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11 results on '"Laboratoire de Génétique Moléculaire et d'Histocompatibilité [Brest]"'

1. Transformation d’un mélanocytome méningé en mélanome : étude clinique, histopathologique et cytogénétique

Author

Romuald Seizeur, Amélie Bourhis, Marianne Bourhis, Pascale Marcorelles, Elsa Magro, Isabelle Quintin-Roué, Arnaud Uguen, Sylvia Redon, CCSD, Accord Elsevier, Service d'Anatomie et Pathologie, Brest, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CHRU Brest - Laboratoire d'Anatomo-Pathologie (CHU - AnaPath), Laboratoire de Génétique Moléculaire et d'Histocompatibilité [Brest], Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service d'ophtalmologie [Brest], Université de Brest (UBO)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Université de Bretagne Occidentale - UFR Médecine et Sciences de la Santé (UBO UFR MSS), Université de Brest (UBO), Service de neurochirurgie [Brest], Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), Lymphocytes B, Autoimmunité et Immunothérapies (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-LabEX IGO Immunothérapie Grand Ouest, and Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Institut Brestois Santé Agro Matière (IBSAM)

Subjects
0301 basic medicine, medicine.medical_specialty, Pathology, [SDV.IMM] Life Sciences [q-bio]/Immunology, Meningeal melanocytoma, Meningeal melanoma, [SDV]Life Sciences [q-bio], Mélanocytome méningé, Pathology and Forensic Medicine, Malignant transformation, Cytogenetics, 03 medical and health sciences, 0302 clinical medicine, medicine, Cytogénétique, business.industry, Mélanome méningé, Melanoma, Meningeal Melanoma, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], Tumor Subtype, 030104 developmental biology, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Immunohistochemistry, Melanocytoma, business
Abstract

International audience; Meningeal melanocytic tumors are rare. We report an exceptional case of transformation of a meningeal melanocytoma in a malignant melanoma. The course of the disease extents from 61-years to 85-years and ends with the death of the patient. Besides histopathological and immunohistochemical data, we also report the array CGH study of the melanocytoma and melanoma components suggesting the malignant transformation from whole chromosome gains in the melanocytoma to additional segmental aberrations in the malignant melanoma. Beyond the rarity of this tumor subtype, this case report highlights the potential interest of molecular analyses for diagnostic and prognostic purposes in the field of meningeal melanocytic tumors.

Published
2019
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2. Functional characterization and phenotypic spectrum of three recurrent disease-causing deep intronic variants of the CFTR gene

Author

Anne Bergougnoux, J.-P. Altieri, C. Raynal, Thierry Bienvenu, Guy Lalau, Michel Koenig, Jessica Varilh, E. Girodon, Magali Taulan-Cadars, Mireille Claustres, M.-P. Audrézet, Alexandra Pommier, Karine Deletang, Florence Houriez, A. Pagin, Claude Férec, Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Cochin [AP-HP], Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire de Génétique Moléculaire et d'Histocompatibilité [Brest], Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), and Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Hôpital Morvan [Brest]

Subjects
Adult, Male, 0301 basic medicine, Pulmonary and Respiratory Medicine, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, Cystic Fibrosis, [SDV]Life Sciences [q-bio], Cystic Fibrosis Transmembrane Conductance Regulator, Locus (genetics), Deep intronic variants, Cystic fibrosis, DNA sequencing, Male infertility, CFTR gene, 03 medical and health sciences, 0302 clinical medicine, Recurrence, Genotype, medicine, Humans, Child, 10. No inequality, Pseudo-exon inclusion, Splicing alteration, Genetics, business.industry, Haplotype, Genetic Variation, Infant, respiratory system, medicine.disease, Phenotype, Introns, 3. Good health, 030104 developmental biology, 030228 respiratory system, Child, Preschool, Pediatrics, Perinatology and Child Health, RNA splicing, Female, Large phenotypic spectrum, business
Abstract

International audience; BACKGROUND:The CFTR genotype remains incomplete in 1% of Cystic Fibrosis (CF) cases, because only one or no disease-causing variants is detected after extended analysis. This fraction is probably higher in CFTR-Related Disorders (CFTR-RD). Deep-intronic CFTR variants are putative candidates to fill this gap. However, the recurrence, phenotypic spectrum and full molecular characterization of newly reported variants are unknown.METHODS:Minigenes and analysis of CFTR transcripts in nasal epithelial cells were used to determine the impact on CFTR splicing of intronic variants that we previously identified by next generation sequencing of the whole CFTR locus. Phenotypic data were collected in 19 patients with CF and CFTR-RD, in whom one of the deep intronic variants has been detected.RESULTS:Three deep-intronic variants promoted the inclusion of pseudo-exons (PE) in the CFTR transcript, hindering the synthesis of a functional protein. The c.2989-313A > T variant, detected in four patients with CF or CFTR-RD from three different families, led to the inclusion of a 118 bp PE. The c.3469-1304C > G variant promoted the inclusion of a 214 bp-PE and was identified in five patients with CF from four families. Haplotype analysis confirmed that this variant was associated with one CF chromosome of African origin. The most represented variant in our cohort was the c.3874-4522A > G, detected in 10 patients with various phenotypes, from male infertility to CF with pancreatic insufficiency.CONCLUSION:These three deep intronic CFTR variants are associated with a large phenotypic spectrum, including typical CF. They should be included in CF diagnostic testing and carrier screening strategies.

Published
2019
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3. Novel diagnostic tool for prediction of variant spliceogenicity derived from a set of 395 combined in silico/in vitro studies: an international collaborative effort

Author

Gérald Le Gac, Alexandra Martins, Pascaline Gaildrat, Florence Coulet, Françoise Revillon, Antoine Rousselin, Sandrine M. Caputo, Marine Guillaud-Bataille, Chandran Ka, Mélanie Léoné, Nadia Boutry-Kryza, Virginie Caux-Moncoutier, Claude Férec, Capucine Delnatte, Danielle Muller, Grégoire Davy, Amanda B. Spurdle, Maria Rossing, Raphaël Leman, Yann Fichou, Michael T. Parsons, Barbara Wappenschmidt, Violaine Bourdon, Joanna Sokolowska, Nicolas Sevenet, Claude Houdayer, M.-P. Audrézet, Brigitte Bressac-de Paillerets, Françoise Bonnet-Dorion, Sylvie Mazoyer, Gaia Castelain, Sophie Krieger, Laurent Castera, Etienne Rouleau, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), Institut Curie [Paris], Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Validation et identification de nouvelles cibles en oncologie (VINCO), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique (Biologie pathologie), Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), University Hospital of Cologne [Cologne], IT University of Copenhagen (ITU), Centre Paul Strauss, CRLCC Paul Strauss, Laboratoire d'oncogénétique moléculaire, Unite d'Oncogenese Virale, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER-Université de Lille-UNICANCER, QIMR Berghofer Medical Research Institute, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service de Génétique Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique médicale [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre hospitalier universitaire de Nantes (CHU Nantes), Etablissement Français du Sang Bretagne, EFS, Laboratoire de Génétique Moléculaire et d'Histocompatibilité [Brest], Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), COMBE, Isabelle, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), UNICANCER, Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), IT University of Copenhagen, Institut Gustave Roussy (IGR), Service d'Oncologie Génétique, de Prévention et Dépistage, Laboratoire d'Oncologie Moléculaire Humaine, Université Lille Nord de France (COMUE)-UNICANCER-Université Lille Nord de France (COMUE)-UNICANCER, CHU Pontchaillou [Rennes], Université de Caen Normandie - UFR Santé (UNICAEN Santé), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Centre René Gauducheau, and CRLCC René Gauducheau

Subjects
0301 basic medicine, International Cooperation, RNA Splicing, In silico, Spice, Breast Neoplasms, Computational biology, Biology, Sensitivity and Specificity, Set (abstract data type), 03 medical and health sciences, Exon, 0302 clinical medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, Consensus sequence, RNA and RNA-protein complexes, Humans, Computer Simulation, 030304 developmental biology, BRCA2 Protein, Ovarian Neoplasms, Internet, 0303 health sciences, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], BRCA1 Protein, Intron, Computational Biology, Genetic Variation, Reproducibility of Results, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], In vitro, 030104 developmental biology, 030220 oncology & carcinogenesis, RNA splicing, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, RNA Splice Sites, RNA characterisation and manipulation, Corrigendum, Computational Methods, Optimal decision
Abstract

Variant interpretation is the key issue in molecular diagnosis. Spliceogenic variants exemplify this issue as each nucleotide variant can be deleterious via disruption or creation of splice site consensus sequences. Consequently, reliable in silico prediction of variant spliceogenicity would be a major improvement. Thanks to an international effort, a set of 395 variants studied at the mRNA level and occurring in 5′ and 3′ consensus regions (defined as the 11 and 14 bases surrounding the exon/intron junction, respectively) was collected for 11 different genes, including BRCA1, BRCA2, CFTR and RHD, and used to train and validate a new prediction protocol named Splicing Prediction in Consensus Elements (SPiCE). SPiCE combines in silico predictions from SpliceSiteFinder-like and MaxEntScan and uses logistic regression to define optimal decision thresholds. It revealed an unprecedented sensitivity and specificity of 99.5 and 95.2%, respectively, and the impact on splicing was correctly predicted for 98.8% of variants. We therefore propose SPiCE as the new tool for predicting variant spliceogenicity. It could be easily implemented in any diagnostic laboratory as a routine decision making tool to help geneticists to face the deluge of variants in the next-generation sequencing era. SPiCE is accessible at (https://sourceforge.net/projects/spicev2-1/).

Published
2018
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4. CFTR gene variants: a predisposition factor to aquagenic palmoplantar keratoderma

Author

Claude Férec, F. Dufernez, M.-P. Audrézet, C. Raynal, A. Pagin, F. Cabet, M.-P. Reboul, Pascale Fanen, E. Girodon, Anne Bergougnoux, Patricia Fergelot, Thierry Bienvenu, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), 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), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire de Génétique Moléculaire et d'Histocompatibilité [Brest], Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Hospices Civils de Lyon (HCL), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Bordeaux [Bordeaux], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Hôpital Henri Mondor, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), and Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Genetics, Male, 0303 health sciences, business.industry, Cystic Fibrosis Transmembrane Conductance Regulator, Water, Dermatology, medicine.disease, Cftr gene, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Palmoplantar keratoderma, Keratoderma, Palmoplantar, Case-Control Studies, Mutation, medicine, Humans, Female, Genetic Predisposition to Disease, business, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology, 030304 developmental biology
Abstract

International audience

Published
2019
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5. HLA-DRB3/4/5 mismatches are associated with increased risk of acute GVHD in 10/10 matched unrelated donor hematopoietic cell transplantation

Author

Virginie Moalic, A. Parissiadis, Mauricette Michallet, Matthieu Filloux, Florent Delbos, Marie-Thérèse Rubio, Edouard Forcade, Patrice Chevallier, A. Dormoy, Xavier Lafarge, Virginie Renac, Anne Cesbron, Béatrice Pédron, Christophe Picard, Pascale Loiseau, Abdelali Boudifa, Kahina Amokrane, Federico Garnier, F Quainon, Dominique Masson, Peter van Endert, Françoise Hau, M Fort, Raphaël Porcher, Ibrahim Yakoub-Agha, Valérie Dubois, Isabelle Jollet, Julie Bonneau, Etienne Daguindau, Natacha Maillard, Gérard Socié, Anne Kennel, Jacques-Olivier Bay, Anne Devys, Erwann Quelvennec, Régis Peffault de Latour, Stéphanie Ducreux, Myriam Labalette, Claude-Eric Bulabois, Muriel De Matteis, Etablissement français du sang - Auvergne-Rhône-Alpes (EFS), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Service de neurophysiologie clinique (CHRU Lille), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire d'Immunologie (EA 2686), Université de Lille, Droit et Santé, Service d'hématologie [Hôpital Edouard Herriot - HCL], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Composantes innées de la réponse immunitaire et différenciation (CIRID), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Département de cancérologie et d'hématologie, CHU Grenoble-Hôpital Michallon, Service d'hématologie, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Etablissement français du sang [Angers], Laboratoire de Génétique Moléculaire et d'Histocompatibilité [Brest], Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Etablissement français du sang - Normandie (EFS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), Diabète de Type 1 : mécanismes et traitements immunologiques, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'histocompatibilité et d'immunogénétique [Angers], Université d'Angers (UA), Développement du Systeme Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire de Biologie Médicale [Rennes], Etablissement français du sang [Rennes] (EFS Bretagne), Etablissement Français du Sang - Grand Est (EFS - alsace strasbourg), CHU Toulouse [Toulouse], Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Etablissement français du sang [Poitiers] (EFS), Centre hospitalier universitaire de Nantes (CHU Nantes), Etablissement Français du Sang [Nantes], CHU Clermont-Ferrand, Etablissement français du sang [Clermont-Ferrand] (EFS), Agence de la biomédecine [Saint-Denis la Plaine], Hopital Saint-Louis [AP-HP] (AP-HP), Immunogénétique humaine, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'épidémiologie, biostatistique et recherche clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz, CHU Pitié-Salpêtrière [APHP], Centre National de la Recherche Scientifique (CNRS)-Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté]), CHU Saint Louis [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]

Subjects
Oncology, medicine.medical_specialty, Hematopoietic cell, business.industry, [SDV]Life Sciences [q-bio], Hazard ratio, Hematology, Disease, Matched Unrelated Donor, 3. Good health, Transplantation, 03 medical and health sciences, 0302 clinical medicine, Increased risk, Unrelated Donor, 030220 oncology & carcinogenesis, Internal medicine, medicine, business, 030215 immunology, HLA-DRB3
Abstract

International audience; Matching for HLA‐A, ‐B, ‐C, and ‐DRB1 loci (8/8 match) is currently the gold standard for unrelated donor hematopoietic cell transplantation (HCT). In Europe, patients are also matched at the HLA‐DQB1 loci (10/10 match). However, there is increasing evidence that matching at HLA‐DRB3/4/5 loci may help to lower transplant‐related morbidity and mortality. We therefore investigated the impact of HLA‐DRB3/4/5 mismatches on outcomes in 1975 patients who received a first 10/10 matched unrelated donor (MUD) HCT in France from 2000 to 2012 for a hematological malignancy. High‐resolution typing was performed at HLA‐A, ‐B, ‐C, ‐DRB1, ‐DQB1, ‐DPB1, and ‐DRB3/4/5 loci for all donor/recipient pairs. Compared with DRB3/4/5‐matched pairs, patients who received a MUD HCT from a DRB3/4/5 mismatched donor had a significantly increased risk of grade II‐IV acute graft‐versus‐host disease (aGVHD) (Adjusted Hazard Ratio (HR) 1.43 (1.07 to 1.90)) associated with lower graft‐versus‐host disease‐free and relapse‐free survival (GRFS) (Adjusted HR 1.20 (1.02 to 1.42)). Conversely, we observed no differences in terms of chronic GVHD, nonrelapse mortality, relapse and overall survival. However, we believe that patients stand to benefit from DRB3/4/5 loci being considered for unrelated donor selection to improve GRFS and then quality of life after unrelated HCT.

Published
2018
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6. Do pregnancies reduce iron overload in HFE hemochromatosis women? results from an observational prospective study

Author

Jean Baptiste Nousbaum, Gérald Le Gac, Marianne Uguen, Virginie Scotet, Marie Christine Merour, Brigitte Chanu, Claude Férec, C. L'Hostis, Céline Triponey, Philippe Saliou, BMC, BMC, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d’Hygiène et de Santé Publique [Brest], Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Etablissement Français du Sang Bretagne, EFS, Service d'Hépato-Gastroentérologie [CHRU Brest], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), Laboratoire de Génétique Moléculaire et d'Histocompatibilité [Brest], This study was supported by a grant from the Etablissement Français du Sang., EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), and Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Hôpital Morvan [Brest]

Subjects
0301 basic medicine, Male, [SDV]Life Sciences [q-bio], Disease, Body Mass Index, 0302 clinical medicine, Phlebotomy, Genetic hemochromatosis, Risk Factors, Pregnancy, Epidemiology, Iron overload, Prospective cohort study, biology, Obstetrics, Confounding, Homozygote, Obstetrics and Gynecology, Middle Aged, 3. Good health, [SDV] Life Sciences [q-bio], Phenotype, Regression Analysis, 030211 gastroenterology & hepatology, Female, France, Hemochromatosis, Menopause, Research Article, Adult, medicine.medical_specialty, Alcohol Drinking, Iron, lcsh:Gynecology and obstetrics, 03 medical and health sciences, Sex Factors, Hepcidin, medicine, Humans, Hemochromatosis Protein, lcsh:RG1-991, business.industry, Pregnancy Complications, Hematologic, medicine.disease, 030104 developmental biology, Ferritins, biology.protein, business
Abstract

International audience; BACKGROUND:HFE hemochromatosis is an inborn error of iron metabolism linked to a defect in the regulation of hepcidin synthesis. This autosomal recessive disease typically manifests later in women than men. Although it is commonly stated that pregnancy is, with menses, one of the factors that offsets iron accumulation in women, no epidemiological study has yet supported this hypothesis. The aim of our study was to evaluate the influence of pregnancy on expression of the predominant HFE p.[Cys282Tyr];[Cys282Tyr] genotype.METHODS:One hundred and forty p.Cys282Tyr homozygous women enrolled in a phlebotomy program between 2004 and 2011 at a blood centre in western Brittany (France) were included in the study. After checking whether the disease expression was delayed in women than in men in our study, the association between pregnancy and iron overload was assessed using multivariable regression analysis.RESULTS:Our study confirms that women with HFE hemochromatosis were diagnosed later than men cared for during the same period (52.6 vs. 47.4 y., P

Published
2018
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7. Severe infantile isolated exocrine pancreatic insufficiency caused by the complete functional loss of the SPINK1 gene

Author

David Neil Cooper, Renaud Touraine, Théa Venet, Sylvie Destombe, Hugues Patural, Cécile Talbotec, Kareen Billiemaz, Emmanuelle Masson, Claude Férec, Jian-Min Chen, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Génétique Moléculaire et d'Histocompatibilité [Brest], Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Gastro-Entérologie, Hépatologie et Nutrition, Pédiatriques (CHU Necker - Enfants Malades [AP-HP]), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Génétique Clinique (CHU de Saint-Etienne), Cardiff University, Université de Bretagne Occidentale - UFR Médecine et Sciences de la Santé (UBO UFR MSS), Université de Brest (UBO), Etablissement français du sang [Rennes] (EFS Bretagne), Chen, Jian-Min, EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Gastro-Entérologie, Hépatologie et Nutrition pédiatriques (CHU Necker - Enfants Malades [AP-HP]), CHU Necker - Enfants Malades [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
0301 basic medicine, Untranslated region, medicine.medical_specialty, Pathology, Cystic Fibrosis, Alu element, Biology, Cystic fibrosis, Alu insertion, chronic pancreatitis, 03 medical and health sciences, pancreatic lipomatosis, 0302 clinical medicine, Alu Elements, Internal medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, medicine, SPINK1 Gene, Humans, Lipomatosis, Genetic Predisposition to Disease, Exocrine pancreatic insufficiency, Bone Marrow Diseases, Pancreatic Secretory Trypsin Inhibitor, Genetics (clinical), Sequence Deletion, Homozygote, Infant, Pancreatic Diseases, medicine.disease, Magnetic Resonance Imaging, Phenotype, Shwachman-Diamond Syndrome, Pathophysiology, exocrine pancreatic insufficiency, 3. Good health, Mutagenesis, Insertional, 030104 developmental biology, Endocrinology, Trypsin Inhibitor, Kazal Pancreatic, SPINK1 gene, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, 030211 gastroenterology & hepatology
Abstract

International audience; Exocrine pancreatic insufficiency (EPI) is rare in children, with most if not all cases occurring as part of syndromic conditions such as cystic fibrosis and Shwachman-Diamond syndrome. Here we report two cases, both presenting with severe EPI around 5 months of age. Characterized by diffuse pancreatic lipomatosis, they otherwise exhibited no remarkable deficiencies in other organs. Novel non-identical homozygous variants (a deletion removing the entire SPINK1 gene and an insertion of a full-length inverted Alu element into the 3'-untranslated region of the SPINK1 gene) resulting in the complete functional loss of the SPINK1 gene (encoding pancreatic secretory trypsin inhibitor) were identified in each patient. Having correlated our findings with current knowledge of SPINK1's role in exocrine pancreas pathophysiology, we propose that complete and partial functional losses of the SPINK1 gene are associated with quite distinct phenotypes, the former causing a new pediatric disease entity of severe infantile isolated EPI.

Published
2017
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8. Guidelines for the clinical management and follow-up of infants with inconclusive cystic fibrosis diagnosis through newborn screening

Author

E. Deneuville, M.-P. Audrézet, J. Brouard, N. Wizla, N. Remus, L. Couderc Kohen, Emmanuelle Girodon, S. Vrielynck, K. LLerena, C. Raynal, Laurence Weiss, Thao Nguyen-Khoa, Isabelle Sermet-Gaudelus, M. Le Bourgeois, Michel Roussey, Cystic Fibrosis Center - hôpital Necker, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Cystic Fibrosis Center - Hôpital Côte de Nacre Caen, Laboratoire de Génétique Moléculaire et d'Histocompatibilité [Brest], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Hôpital Morvan [Brest], Cystic Fibrosis Center - Hôpital Charles Nicolle Rouen, Cystic Fibrosis Center - Hôpital Hautepierre Strasbourg, Cystic Fibrosis Center - Hôpital Jeanne de Flandres Lille, Cystic Fibosis Center - Hôpital Mères Enfants Lyon, Cystic Fibrosis Center - CHU Grenoble, Cystic Fibrosis Center - CHU Rennes, Cystic Fibrosis Center - CHI Créteil, Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Association Française pour le Dépistage et la Prévention des Handicaps de l'Enfant, and Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)

Subjects
Pediatrics, medicine.medical_specialty, Cystic Fibrosis, Cystic fibrosis, SWEAT, 03 medical and health sciences, Neonatal Screening, 0302 clinical medicine, 030225 pediatrics, Rare mutations, medicine, Humans, Immunoreactive trypsinogen, Medical diagnosis, ComputingMilieux_MISCELLANEOUS, Newborn screening, biology, medicine.diagnostic_test, business.industry, Infant, Newborn, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Cystic fibrosis transmembrane conductance regulator, 3. Good health, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, 030228 respiratory system, Pediatrics, Perinatology and Child Health, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, biology.protein, Sputum, medicine.symptom, business, Algorithms, Follow-Up Studies
Abstract

Summary Neonatal screening for cystic fibrosis (CF) can detect infants with elevated immunoreactive trypsinogen (IRT) levels and inconclusive sweat tests and/or CFTR DNA results. These cases of uncertain diagnosis are defined by (1) either the presence of at most one CF-associated cystic fibrosis transmembrane conductance regulator (CFTR) mutation with sweat chloride values between 30 and 59 mmol/L or (2) two CFTR mutations with at least one of unknown pathogenic potential and a sweat chloride concentration below 60 mmol/L. This encompasses various clinical situations whose progression cannot be predicted. In these cases, a sweat chloride test has to be repeated at 12 months, and if possible at 6 and 24 months of life along with extended CFTR sequencing to detect rare mutations. When the diagnosis is not definite, CFTR functional explorations may provide a better understanding of CFTR dysfunction. The initial evaluation of these infants must be conducted in dedicated CF reference centers and should include bacteriological sputum analysis, chest radiology, and fecal elastase assay. The primary care physicians in charge of these patients should be familiar with the current management of CF and should work in collaboration with CF centers. A follow-up should be performed in a CF reference center at 3, 6, and 12 months of life and every year thereafter. Any symptom indicative of CF requires immediate reevaluation of the diagnosis. These guidelines were established by the “neonatal screening and difficult diagnoses” working group of the French CF society. Their objective is to standardize the management of infants with unclear diagnosis.

Published
2017
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9. Revisiting the molecular epidemiology of factor XI deficiency: Nine new mutations and an original large 4qTer deletion in western Brittany (France)

Author

Paul Guéguen, Cédric Le Maréchal, Sylvia Quéméner-Redon, Angélique Chauvin, Claude Férec, Brigitte Pan-Petesch, Jean-François Abgrall, Génétique moléculaire et génétique épidémiologique, Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hématologie biologique, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Laboratoire de Génétique Moléculaire et d'Histocompatibilité [Brest], Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), LFB for their financial support., and Le Marechal, Cedric

Subjects
Adult, Male, 0301 basic medicine, Heterozygote, Adolescent, DNA Mutational Analysis, Population, [SDV.GEN] Life Sciences [q-bio]/Genetics, genetic analysis, 030204 cardiovascular system & hematology, Biology, medicine.disease_cause, Genetic analysis, Article, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, deletion, education, Blood Coagulation, Factor XI, Alleles, Aged, Gene Rearrangement, Genetics, Comparative Genomic Hybridization, Molecular Epidemiology, [SDV.GEN]Life Sciences [q-bio]/Genetics, education.field_of_study, Mutation, Models, Genetic, Molecular epidemiology, Exons, Hematology, Gene rearrangement, Middle Aged, Telomere, Ashkenazi jews, 3. Good health, Factor XI deficiency, 030104 developmental biology, Female, Allelic heterogeneity, France, Chromosome Deletion, Chromosomes, Human, Pair 4, mutation, F11 gene
Abstract

