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1. Rare genetic susceptibility variants assessment in autism spectrum disorder: detection rate and practical use

Author

Thomas Husson, François Lecoquierre, Kevin Cassinari, Camille Charbonnier, Olivier Quenez, Alice Goldenberg, Anne-Marie Guerrot, Anne-Claire Richard, Valérie Drouin-Garraud, Anne-Claire Brehin, Maryam Soleimani, Romain Taton, Maud Rotharmel, Antoine Rosier, Pascal Chambon, Nathalie Le Meur, Géraldine Joly-Helas, Pascale Saugier-Veber, Anne Boland, Jean-François Deleuze, Robert Olaso, Thierry Frebourg, Gael Nicolas, Olivier Guillin, and Dominique Campion

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a strong genetic component whose knowledge evolves quickly. Next-generation sequencing is the only effective technology to deal with the high genetic heterogeneity of ASD in a clinical setting. However, rigorous criteria to classify rare genetic variants conferring ASD susceptibility are currently lacking. We have performed whole-exome sequencing to identify both nucleotide variants and copy number variants (CNVs) in 253 ASD patients, including 68 patients with intellectual disability (ID) and 90 diagnosed as Asperger syndrome. Using explicit criteria to classify both susceptibility genes and susceptibility variants we prioritized 217 genes belonging to the following categories: syndromic genes, genes with an excess of de novo protein truncating variants and genes targeted by rare CNVs. We obtained a susceptibility variant detection rate of 19.7% (95% CI: [15–25.2%]). The rate for CNVs was 7.1% (95% CI: [4.3–11%]) and 12.6% (95% CI: [8.8–17.4%]) for nucleotide variants. The highest rate (30.1%, 95% CI: [20.2–43.2%]) was obtained in the ASD + ID subgroup. A strong contributor for at risk nucleotide variants was the recently identified set of genes (n = 81) harboring an excess of de novo protein truncating variants. Since there is currently no evidence that the genes targeted here are necessary and sufficient to cause ASD, we recommend to avoid the term “causative of ASD” when delivering the information about a variant to a family and to use instead the term “genetic susceptibility factor contributing to ASD”.

Published
2020
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2. The genetic landscape and clinical spectrum of nephronophthisis and related ciliopathies

