel, Lydie, Burglen, Sandrine, Chantot-Bastaraud, Thierry, Bienvenu, Clarisse, Baumann, Laurence, Perrin, Séverine, Drunat, Pierre-Simon, Jouk, Klaus, Dieterich, Françoise, Devillard, Didier, Lacombe, Nicole, Philip, Sabine, Sigaudy, Anne, Moncla, Chantal, Missirian, Catherine, Badens, Nathalie, Perreton, Christel, Thauvin-Robinet, Réseau, AChro-Puce, Jean-Michel, Pedespan, Caroline, Rooryck, Cyril, Goizet, Catherine, Vincent-Delorme, Bénédicte, Duban-Bedu, Nadia, Bahi-Buisson, Alexandra, Afenjar, Kim, Maincent, Delphine, Héron, Jean-Luc, Alessandri, Dominique, Martin-Coignard, Gaëtan, Lesca, Massimiliano, Rossi, Martine, Raynaud, Patrick, Callier, Anne-Laure, Mosca-Boidron, Nathalie, Marle, Charles, Coutton, Véronique, Satre, Cédric Le, Caignec, Valérie, Malan, Serge, Romana, Boris, Keren, Anne-Claude, Tabet, Valérie, Kremer, Sophie, Scheidecker, Adeline, Vigouroux, Marilyn, Lackmy-Port-Lis, Damien, Sanlaville, Marianne, Till, Maryline, Carneiro, Brigitte, Gilbert-Dussardier, Marjolaine, Willems, Hilde, Van Esch, Vincent Des, Portes, and Salima, El Chehadeh
Subjects: Adult, Male, Chromosomes, Human, X, Epilepsy, Adolescent, Methyl-CpG-Binding Protein 2, Developmental Disabilities, Hypertension, Pulmonary, Infant, Stereotypic Movement Disorder, Pedigree, Young Adult, Hyperopia, Phenotype, Child, Preschool, Intellectual Disability, Mental Retardation, X-Linked, Somatosensory Disorders, Exotropia, Humans, France, Child
Abstract: The Xq28 duplication involving the
Published: 2017

50. Biallelic mutation of UNC50, encoding a protein involved in AChR trafficking, is responsible for arthrogryposis

Author: Paulette Mezin, Jean-Louis Bessereau, Pierre-Simon Jouk, Judith Melki, Ivo Gut, Loic Quevarec, Manuela D'Alessandro, Aurore-Cecile Valfort, Sandrina Turczynski, Klaus Dieterich, Emanuela Abiusi, and Marta Gut
Subjects: 0301 basic medicine, Biallelic Mutation, Male, Mutant, Neuromuscular Junction, Locus (genetics), Biology, arthrogryposis, UNC50, Settore MED/03 - GENETICA MEDICA, Frameshift mutation, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, Animals, Humans, Receptors, Cholinergic, Amino Acid Sequence, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Frameshift Mutation, Molecular Biology, Genetics (clinical), Alleles, Acetylcholine receptor, Arthrogryposis, Arthrogryposis multiplex congenita, Membrane Proteins, RNA-Binding Proteins, General Medicine, Stillbirth, Disease gene identification, Molecular biology, Pedigree, Disease Models, Animal, Protein Transport, 030104 developmental biology, Female, medicine.symptom, UNC50, 030217 neurology & neurosurgery
Abstract: Arthrogryposis multiplex congenita (AMC) is a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements. Homozygosity mapping of disease loci combined with whole exome sequencing in a consanguineous family presenting with lethal AMC allowed the identification of a homozygous frameshift deletion in UNC50 gene (c.750_751del:p.Cys251Phefs*4) in the index case. To assess the effect of the mutation, an equivalent mutation in the Caenorhabditis elegans orthologous gene was created using CRISPR/Cas9. We demonstrated that unc-50(kr331) modification caused the loss of acetylcholine receptor (AChR) expression in C. elegans muscle. unc-50(kr331) animals were as resistant to the cholinergic agonist levamisole as unc-50 null mutants suggesting that AChRs were no longer expressed in this animal model. This was confirmed by using a knock-in strain in which a red fluorescent protein was inserted into the AChR locus: no signal was detected in unc-50(kr331) background, suggesting that UNC-50, a protein known to be involved in AChR trafficking, was no longer functional. These data indicate that biallelic mutation in the UNC50 gene underlies AMC through a probable loss of AChR expression at the neuromuscular junction which is essential for the cholinergic transmission during human muscle development.
Published: 2017

Catalog

Books, media, physical & digital resources

See catalog results

Searchworks

Select search scope, currently: Articles Catalog books, media & more in Jio Institute collections Articles journal articles & other e-resources

Search

Search Constraints

Refine your results

Search Limiters

Topic

Publication Year Range

Language

Publication Type

Journal

Database

Publisher

76 results on '"Klaus Dieterich"'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources