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1. 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: Genetics, Molecular Medicine, Genetics (clinical)
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
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2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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
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9. 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
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10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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

28. 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

29. 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

30. 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

31. 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

32. 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

33. 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

34. 'Lowe syndrome: A particularly severe phenotype without clinical kidney involvement'

Author: Klaus Dieterich, Ahmed A. ElBeheiry, Julien Fauré, Julien Thevenon, John Rendu, and Ebtesam M. Abdalla
Subjects: 0301 basic medicine, Adult, Male, Oculocerebrorenal syndrome, Central nervous system, 030232 urology & nephrology, Bioinformatics, Kidney, Cataract, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Catalytic Domain, Genetics, medicine, Humans, Abnormalities, Multiple, Genetics (clinical), business.industry, Glaucoma, medicine.disease, Phenotype, Pathophysiology, Phosphoric Monoester Hydrolases, 030104 developmental biology, medicine.anatomical_structure, Oculocerebrorenal Syndrome, Mutation, OCRL, Egypt, Psychomotor Disorders, Psychomotor disorder, business, Kidney disease
Abstract: Lowe syndrome (LS) is a very rare disorder of phosphatidylinositol metabolism, which manifests with a complex phenotype comprising a clinical triad encompassing major abnormalities of the eyes, the kidneys, and the central nervous system. We are reporting a 23-year-old Egyptian male with a severe phenotype of LS with a minimal kidney disease. Direct sequencing of the OCRL gene detected a p.His375Arg mutation in the catalytic domain of the protein. The patient suffered from bilateral congenital cataracts and glaucoma, striking growth deficiency, severe psychomotor disability, a severe osteopathy, and seizures, but only minimal renal dysfunction. Although the biological mechanisms underlying the pathophysiology of LS manifestations is yet unclear, it has been proposed that growth delay and osteopathy are linked to a renal dysfunction. This report, however, argues this association and suggests that kidney dysfunction may partially explain the growth deficiency and bone abnormalities, but other still undefined factors might have a potential impact.
Published: 2017

35. Mutations in Histone Acetylase Modifier BRPF1 Cause an Autosomal-Dominant Form of Intellectual Disability with Associated Ptosis

Author: Marjon van Slegtenhorst, Jean-Louis Mandel, Paul R. Mark, Jane Juusola, Gretchen Von Allmen, Elise Schaefer, Aurora Pujol, Grazia M.S. Mancini, Francesca Mattioli, Gaëlle Vieville, Marielle Alders, Mark Engelen, Charles Coutton, Klaus Dieterich, Alex Magee, Jan Maarten Cobben, Amélie Piton, 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), Les Hôpitaux Universitaires de Strasbourg (HUS), Institut de génétique médicale d’Alsace, Belfast City Hospital, Spectrum Health [Grand Rapids], Erasmus University Medical Center [Rotterdam] (Erasmus MC), CHU Grenoble Alpes - Site NORD [La Tronche], hôpital couple-enfant [CHU Grenoble Alpes], McGovern Medical School [Houston, Texas], The University of Texas Health Science Center at Houston (UTHealth), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Centre Hospitalier Universitaire [Grenoble] (CHU), Institut Albert Bonniot, GeneDx [Gaithersburg, MD, USA], Catalan Institution for Research & Advanced Studies [Barcelona, Catalonia, Spain] (ICREA), ARD - Amsterdam Reproduction and Development, Human Genetics, ANS - Cellular & Molecular Mechanisms, Paediatric Genetics, ACS - Pulmonary hypertension & thrombosis, and Clinical Genetics
Subjects: 0301 basic medicine, Adult, Male, Haploinsufficiency, Biology, Blepharophimosis, medicine.disease_cause, Frameshift mutation, 03 medical and health sciences, Report, Intellectual Disability, Genetics, medicine, Blepharoptosis, Humans, Child, Frameshift Mutation, Genetics (clinical), Exome sequencing, Adaptor Proteins, Signal Transducing, Genes, Dominant, Histone Acetyltransferases, Mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, Genetic heterogeneity, Point mutation, Nuclear Proteins, Acetylation, Methyltransferases, Syndrome, medicine.disease, Molecular biology, Hypotonia, DNA-Binding Proteins, 030104 developmental biology, Phenotype, Child, Preschool, Muscle Hypotonia, Female, Chromosomes, Human, Pair 3, medicine.symptom, Chromosome Deletion
Abstract: Intellectual disability (ID) is a common neurodevelopmental disorder exhibiting extreme genetic heterogeneity, and more than 500 genes have been implicated in Mendelian forms of ID. We performed exome sequencing in a large family affected by an autosomal-dominant form of mild syndromic ID with ptosis, growth retardation, and hypotonia, and we identified an inherited 2 bp deletion causing a frameshift in BRPF1 (c.1052_1053del) in five affected family members. BRPF1 encodes a protein modifier of two histone acetyltransferases associated with ID: KAT6A (also known as MOZ or MYST3) and KAT6B (MORF or MYST4). The mRNA transcript was not significantly reduced in affected fibroblasts and most likely produces a truncated protein (p.Val351Glyfs(∗)8). The protein variant shows an aberrant cellular location, loss of certain protein interactions, and decreased histone H3K23 acetylation. We identified BRPF1 deletions or point mutations in six additional individuals with a similar phenotype. Deletions of the 3p25 region, containing BRPF1 and SETD5, cause a defined ID syndrome where most of the clinical features are attributed to SETD5 deficiency. We compared the clinical symptoms of individuals carrying mutations or small deletions of BRPF1 alone or SETD5 alone with those of individuals with deletions encompassing both BRPF1 and SETD5. We conclude that both genes contribute to the phenotypic severity of 3p25 deletion syndrome but that some specific features, such as ptosis and blepharophimosis, are mostly driven by BRPF1 haploinsufficiency
Published: 2017

36. Delineation of the 3p14.1p13 microdeletion associated with syndromic distal limb contractures

Author: Michel Francoise, Patrick Callier, Steven A. Vokes, Susanne Kjaergaard, Laurence Duplomb, Thomas Lee Dahm, Julien Thevenon, Nicole Monnier, Marie Hélène Aubriot-Lorton, Frédéric Huet, Tara Montgomery, Haley O. Tucker, Clémence Ragon, Nathalie Marle, Katherine Neas, Francine Mugneret, Pierre-Simon Jouk, Joël Lunardi, Klaus Dieterich, Laurence Faivre, Christel Thauvin-Robinet, Anne Laure Mosca-Boidron, Joanne Dixon, 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 ), Génétique des Anomalies du Développement ( GAD ), Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC, Laboratoire de biochimie et génétique moléculaire, CHU Grenoble, Laboratoire de cytogénétique (CHU de Dijon), Centre de génétique et Centre de référence maladies rares et anomalies du développement et syndromes malformatifs du Centre Est, Département de Génétique et Procréation UF-Hôpital Couple Enfant de Grenoble-CHU Grenoble, Service de pédiatrie, Centre Hospitalier Wiliam Morey, Northern Genetics Service, Newcastle University [Newcastle], Department of Clinical Genetic, Rigshospitalet [Copenhagen], Central and Southern Regional Genetic Services, Wellington Hospital Private, Department of Pediatrics, Nordsjællands Hospital - Hillerød, Service de pédiatrie (CHU de Dijon), Service de Pathologie [CHU de Dijon], Section of Molecular Cell & Developmental Biology, Institute for Cellular and Molecular Biology-University of Texas at Austin [Austin], Graduate Program in Cell and Molecular Biology, University of Texas at Austin [Austin], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Centre Hospitalier Chalon-sur-Saône William Morey, Department of Clinical Genetics [Copenhagen], Copenhagen University Hospital-Copenhagen University Hospital, University of Texas at Austin [Austin]- Institute for Cellular and Molecular Biology, and Roux-Buisson, Nathalie
Subjects: Male, Pathology, medicine.medical_specialty, Contracture, [SDV]Life Sciences [q-bio], Locus (genetics), FOXP1, Biology, Mice, distal limb contractures, symbols.namesake, Exon, EIF4E3, Intellectual disability, Genetics, medicine, Animals, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 3p141p13 microdeletion, Genetics (clinical), Arthrogryposis, Chromosome Aberrations, Mice, Knockout, Sanger sequencing, Comparative Genomic Hybridization, [ SDV ] Life Sciences [q-bio], Extremities, Forkhead Transcription Factors, Syndrome, Microdeletion syndrome, medicine.disease, Blepharophimosis, Phenotype, Repressor Proteins, [SDV] Life Sciences [q-bio], array-CGH, [ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], symbols, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Chromosomes, Human, Pair 3, France, Carrier Proteins, intronic regulatory sequence
Abstract: International audience; Distal limb contractures (DLC) represent a heterogeneous clinical and genetic condition. Overall, 20–25% of the DLC are caused by mutations in genes encoding the muscle contractile apparatus. Large interstitial deletions of the 3p have already been diagnosed by standard chromosomal analysis, but not associated with a specific phenotype. We report on four patients with syndromic DLC presenting with a de novo 3p14.1p13 micro-deletion. The clinical features associated multiple contractures, feeding problems, developmental delay, and intellectual disability. Facial dysmorphism was constant with low-set posteriorly rotated ears and blepharophimosis. Review of previously reported cases with a precise mapping of the deletions, documented a 250 kb smallest region of overlap (SRO) necessary for DLC. This region contained one gene, EIF4E3, the first three exons of the FOXP1 gene, and an intronic enhancer of FOXP1 named hs1149. Sanger sequencing and locus quantification of hs1149, EIF4E3, and FOXP1 in a cohort of 11 French patients affected by DLC appeared normal. In conclusion, we delineate a new microdeletion syndrome involving the 3p14.1p13 locus and associated with DLC and severe developmental delay.
Published: 2014

37. 13q31.1 microdeletion: A prenatal case report with macrocephaly and macroglossia

Author: Pierre-Simon Jouk, Virginie Guigue, Brice Poreau, Klaus Dieterich, Candice Ronin, Stéphanie Lin, Sophie Brouillet, Charles Coutton, Véronique Satre, Christophe Barbier, C Bosson, and Françoise Devillard
Subjects: MAPK/ERK pathway, Adult, Candidate gene, Prenatal diagnosis, RASopathy, Biology, Bioinformatics, Germline mutation, Fetus, Costello syndrome, Macroglossia, Pregnancy, Genetics, medicine, Humans, Genetics (clinical), Chromosomes, Human, Pair 13, Macrocephaly, Intracellular Signaling Peptides and Proteins, Membrane Proteins, General Medicine, Syndrome, medicine.disease, Megalencephaly, Female, medicine.symptom, Gene Deletion
Abstract: We report on a female fetus with macrocephaly and macroglossia harbouring 13q31.1 microdeletion encompassing three genes: SPRY2, NDFIP2 and RBM26. NDFIP2 protein is involved in ubiquitination and in Ras/mitogen-activated protein kinase (MAPK) signaling pathways. SPRY2 protein is part of Sprout protein family and inhibits the Ras/MAPK pathways. Ras/MAPK pathway plays important role in complex cellular programs including cell differentiation and proliferation. Germline mutations in genes encoding protein involved in the MAPK cascade is responsible for a wide family of developmental disorders known as RASopathies. Some RASopathies, such as Costello syndrome, present a phenotype with (relative) macrocephaly as perinatal features. However, prenatal-onset macroglossia are generally absent in this syndrome but rather suggestive of the Beckwith-Wiedemann syndrome for which molecular testing were negative. Phenotype-genotype correlation with patients from DECIPHER defines NDFIP2 and SPRY2 as a possible candidate genes for a RASopathy potentially responsible for the clinical features in the fetus. Finally, this original case of 13q31.1 microdeletion underlines the importance of array-CGH in prenatal diagnosis with sonographic signs such as macroglossia and/or macrocephaly. In this case, genetic investigation should be not limited to the search of well-known genetic causes and other genomic microdeletions should be considered as alternative diagnoses for macroglossia.
Published: 2015

38. The neuronal endopeptidase ECEL1 is associated with a distinct form of recessive distal arthrogryposis

Author: André Mégarbané, Cécile Laroche, Isabelle Marty, Klaus Dieterich, Nicole Monnier, Damien Sternberg, Pierre-Simon Jouk, Jie Zhou, Susana Quijano-Roy, Daniela Avila Smirnow, Pascale Marcorelles, Robert Carlier, Sylvie Odent, Brigitte Estournet, Julien Fauré, Norma B. Romero, Sandra Mercier, Judith Melki, Joël Lunardi, INSERM U836, équipe 4, Muscles et pathologies, Stéroides et système nerveux : physiopathologie moléculaire et clinique, Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Département de Génétique et Procréation, CHU Grenoble-CHU Grenoble-Centre de Référence des Anomalies et du Développement, CHU Grenoble-Hôpital Couple Enfant-Hôpital Couple Enfant, Service de Pédiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Raymond Poincaré [AP-HP]-Centre de Référence Maladies Neuromusculaires (GNMH), Centre d’Investigation Clinique 1429 [Garches] (CIC 1429), Hôpital Raymond Poincaré [AP-HP]-Institut National de la Santé et de la Recherche Médicale (INSERM), 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)-Laboratoire de Biochimie Génétique et Moléculaire, CHU Grenoble-Institut de Biologie et de Pathologie (IBP)-CHU Grenoble-Institut de Biologie et de Pathologie (IBP), Centre de Référence des Anomalies et du Développement, CHU Grenoble-Hôpital Couple Enfant, Service d'Imagerie Médicale [Raymond-Poincaré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Raymond Poincaré [AP-HP], Service de Pédiatrie médicale [CHU Limoges], CHU Limoges, CHRU Brest - Laboratoire d'Anatomo-Pathologie (CHU - AnaPath), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Unité de génétique médicale, Université Saint-Joseph de Beyrouth (USJ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service d'Anatomopathologie, 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) (AP-HP)-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) (AP-HP)-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), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Génétique et Procréation, CHU Grenoble, Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), Association Française contre les Pyopathies, PHRC (AOM 10181), Inserm, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-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)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Roux-Buisson, Nathalie
Subjects: Central Nervous System, Pathology, Genetic Linkage, [SDV.GEN] Life Sciences [q-bio]/Genetics, medicine.disease_cause, Compound heterozygosity, Endothelins, Consanguinity, Mice, 0302 clinical medicine, MESH: Embryonic Development, MESH: Animals, 10. No inequality, Genetics (clinical), Arthrogryposis, Motor Neurons, 0303 health sciences, Mutation, Homozygote, Chromosome Mapping, Metalloendopeptidases, General Medicine, Anatomy, Muscle atrophy, 3. Good health, Pedigree, Phenotype, medicine.symptom, MESH: Motor Neurons, MESH: Homozygote, medicine.hormone, medicine.medical_specialty, MESH: Mutation, MESH: Pedigree, MESH: Arthrogryposis, MESH: Genetic Linkage, MESH: Metalloendopeptidases, Embryonic Development, Genes, Recessive, Biology, MESH: Phenotype, 03 medical and health sciences, Genetics, medicine, MESH: Central Nervous System, Animals, Humans, Molecular Biology, MESH: Mice, MESH: Genes, Recessive, 030304 developmental biology, Muscle contracture, MESH: Consanguinity, [SDV.GEN]Life Sciences [q-bio]/Genetics, Arthrogryposis multiplex congenita, MESH: Humans, Heterozygote advantage, MESH: Chromosome Mapping, 030217 neurology & neurosurgery
Abstract: International audience; Distal arthrogryposis (DA) is a heterogeneous subgroup of arthrogryposis multiplex congenita (AMC), a large family of disorders characterized by multiple congenital joint limitations due to reduced fetal movements. DA is mainly characterized by contractures afflicting especially the distal extremities without overt muscular or neurological signs. Although a limited number of genes mostly implicated in the contractile apparatus have been identified in DA, most patients failed to show mutations in currently known genes. Using a pangenomic approach, we demonstrated linkage of DA to chromosome 2q37 in two consanguineous families and the endothelin-converting enzyme like 1 (ECEL1) gene present in this region was associated with DA. Screening of a panel of 20 families with non-specific DA identified seven homozygous or compound heterozygous mutations of ECEL1 in a total of six families. Mutations resulted mostly in the absence of protein. ECEL1 is a neuronal endopeptidase predominantly expressed in the central nervous system and brain structures during fetal life in mice and human. ECEL1 plays a major role in intramuscular axonal branching of motor neurons in skeletal muscle during embryogenesis. A detailed review of clinical findings of DA patients with ECEL1 mutations revealed a homogeneous and recognizable phenotype characterized by limited knee flexion, flexed third to fifth fingers and severe muscle atrophy predominant on lower limbs and tongue that suggested a common pathogenic mechanism. We described a new and homogenous phenotype of DA associated with ECEL1 that resulted in symptoms involving rather the peripheral than the central nervous system and suggesting a developmental dysfunction.
Published: 2012

39. The Aurora Kinase C c.144delC mutation causes meiosis I arrest in men and is frequent in the North African population

Author: Mohamed Zahi, Marie-Christine Jacob, Sellama Nadifi, François Vialard, Yorgos Nikas, Raoudha Zouari, Abdelaziz Sefiani, Pierre-Simon Jouk, Hanane Bellayou, Nadia Prisant, Abdelali Zoghmar, Marie Roberte Guichaoua, Delphine Martinez, Klaus Dieterich, Joël Lunardi, Mehrdad Noruzinia, Mahmoud Kharouf, Sylviane Hennebicq, Stéphane Viville, Denise Escalier, Radu Harbuz, Isabelle Koscinski, Jacqueline Lornage, Pierre F. Ray, B. Sèle, Département de génétique et procréation, Université Joseph Fourier - Grenoble 1 (UJF)-Hôpital Couple-Enfant, Clinique de Promotion des Sciences de la Reproduction [Tunis] (CPSR), Polyclinique les Jasmins [Tunis], Laboratoire de Cytogénétique, CHI Poissy-Saint-Germain, Laboratoire de Génétique et Pathologie Moléculaire, Faculté de Médecine et Pharmacie Casablanca, Assistance médicale à la procréation, Biologie de reproduction - Stérilité [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), Centre de Médecine de la Reproduction, Laboratoire de biologie de la reproduction, Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Service de Biologie de la Reproduction, CHU Strasbourg, Department of Hematology, Tarbiat Modares University [Tehran], Département de génétique médicale, Institut National d'Hygiène, Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre privé de Fécondation in vitro, RFMQ, 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 )-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 Joseph Fourier - Grenoble 1 (UJF)-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)-Département de génétique et procréation, Université Joseph Fourier - Grenoble 1 (UJF)-Hôpital Couple-Enfant-Hôpital Couple-Enfant, Laboratoire d'Immunocytologie, EFS, Bases moléculaires et cellulaires des maladies génétiques, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Athens Innovative Microscopy, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), ARCHAMPS, Clinique de la reproduction les Jasmins, CHU Pitié-Salpêtrière [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)-Université Pierre et Marie Curie - Paris 6 (UPMC), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Département de génétique et procréation, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Roux-Buisson, Nathalie
Subjects: Male, MESH: Tissue Donors, DNA Mutational Analysis, MESH: Africa, Northern, MESH: Flow Cytometry, Nucleic Acid Denaturation, medicine.disease_cause, Oogenesis, 0302 clinical medicine, Africa, Northern, Aurora Kinases, Aurora Kinase C, MESH: DNA Mutational Analysis, Chromatography, High Pressure Liquid, Genetics (clinical), Genetics, 0303 health sciences, education.field_of_study, Mutation, 030219 obstetrics & reproductive medicine, MESH: Spermatozoa, Exons, General Medicine, Flow Cytometry, Spermatozoa, Tissue Donors, Meiosis, Meiotic cytokinesis, Female, MESH: Spermatogenesis, Infertility, MESH: Mutation, Population, Black People, MESH: Nucleic Acid Denaturation, Protein Serine-Threonine Kinases, Biology, Models, Biological, MESH: Protein-Serine-Threonine Kinases, 03 medical and health sciences, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Spermatogenesis, education, MESH: Chromatography, High Pressure Liquid, Molecular Biology, 030304 developmental biology, MESH: Humans, MESH: Models, Biological, MESH: Fertility, medicine.disease, MESH: Male, MESH: Meiosis, Fertility, MESH: African Continental Ancestry Group, MESH: Exons, MESH: Female
Abstract: International audience; Infertility concerns a minimum of 70 million couples worldwide. An important proportion of cases is believed to have a genetic component, yet few causal genes have been identified so far. In a previous study, we demonstrated that a homozygous mutation (c.144delC) in the Aurora Kinase C (AURKC) gene led to the production of large-headed polyploid multi-flagellar spermatozoa, a primary infertility phenotype mainly observed in North Africans. We now want to estimate the prevalence of the defect, to improve our understanding of AURKC physiopathology in spermatogenesis and assess its implication in oogenesis. A carrier frequency of 1/50 was established from individuals from the Maghrebian general population, comparable to that of Y-microdeletions, thus far the only known recurrent genetic event altering spermatogenesis. A total of 62 patients were genotyped, all who had a typical phenotype with close to 100% large-headed spermatozoa were homozygously mutated (n = 32), whereas no AURKC mutations were detected in the others. Two homozygous females were identified; both were fertile indicating that AURKC is not indispensible in oogenesis. Previous FISH results had showed a great chromosomal heterogeneity in these patient's spermatozoa. We demonstrate here by flow cytometry that all spermatozoa have in fact a homogeneous 4C DNA content and are thus all blocked before the first meiotic division. Our data thus indicate that a functional AURKC protein is necessary for male meiotic cytokinesis while its absence does not impair oogenesis.
Published: 2009