Author

Friederike Petzold, Katy Billot, Xiaoyi Chen, Charline Henry, Emilie Filhol, Yoann Martin, Marina Avramescu, Maxime Douillet, Vincent Morinière, Pauline Krug, Cécile Jeanpierre, Kalman Tory, Olivia Boyer, Anita Burgun, Aude Servais, Remi Salomon, Alexandre Benmerah, Laurence Heidet, Nicolas Garcelon, Corinne Antignac, Mohamad Zaidan, Sophie Saunier, Tania Attié-Bitach, Valerie Comier-Daire, Jean-Michel Rozet, Yaacov Frishberg, Brigitte Llanas, Michel Broyer, Nabil Mohsin, Marie-Alice Macher, Nicole Philip, Véronique Baudouin, Damian Brackman, Chantal Loirat, Marina Charbit, Maud Dehennault, Claude Guyot, Pierre Bataille, Mariet Elting, Georges Deschenes, Andrea Gropman, Geneviève Guest, Marie-France Gagnadoux, Philippe Nicoud, Pierre Cochat, Bruno Ranchin, Albert Bensman, Anne-Marie Guerrot, Bertrand Knebelmann, Ilmay Bilge, Danièle Bruno, Stéphane Burtey, Caroline Rousset Rouvière, Valérie Caudwell, Denis Morin, Hélène Dollfus, Anne Maisin, Christian Hamel, Eric Bieth, Sophie Gie, Judith Goodship, Gwenaelle Roussey, Hermine La Selve, Hubert Nivet, Lucie Bessenay, Mathilde Caillez, Jean Bernard Palcoux, Stéphane Benoît, Philippe Dubot, Marc Fila, Fabienne Giuliano, Daouya Iftene, Michele Kessler, Theresa Kwon, Anine Lahoche, Audrey Laurent, Anne-Laure Leclerc, David Milford, Thomas Neuhaus, Sylvie Odent, Philippe Eckart, Dominique Chauveau, Patrick Niaudet, Horacio Repetto, Sophie Taque, Alexandra Bruel, Alexandra Noel-Botte, Emma Allain Launay, Lisa Allard, Dany Anlicheau, Anne-Laure Adra, Arnaud Garnier, Arvind Nagra, Remy Baatard, Justine Bacchetta, Banu Sadikoglu, Christine Barnerias, Anne Barthelemy, Lina Basel, Nader Bassilios, Hedi Ben Maiz, Fatma Ben Moussa, Faïza Benmati, Romain Berthaud, Aurélia Bertholet, Dominique Blanchier, Jean Jacques Boffa, Karim Bouchireb, Ihab Bouhabel, Zakaria Boukerroucha, Guylhène Bourdat-Michel, Odile Boute, Karine Brochard, Roseline Caumes, Siham Chafai Elalaoui, Bernard Chamontin, Marie Caroline Chastang, Christine Pietrement, Christine Richer, Christophe Legendre, Karin Dahan, Fabienne Dalla-Vale, Damien Thibaudin, Maxime Dauvergne, Salandre Davourie, Martin Debeukelaer, Jean Daniel Delbet, Constantinos Deltas, Denis Graber, Nadège Devillars, Boucar Diouf, Martine Doco Fenzy, Jean-Luc André, Dominique Joly, Alan Fryer, Laetitia Albano, Elisabeth Cassuto, Aline Pincon, Ana Medeira, Annabelle Chaussenot, Anne Mensire-Marinier, Francois Bouissou, Stephane Decramer, Armand Bottani, Aurélie Hummel, Alexandre Karras, Avi Katz, Christine Azema, Bénédicte Janbon, Bernard Roussel, Claude Bonniol, Christiophe Mariat, Gérard Champion, Deborah Chantreuil, Nicolas Chassaing, Christiane Mousson, Christine Baudeau, Delphine Hafdar Cuntz, Cyril Mignot, Laurene Dehoux, Didier Lacombe, Thierry Hannedouche, Elodie Mérieau, Emmanuelle Charlin, Eric Gauthier, Florent Plasse, Stanislas Faguer, Fanny Lebas, Florence Demurger, Francesco Emma, François Cartault, Geneviève Dumont, Nathalie Godefroid, Vincent Guigonis, Sophie Hillaire, Jaap Groothoff, Jan Dudley, Noémie Jourde-Chiche, Khalil El Karoui, Saoussen Krid, Krier Coudert, Larbi Bencheick, Laurent Yver, Marie-Pierre Lavocat, Le Monies De Sagazan, Valerie Leroy, Lise Thibaudin, Liz Ingulli, Lorraine Gwanmesia, Lydie Burglen, Marie-Hélène Saïd-Menthon, Marta Carrera, Mathilde Nizon, Catherine Melander, Michel Foulard, Monique Blayo, Jacques Prinseau, Nadine Jay, Nathalie Brun, Nicolas Camille, François Nobili, Olivier Devuyst, Ouafa Ben Brahim, Paloma Parvex, Laurence Perrin Sabourin, Philippe Blanc, Philippe Vanhille, Pierre Galichon, Sophie Pierrepont, Vincent Planquois, Gwenaelle Poussard, Claire Pouteil Noble, Radia Allal, Raphaelle Bernard, Raynaud Mounet, Rémi Cahen, Renaud Touraine, Claire Rigothier, Amélie Ryckewaert, Mathieu Sacquepee, Salima El Chehadeh, Charlotte Samaille, Shuman Haq, Ari Simckes, Stéphanie Lanoiselée, Stephanie Tellier, Jean-François Subra, Sylvie Cloarec, Julie Tenenbam, Thomas Lamy, Valérie Drouin Garraud, Huguette Valette, Vanina Meyssonnier, Rosa Vargas-Poussou, Yves Snajer, Sandrine Durault, Emmanuelle Plaisier, Etienne Berard, Fadi Fakhouri, Ferielle Louillet, Paul Finielz, Michel Fischbach, Bernard Foliguet, Hélène Francois-Pradier, Florentine Garaix, Marion Gerard, Gianfranco Rizzoni, Brigitte Gilbert, Denis Glotz, Astrid Godron Dubrasquet, Jean-Pierre Grünfeld, Guillaume Bollee, Michelle Hall, Sverker Hansson, Damien Haye, Hélène Taffin, Friedhelm Hildebrandt, Maryvonne Hourmand, Hümya Kayserili, Ivan Tack, Marie Line Jacquemont, Jennifer Fabre-Teste, Cliff Kashtan, Kkoen Van Hoeck, Alexandre Klein, Yannick Knefati, Nine Knoers, Martin Konrad, Alain Lachaux, Isabelle Landru, Gilbert Landthaler, Philippe Lang, Patrick Le Pogamp, Tristan Legris, Catherine Didailler, Thierry Lobbedez, Loïc de Parscau, Lucile Pinson, Hervé Maheut, Marc Duval-Arnould, Marlène Rio, Marie-Claire Gubler, Pierre Merville, Guillaume Mestrallet, Maite Meunier, Karine Moreau, Jérôme Harambat, Graeme Morgan, Georges Mourad, Niksic Stuber, Odile Boespflug-Tanguy, Olivier Dunand, Olivier Niel, Nacera Ouali, Paolo Malvezzi, Pauline Abou Jaoude, Solenne Pelletier, Julie Peltier, M.B. Petersen, Philippe Michel, Philippe Rémy, Jean-Baptiste Philit, Valérie Pichault, Thierry Billette de Villemeur, Bernard Boudailliez, Bruno Leheup, Claire Dossier, Djamal-Dine Djeddi, Yves Berland, Bruno Hurault de Ligny, Susan Rigden, Christophe Robino, Annick Rossi, Sabine Sarnacki, Messaoud Saidani, Albane Brodin Sartorius, Elise Schäfer, Sztriha Laszlo, Marie-Christine Thouret, Angélique Thuillier-Lecouf, Howard Trachtman, Claire Trivin, Michel Tsimaratos, Rita Van Damme-Lombaerts, Marjolaine Willems, Michel Youssef, Ariane Zaloszyc, Alexis Zawodnik, and Marie-Julia Ziliotis

Subjects
Nephrology
Abstract

Nephronophthisis (NPH) is an autosomal-recessive ciliopathy representing one of the most frequent causes of kidney failure in childhood characterized by a broad clinical and genetic heterogeneity. Applied to one of the worldwide largest cohorts of patients with NPH, genetic analysis encompassing targeted and whole exome sequencing identified disease-causing variants in 600 patients from 496 families with a detection rate of 71%. Of 788 pathogenic variants, 40 known ciliopathy genes were identified. However, the majority of patients (53%) bore biallelic pathogenic variants in NPHP1. NPH-causing gene alterations affected all ciliary modules defined by structural and/or functional subdomains. Seventy six percent of these patients had progressed to kidney failure, of which 18% had an infantile form (under five years) and harbored variants affecting the Inversin compartment or intraflagellar transport complex A. Forty eight percent of patients showed a juvenile (5-15 years) and 34% a late-onset disease (over 15 years), the latter mostly carrying variants belonging to the Transition Zone module. Furthermore, while more than 85% of patients with an infantile form presented with extra-kidney manifestations, it only concerned half of juvenile and late onset cases. Eye involvement represented a predominant feature, followed by cerebellar hypoplasia and other brain abnormalities, liver and skeletal defects. The phenotypic variability was in a large part associated with mutation types, genes and corresponding ciliary modules with hypomorphic variants in ciliary genes playing a role in early steps of ciliogenesis associated with juvenile-to-late onset NPH forms. Thus, our data confirm a considerable proportion of late-onset NPH suggesting an underdiagnosis in adult chronic kidney disease.

Published
2023
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3. Clinical, laboratory and molecular findings and long-term follow-up data in 96 French patients with PMM2-CDG (phosphomannomutase 2-congenital disorder of glycosylation) and review of the literature

Author

Dominique Martin-Coignard, Olivier Pincemaille, Claire de Barace, Nathalie Boddaert, Michel Polak, Tiffany Pascreau, Nathalie Seta, Christine Francannet, Gilles Morin, Valérie Cormier-Daire, François Labarthe, Manuel Schiff, Alexis Brice, Anaïs Brassier, Arnaud Bruneel, Patrick Edery, Alina Arion, Isabelle Fontan, Brigitte Chabrol, Cyril Gitiaux, Emmanuel de Maistre, Anne de Saint-Martin, Valérie Drouin-Garraud, Maud Bidet, Magali Barth, Catherine Bloch, Thierry Dupré, Céline Roda, Nathalie Bednarek, Sandrine Vuillaumier-Barrot, Marie-Chantal Chevalier, Géraldine Viot, François Feillet, Annick Toutain, Sylvie Lamoureux, Christel Thauvin-Robinet, Marie Hully, Delphine Borgel, Cyril Mignot, Nathalie Dorison, Bernard Echenne, Agathe Roubertie, Delphine Héron, Roger Buissonnière, Marie-Lorraine Monin, and Pascale de Lonlay

Subjects
Male, 0301 basic medicine, Pediatrics, medicine.medical_specialty, Adolescent, 03 medical and health sciences, Pericarditis, Congenital Disorders of Glycosylation, 0302 clinical medicine, Tubulopathy, Hydrops fetalis, Genetics, Humans, Medicine, Hypoalbuminemia, Child, Alleles, Genetic Association Studies, Genetics (clinical), business.industry, Infant, medicine.disease, Hypotonia, Phenotype, 030104 developmental biology, Amino Acid Substitution, Phosphotransferases (Phosphomutases), Inborn error of metabolism, Child, Preschool, Mutation, Female, medicine.symptom, business, Nephrotic syndrome, Congenital disorder of glycosylation, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract

Background Phosphomannomutase 2-congenital disorder of glycosylation (PMM2-CDG) is a multisystem inborn error of metabolism. Objectives To better characterise the natural history of PMM2-CDG. Methods Medical charts of 96 patients with PMM2-CDG (86 families, 41 males, 55 females) were retrospectively reviewed. Data on clinical, laboratory and molecular parameters at diagnosis were analysed. Follow-up data at last examination were reported for 25 patients. Results The patients were born between 1963 and 2011. Diagnosis of PMM2-CDG was made at a mean (SD) age of 6.8 (8.5) years. The presenting signs were mostly neurological (hypotonia, intellectual disability, cerebellar syndrome) and observed in almost all the patients. A total of 38 patients (14 males, 24 females) exhibited, in addition to neurological signs, visceral features including at least one of these: feeding difficulty requiring a nutritional support (n=23), cardiac features (n=20; pericarditis: 14, cardiac malformation: 9, cardiomyopathy: 2), hepato-gastrointestinal features (n=12; chronic diarrhoea: 7, protein-losing enteropathy: 1, ascites: 3, liver failure: 1, portal hypertension: 1), kidney features (n=4; nephrotic syndrome: 2, tubulopathy: 2) and hydrops fetalis (n=1). Twelve patients died at a mean age of 3.8 years (especially from pericarditis and other cardiac issues). Laboratory abnormalities mostly included elevated transaminases and abnormal coagulation parameters. High thyreostimulin levels, hypocholesterolemia, hypoalbuminemia and elevated transaminases were associated with the visceral phenotype. Besides the common Arg141His PMM2 variant harboured by half of the patients, 45 different variants were observed. Conclusions PMM2-CDG clinical phenotype is heterogeneous in terms of clinical course, with no clear division between neurological and visceral presentations.

Published
2017
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4. TTC12 loss-of-function mutations cause primary Ciliary Dyskinesia and unveil distinct dynein assembly mechanisms in motile cilia versus flagella

Author

Lucie Thomas, Khaled Bouhouche, Marjorie Whitfield, Guillaume Thouvenin, Andre Coste, Bruno Louis, Claire Szymanski, Emilie Bequignon, Jean-François Papon, Manon Castelli, Michel Lemullois, Xavier Dhalluin, Valérie Drouin-Garraud, Guy Montantin, Sylvie Tissier, Philippe Duquesnoy, Bruno Copin, Florence Dastot, Sandrine Couvet, Anne-Laure Barbotin, Catherine Faucon, Isabelle Honore, Bernard Maitre, Nicole Beydon, Aline Tamalet, Nathalie Rives, France Koll, Estelle Escudier, Anne-Marie Tassin, Aminata Touré, Valérie Mitchell, Serge Amselem, Marie Legendre, Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM), Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-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), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Biogenèse et Fonction de la Structure Centriolaire et Ciliaire (BIOCIL), Département Biologie Cellulaire (BioCell), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Biomécanique & Appareil Respiratoire (BAR), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Service d'ORL [Créteil], Centre Hospitalier Intercommunal de Créteil (CHIC), IMRB - 'Biomechanics and Respiratory Apparatus' [Créteil] (U955 Inserm - UPEC), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Claude Huriez [Lille], CHU Lille, Service d’ORL et de chirurgie cervico-faciale [CHU Le Kremlin-Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Hôpital Albert Calmette, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Charles Nicolle [Rouen], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), UF de Génétique moléculaire [CHU Trousseau], CHU Trousseau [APHP], Gamétogenèse et Qualité du Gamète - ULR 4308 (GQG), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Université de Lille, CHU Rouen, Normandie Université (NU), Hôpital Jeanne de Flandres, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Maladies génétiques d'expression pédiatrique (U933), Normandie Université (NU)-Normandie Université (NU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and CCSD, Accord Elsevier

Subjects
0301 basic medicine, Male, Axoneme, [SDV]Life Sciences [q-bio], primary ciliary dyskinesia, 0302 clinical medicine, hemic and lymphatic diseases, Child, Genetics (clinical), Primary ciliary dyskinesia, Cilium, Homozygote, Inner dynein arm, Middle Aged, Phenotype, Cell biology, Pedigree, [SDV] Life Sciences [q-bio], Flagella, Motile cilium, Sperm Motility, Female, CRISPR-Cas9, Ciliary Motility Disorders, Adult, dynein arm assembly, Dynein, Biology, Flagellum, Article, TTC12, 03 medical and health sciences, Young Adult, Genetics, medicine, Humans, Infertility, Male, Ciliate, cilia, Dyneins, Proteins, nutritional and metabolic diseases, biology.organism_classification, medicine.disease, sperm flagella, 030104 developmental biology, Sperm Tail, Mutation, 030217 neurology & neurosurgery
Abstract

International audience; Cilia and flagella are evolutionarily conserved organelles whose motility relies on the outer and inner dynein arm complexes (ODAs and IDAs). Defects in ODAs and IDAs result in primary ciliary dyskinesia (PCD), a disease characterized by recurrent airway infections and male infertility. PCD mutations in assembly factors have been shown to cause a combined ODA-IDA defect, affecting both cilia and flagella. We identified four loss-of-function mutations in TTC12, which encodes a cytoplasmic protein, in four independent families in which affected individuals displayed a peculiar PCD phenotype characterized by the absence of ODAs and IDAs in sperm flagella, contrasting with the absence of only IDAs in respiratory cilia. Analyses of both primary cells from individuals carrying TTC12 mutations and human differentiated airway cells invalidated for TTC12 by a CRISPR-Cas9 approach revealed an IDA defect restricted to a subset of single-headed IDAs that are different in flagella and cilia, whereas TTC12 depletion in the ciliate $Paramecium\ tetraurelia$ recapitulated the sperm phenotype. Overall, our study, which identifies TTC12 as a gene involved in PCD, unveils distinct dynein assembly mechanisms in human motile cilia versus flagella.

Published
2020
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5. Dilated Cardiomyopathy and Premature Ovarian Failure Unveiling Propionic Aciduria

Author

Soumeya Bekri, Catherine Nafeh-Bizet, Stéphanie Gobin, Abdellah Tebani, Sarah Grotto, Bénédicte Sudrié-Arnaud, Bernadette Chadefaux-Vekemans, and Valérie Drouin-Garraud

Subjects
Adult, Cardiomyopathy, Dilated, 0301 basic medicine, medicine.medical_specialty, Propionic Acidemia, Clinical Biochemistry, Cardiomyopathy, Primary Ovarian Insufficiency, 030105 genetics & heredity, Gastroenterology, 03 medical and health sciences, Internal medicine, Idiopathic dilated cardiomyopathy, medicine, Humans, Ejection fraction, medicine.diagnostic_test, business.industry, Biochemistry (medical), Complete blood count, Dilated cardiomyopathy, medicine.disease, Antral follicle, Premature ovarian failure, Female, Macrocytic anemia, business
Abstract

A 28-year-old woman presented with premature ovarian failure (POF).8 She was the eldest of 4 children and her siblings were all healthy. She underwent heart transplantation at 17 years of age following acute cardiac decompensation due to hypokinetic dilated cardiomyopathy (DCM). At this time, her left ventricle ejection fraction collapsed to 20%, although no arrhythmia or conduction abnormalities were observed, and psychomotor and cognitive functions were normal. She was determined to have idiopathic dilated cardiomyopathy for which a genetic/metabolic etiology was not considered at the time. Posttransplantation follow-up was satisfactory, with normal cardiac function. During her most recent presentation with POF, she underwent endocrine function assessment for infertility. Concentrations of serum markers were highly suggestive of diminished ovarian reserve: follicle-stimulating hormone = 20 UI/L [reference interval (RI): 1.7–7.7]; estradiol = 59 pg/mL (RI: 50–230); anti-Mullerian hormone = 1 μg/L (RI: 2.5–6). The antral follicle count was 5, consistent with POF. Additional investigations, including thyroid hormone testing, karyotype, and fragile X study, were normal. Routine biochemistry testing, including plasma ammonia, bicarbonate, and electrolytes, was also unremarkable. A complete blood count revealed mild macrocytic anemia (hemoglobin = 11.1 g/dL, …

Published
2018
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6. Hypersociability associated with developmental delay, macrocephaly and facial dysmorphism points to CHD3 mutations

Author

François Lecoquierre, Anne Boland, Valérie Drouin-Garraud, Gaël Nicolas, Thierry Frebourg, Juliette Coursimault, Jean-François Deleuze, J. Lechevallier, Anne-Claire Brehin, and Pascale Saugier-Veber

Subjects
Male, Hypersociability, Pediatrics, medicine.medical_specialty, Developmental Disabilities, Craniofacial Abnormalities, Young Adult, Intellectual disability, Genetics, medicine, Humans, Global developmental delay, Hypertelorism, Social Behavior, Genetics (clinical), business.industry, DNA Helicases, Macrocephaly, Syndrome, General Medicine, medicine.disease, Megalencephaly, Developmental disorder, Autism spectrum disorder, Mutation, Speech delay, medicine.symptom, business, Mi-2 Nucleosome Remodeling and Deacetylase Complex
Abstract

CHD3-related syndrome, also known as Snijders Blok-Campeau syndrome, is a rare developmental disorder described in 2018, caused by de novo pathogenic variants in the CHD3 gene. This syndrome is characterized by global developmental delay, speech delay, intellectual disability, hypotonia and behavioral disorders including autism spectrum disorder (ASD). Typical dysmorphic features include macrocephaly, hypertelorism, enophthalmia, sparse eyebrows, bulging forehead, midface hypoplasia, prominent nose and pointed chin. To our knowledge, there have been no other clinical descriptions of patients since the initial publication. We report the clinical description of a 21-year-old patient harboring a pathogenic de novo variant in CHD3. We reviewed the clinical features of the 35 previously reported patients. Main features were severe intellectual disability, dysmorphic facies, macrocephaly, cryptorchidism, pectus carinatum, severe ophthalmologic abnormalities and behavioral disorders including ASD, and a frank happy demeanor. Hypersociability, which was a noticeable clinical feature in our case, despite ASD, is an uncommon behavioral feature in syndromic intellectual disabilities. Our report supports hypersociability as a suggestive feature of CHD3-related syndrome along with developmental delay, macrocephaly and a dysmorphic facies.

Published
2021
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7. Complementarity of electrophoretic, mass spectrometric, and gene sequencing techniques for the diagnosis and characterization of congenital disorders of glycosylation

Author

Marie-Line Jacquemont, Nathalie Seta, Valérie Drouin-Garraud, François Fenaille, André Mégarbané, Arnaud Bruneel, David Cheillan, Coralie Ruel, Sandrine Vuillaumier-Barrot, Thierry Dupré, Aline Cano, Sophie Cholet, Biochimie Métabolique et Cellulaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris-Sud - Paris 11 (UP11), Institut National de la Recherche Agronomique (INRA), CHU Rouen, Normandie Université (NU), Centre Hospitalier Universitaire Sud Reunion, Partenaires INRAE, Hôpital de la Timone [CHU - APHM] (TIMONE), Institut Jérôme Lejeune, Hospices Civils de Lyon (HCL), Service de Pharmacologie et d'Immunoanalyse (SPI), Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Université Paris Saclay (COmUE), Service de Pharmacologie et Immunoanalyse (SPI), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-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)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
0301 basic medicine, Electrophoresis, Male, Glycan, congenital, hereditary, and neonatal diseases and abnormalities, Glycosylation, Adolescent, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Computational biology, Gene mutation, Biology, Biochemistry, DNA sequencing, Mass Spectrometry, Analytical Chemistry, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Capillary electrophoresis, Congenital Disorders of Glycosylation, Polysaccharides, Humans, Child, Glycomics, Glycoproteins, chemistry.chemical_classification, Mucin, Infant, ms, Sequence Analysis, DNA, Mass spectrometric, 2de, 3. Good health, 030104 developmental biology, chemistry, Transferrin, Child, Preschool, biology.protein, lipids (amino acids, peptides, and proteins), Female, 030217 neurology & neurosurgery
Abstract

International audience; Congenital disorders of glycosylation (CDG) are rare autosomal genetic diseases affecting the glycosylation of proteins and lipids. Since CDG-related clinical symptoms are classically extremely variable and nonspecific, a combination of electrophoretic, mass spectrometric, and gene sequencing techniques is often mandatory for obtaining a definitive CDG diagnosis, as well as identifying causative gene mutations and deciphering the underlying biochemical mechanisms. Here, we illustrate the potential of integrating data from capillary electrophoresis of transferrin, two-dimensional electrophoresis of N- and O-glycoproteins, mass spectrometry analyses of total serum N-linked glycans and mucin core1 O-glycosylated apolipoprotein C-III for the determination of various culprit CDG gene mutations. "Step-by-step" diagnosis pathways of four particular and new CDG cases, including MGAT2-CDG, ATP6V0A2-CDG, SLC35A2-CDG, and SLC35A3-CDG, are described as illustrative examples.

Published
2018
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8. Congenital hypogonadotropic hypogonadism with split hand/foot malformation: a clinical entity with a high frequency of FGFR1 mutations

Author

Michel Polak, Carine Villanueva, Lacey Plummer, Franziska Phan-Hug, Michael Hauschild, Juliane Léger, Cheng Xu, Yisrael Sidis, Nelly Pitteloud, Taneli Raivio, Hervé Lefebvre, Elka Jacobson-Dickman, Jean-Claude Carel, Moosa Mohammadi, Dov Tiosano, Sylvie Manouvrier, Gerasimos P. Sykiotis, Pierre Bouloux, Jean-Pierre Rey, Valérie Drouin-Garraud, Youli Hu, Andrew A. Dwyer, Yang Liu, Andrew Beenken, Nicolas de Roux, Johanna Tommiska, and Marion Gérard

Subjects
Proband, Male, medicine.medical_specialty, Kallmann syndrome, MAP Kinase Signaling System, Population, Molecular Sequence Data, Limb Deformities, Congenital, Biology, medicine.disease_cause, Article, congenital hypogonadotropic hypogonadism, 03 medical and health sciences, Internal medicine, medicine, Animals, Humans, Amino Acid Sequence, Receptor, Fibroblast Growth Factor, Type 1, Phosphorylation, education, Genetics (clinical), Conserved Sequence, Genetic Association Studies, 030304 developmental biology, Genetic testing, Adaptor Proteins, Signal Transducing, 0303 health sciences, education.field_of_study, Mutation, medicine.diagnostic_test, fibroblast growth factor receptor 1, Fibroblast growth factor receptor 1, FGF receptor substrate 2α, Hypogonadism, 030305 genetics & heredity, Membrane Proteins, Micropenis, medicine.disease, 3. Good health, Pedigree, Endocrinology, split hand/foot malformation, Female, Congenital Hypogonadotropic Hypogonadism, Adaptor Proteins, Signal Transducing/metabolism, Hypogonadism/congenital, Hypogonadism/genetics, Limb Deformities, Congenital/genetics, Limb Deformities, Congenital/metabolism, Membrane Proteins/metabolism, Receptor, Fibroblast Growth Factor, Type 1/genetics, Receptor, Fibroblast Growth Factor, Type 1/metabolism
Abstract

PURPOSE: Congenital hypogonadotropic hypogonadism (CHH) and split hand/foot malformation (SHFM) are two rare genetic conditions. Here we report a clinical entity comprising the two. METHODS: We identified patients with CHH and SHFM through international collaboration. Probands and available family members underwent phenotyping and screening for FGFR1 mutations. The impact of identified mutations was assessed by sequence- and structure-based predictions and/or functional assays. RESULTS: We identified eight probands with CHH with (n = 3; Kallmann syndrome) or without anosmia (n = 5) and SHFM, seven of whom (88%) harbor FGFR1 mutations. Of these seven, one individual is homozygous for p.V429E and six individuals are heterozygous for p.G348R, p.G485R, p.Q594*, p.E670A, p.V688L, or p.L712P. All mutations were predicted by in silico analysis to cause loss of function. Probands with FGFR1 mutations have severe gonadotropin-releasing hormone deficiency (absent puberty and/or cryptorchidism and/or micropenis). SHFM in both hands and feet was observed only in the patient with the homozygous p.V429E mutation; V429 maps to the fibroblast growth factor receptor substrate 2α binding domain of FGFR1, and functional studies of the p.V429E mutation demonstrated that it decreased recruitment and phosphorylation of fibroblast growth factor receptor substrate 2α to FGFR1, thereby resulting in reduced mitogen-activated protein kinase signaling. CONCLUSION: FGFR1 should be prioritized for genetic testing in patients with CHH and SHFM because the likelihood of a mutation increases from 10% in the general CHH population to 88% in these patients.

Published
2015

9. Baraitser-Winter cerebrofrontofacial syndrome : Delineation of the spectrum in 42 cases

Author

Sara Osimani, Andrew E. Fry, Koenraad Devriendt, Débora Romeo Bertola, Marjan M. Nezarati, Han G. Brunner, Grazia M.S. Mancini, Jorge L. Juncos, Pirayeh Eftekhari, Nataliya Di Donato, Marjolijn C.J. Jongmans, Laurence Faivre, Gilles Morin, Małgorzata J.M. Nowaczyk, Didier Lacombe, Zeichi-Seide Roseli, Conny M. A. van Ravenswaaij, Daniela Melis, Julien Masliah-Planchon, William B. Dobyns, Alexander Hoischen, Hatice Koçak Eker, Marlies Kempers, Andreas Rump, Vera Uliana, Victoria Mok Siu, Fabienne Giuliano, Nicole Philip, Beate Albrecht, Omar A Abdul-Raman, Alain Verloes, Mirjam Klaus, Angela E. Lin, Massimiliano Rossi, Albert David, Bregje W.M. van Bon, Jeanette C. Ramer, Ludivine Templin, Séverine Drunat, Yves Sznajer, Vincent Procaccio, Jean-Baptiste Rivière, Mary Ella M Pierpont, Francesca Faravelli, Judith Allanson, Leina Guion Almeida, Daniela T. Pilz, Cristina Rusu, Nicolas Chassaing, Charles Marques Lourenço, Bruce H. Wainer, Valérie Drouin-Garraud, Hôpital Robert Debré, Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Universitätsklinikum Carl Gustav Carus, Université Paris Diderot - Paris 7 (UPD7), Radboud University Medical Centre [Nijmegen, The Netherlands], University of Mississippi Medical Center (UMMC), Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Children's Hospital of Eastern Ontario [Ottawa, Canada], Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Centre hospitalier universitaire de Nantes (CHU Nantes), University Hospital Gasthuisberg, Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Rouen, Normandie Université (NU), Ospedale Galliera, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Universitaire de Nice (CHU Nice), University of São Paulo (USP), Emory University School of Medicine, Emory University [Atlanta, GA], CHU Bordeaux [Bordeaux], Massachusetts General Hospital [Boston], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Università degli studi di Napoli Federico II, University of Western Ontario (UWO), CHU Amiens-Picardie, McMaster University [Hamilton, Ontario], Pennsylvania State University (Penn State), Penn State System, Hôpital de la Timone [CHU - APHM] (TIMONE), University of Minnesota [MN, USA], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Cliniques Universitaires Saint-Luc [Bruxelles], University Hospital Groningen, University Hospital of Wales [Cardiff, UK], Seattle Children’s Hospital, Clinical Genetics, UCL - SSS/IREC - Institut de recherche expérimentale et clinique, UCL - (SLuc) Centre de génétique médicale UCL, Ethical, Legal, Social Issues in Genetics (ELSI), and Clinical Cognitive Neuropsychiatry Research Program (CCNP)

Subjects
Male, Microcephaly, Pathology, Craniofacial abnormality, [SDV]Life Sciences [q-bio], Medizin, GYRAL MALFORMATIONS, Craniofacial Abnormalities, FUNCTIONAL DIVERSITY, 0302 clinical medicine, Ptosis, Gene Order, Genetics(clinical), Hypertelorism, Non-U.S. Gov't, Child, Genetics (clinical), Arthrogryposis, Dystonia, 0303 health sciences, Research Support, Non-U.S. Gov't, Anatomy, 3. Good health, Phenotype, Child, Preschool, Female, medicine.symptom, Abnormalities, Multiple, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Adult, medicine.medical_specialty, APPARENTLY UNDESCRIBED SYNDROME, Adolescent, Lissencephaly, Biology, Research Support, Article, 03 medical and health sciences, Young Adult, SDG 3 - Good Health and Well-being, medicine, Genetics, Journal Article, Humans, Abnormalities, Multiple, Preschool, 030304 developmental biology, SHALLOW ORBITS, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], GAMMA-ACTIN, Pachygyria, Facies, medicine.disease, IRIS COLOBOMA, Actins, BETA-ACTIN, Amino Acid Substitution, Genetic Loci, Mutation, FACIAL SYNDROME, 030217 neurology & neurosurgery, MENTAL-RETARDATION, GROWTH-RETARDATION
Abstract

International audience; Baraitser-Winter, Fryns-Aftimos and cerebrofrontofacial syndrome types 1 and 3 have recently been associated with heterozygous gain-of-function mutations in one of the two ubiquitous cytoplasmic actin-encoding genes ACTB and ACTG1 that encode beta- and gamma-actins. We present detailed phenotypic descriptions and neuroimaging on 36 patients analyzed by our group and six cases from the literature with a molecularly proven actinopathy (9 ACTG1 and 33 ACTB). The major clinical anomalies are striking dysmorphic facial features with hypertelorism, broad nose with large tip and prominent root, congenital non-myopathic ptosis, ridged metopic suture and arched eyebrows. Iris or retinal coloboma is present in many cases, as is sensorineural deafness. Cleft lip and palate, hallux duplex, congenital heart defects and renal tract anomalies are seen in some cases. Microcephaly may develop with time. Nearly all patients with ACTG1 mutations, and around 60% of those with ACTB mutations have some degree of pachygyria with anteroposterior severity gradient, rarely lissencephaly or neuronal heterotopia. Reduction of shoulder girdle muscle bulk and progressive joint stiffness is common. Early muscular involvement, occasionally with congenital arthrogryposis, may be present. Progressive, severe dystonia was seen in one family. Intellectual disability and epilepsy are variable in severity and largely correlate with CNS anomalies. One patient developed acute lymphocytic leukemia, and another a cutaneous lymphoma, indicating that actinopathies may be cancer-predisposing disorders. Considering the multifaceted role of actins in cell physiology, we hypothesize that some clinical manifestations may be partially mutation specific. Baraitser-Winter cerebrofrontofacial syndrome is our suggested designation for this clinical entity.European Journal of Human Genetics advance online publication, 23 July 2014; doi:10.1038/ejhg.2014.95.

Published
2015
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10. Gender as a Modifying Factor Influencing Myotonic Dystrophy Type 1 Phenotype Severity and Mortality: A Nationwide Multiple Databases Cross-Sectional Observational Study.

Author

Celine Dogan, Marie De Antonio, Dalil Hamroun, Hugo Varet, Marianne Fabbro, Felix Rougier, Khadija Amarof, Marie-Christine Arne Bes, Anne-Laure Bedat-Millet, Anthony Behin, Remi Bellance, Françoise Bouhour, Celia Boutte, François Boyer, Emmanuelle Campana-Salort, Françoise Chapon, Pascal Cintas, Claude Desnuelle, Romain Deschamps, Valerie Drouin-Garraud, Xavier Ferrer, Helene Gervais-Bernard, Karima Ghorab, Pascal Laforet, Armelle Magot, Laurent Magy, Dominique Menard, Marie-Christine Minot, Aleksandra Nadaj-Pakleza, Sybille Pellieux, Yann Pereon, Marguerite Preudhomme, Jean Pouget, Sabrina Sacconi, Guilhem Sole, Tanya Stojkovich, Vincent Tiffreau, Andoni Urtizberea, Christophe Vial, Fabien Zagnoli, Gilbert Caranhac, Claude Bourlier, Gerard Riviere, Alain Geille, Romain K Gherardi, Bruno Eymard, Jack Puymirat, Sandrine Katsahian, and Guillaume Bassez

Subjects
Medicine, Science
Abstract

Myotonic Dystrophy type 1 (DM1) is one of the most heterogeneous hereditary disease in terms of age of onset, clinical manifestations, and severity, challenging both medical management and clinical trials. The CTG expansion size is the main factor determining the age of onset although no factor can finely predict phenotype and prognosis. Differences between males and females have not been specifically reported. Our aim is to study gender impact on DM1 phenotype and severity.We first performed cross-sectional analysis of main multiorgan clinical parameters in 1409 adult DM1 patients (>18 y) from the DM-Scope nationwide registry and observed different patterns in males and females. Then, we assessed gender impact on social and economic domains using the AFM-Téléthon DM1 survey (n = 970), and morbidity and mortality using the French National Health Service Database (n = 3301).Men more frequently had (1) severe muscular disability with marked myotonia, muscle weakness, cardiac, and respiratory involvement; (2) developmental abnormalities with facial dysmorphism and cognitive impairment inferred from low educational levels and work in specialized environments; and (3) lonely life. Alternatively, women more frequently had cataracts, dysphagia, digestive tract dysfunction, incontinence, thyroid disorder and obesity. Most differences were out of proportion to those observed in the general population. Compared to women, males were more affected in their social and economic life. In addition, they were more frequently hospitalized for cardiac problems, and had a higher mortality rate.Gender is a previously unrecognized factor influencing DM1 clinical profile and severity of the disease, with worse socio-economic consequences of the disease and higher morbidity and mortality in males. Gender should be considered in the design of both stratified medical management and clinical trials.

Published
2016
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