40. Absence of beta-tropomyosin is a new cause of Escobar syndrome associated with nemaline myopathy

Author: Joël Lunardi, Nicole Monnier, Paulette Mezin, Pierre-Simon Jouk, Isabelle Marty, Annick Labarre-Vila, Klaus Dieterich, 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), Département d'anatomie et cythologie pathologique, CHU Grenoble-Hôpital Michallon, Centre de Reference des Maladies Neuromusculaires, Département de Génétique et Procréation, and Roux-Buisson, Nathalie
Subjects: Male, DNA Mutational Analysis, Inheritance Patterns, MESH: Tropomyosin, Tropomyosin, MESH: Genetic Markers, medicine.disease_cause, Myopathies, Nemaline, TPM2, MESH: Genotype, 0302 clinical medicine, Nemaline myopathy, MESH: Genetic Screening, MESH: Syndrome, MESH: DNA Mutational Analysis, Genetics (clinical), Genetics, 0303 health sciences, Mutation, MESH: Muscle, Skeletal, MESH: Genetic Predisposition to Disease, Syndrome, Null allele, MESH: Myopathies, Nemaline, Pedigree, RAPSN, medicine.anatomical_structure, Phenotype, Neurology, Child, Preschool, Female, Multiple pterygium syndrome, MESH: Algeria, Adult, Genetic Markers, MESH: Mutation, Genotype, MESH: Pedigree, Biology, MESH: Phenotype, Neuromuscular junction, 03 medical and health sciences, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetic Predisposition to Disease, Genetic Testing, Muscle, Skeletal, 030304 developmental biology, MESH: Humans, MESH: Child, Preschool, MESH: Adult, medicine.disease, MESH: Male, Algeria, Pediatrics, Perinatology and Child Health, Neurology (clinical), MESH: Inheritance Patterns, MESH: Female, 030217 neurology & neurosurgery
Abstract: International audience; While TPM2 mutations identified so far in muscular diseases were all associated with a dominant inheritance pattern, we report the identification of a homozygous null allele mutation in the TPM2 gene in a patient who presented with a recessive form of nemaline myopathy associated with a non-lethal multiple pterygium syndrome (Escobar-MPS MIM# 265000). The TPM2 mutation led to a complete absence of the skeletal muscle isoform of beta-tropomyosin not compensated by expression of other beta-tropomyosin isoforms. Escobar syndrome has been recently described as a prenatal form of myasthenia associated with recessive mutations in genes of the neuromuscular junction (CHRNG, CHRNA1, CHRND, RAPSN). This observation expands the cause of Escobar variant-MPS to a component of the contractile apparatus. This first report of the clinical expression of the complete absence of TPM2 in human indicated that TPM2 expression at the early period of prenatal life plays a major role for normal fetal movements.
Published: 2008

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