SummaryConstitutional deficiency in factor XI (FXI) is a rare bleeding disorder in the general population, with the exception of Ashkenazi Jews. During the last decade, the detection of FXI-deficient patients has shifted from clinical screening identifying mostly severe bleeders to biological screening combining findings of prolonged activated partial thromboplastin time and FXI coagulation activity (FXI:C) below 50 U/dl. The goal of this study was to determine the molecular basis of FXI deficiency in western Brittany, France. Over the course of four years, we detected 98 FXI-deficient patients through biological screening, and 44 patients agreed to participate in this study corresponding to 25 index cases. We developed an efficient mutation detection strategy (combining direct sequencing and QFM-PCR to search for heterozygous rearrangements in a routine setting) that detected F11 mutations in 24 out of the 25 index cases. An unexpected allelic heterogeneity was found, with 14 different single point mutations being detected, among which nine are new. Moreover, a large heterozygous deletion of the entire F11 gene was detected, and was then further defined using a CGH array as a 4q34.2 telomeric deletion of 7 Mb containing 77 genes. We propose that the observed recurrent mutations may be considered as genetic tags of a population. This study highlights the importance of screening for large deletions in molecular studies of F11.

Published
2012
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10. Pneumocystis jirovecii in the air surrounding patients with Pneumocystis pulmonary colonization

Author

Laurence Pougnet, Michèle Virmaux, Anne Totet, Paul Gueguen, Solène Le Gal, Yann Le Meur, Gaétan Le Floch, Aurélien Delluc, Jean-Marie Tonnelier, Céline Damiani, Philippe Castellant, Jean Menotti, Emilie Fréalle, Sylvain Jaffuel, Francis Couturaud, Séverine Ansart, Gilles Nevez, Laboratoire Universitaire de Biodiversité et Ecologie Microbienne (LUBEM), Université de Brest (UBO), Laboratoire de Parasitologie et Mycologiede [CHRU Brest], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Hôpital d'Instruction des Armées Clermont Tonnerre, Service de Santé des Armées, Périnatalité et Risques Toxiques - UMR INERIS_I 1 (PERITOX), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de l'Environnement Industriel et des Risques, Laboratoire de parasitologie et de mycologie médicales [CHU Amiens], CHU Amiens-Picardie, Laboratoire de Parasitologie et Mycologie (Parasito - Myco - LILLE), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Génétique Moléculaire et d'Histocompatibilité [Brest], Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Laboratoire de Traitement de l'Information Medicale (LaTIM), Université européenne de Bretagne - European University of Brittany (UEB)-Télécom Bretagne-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Mines-Télécom [Paris] (IMT), Service de médecine interne 2 et maladies infectieuses, Département de Médecine Interne et Pneumologie [Brest] (DMIP - Brest), Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), Service de Réanimation Médicale (BREST - Réa Med), Optimisation des régulations physiologiques (ORPHY (EA 4324)), Université de Brest (UBO)-Université de Brest (UBO)-Université de Brest (UBO)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Immunologie et Pathologie (EA2216), Université de Brest (UBO)-IFR148, Institut du droit public et de la science politique (IDPSP), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Departments of Medical Parasitology and Mycology, Institut National de l'Environnement Industriel et des Risques (INERIS)-Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Service de Parasitologie-Mycologie [CHRU LIlle], Institut de Microbiologie [CHRU Lille], Pôle de Biologie Pathologie Génétique [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Pôle de Biologie Pathologie Génétique [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université européenne de Bretagne - European University of Brittany (UEB)-Université de Brest (UBO)-Télécom Bretagne-Institut Mines-Télécom [Paris] (IMT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Institut Brestois Santé Agro Matière (IBSAM), Université de Rennes (UR), and Calvez, Ghislaine

Subjects
Microbiology (medical), Adult, Male, Genotype, [SDV]Life Sciences [q-bio], Air Microbiology, Pneumocystis carinii, Airborne transmission, DNA, Ribosomal, Microbiology, 03 medical and health sciences, 0302 clinical medicine, parasitic diseases, medicine, Pneumocystis jirovecii, Humans, Colonization, airborne transmission, 030212 general & internal medicine, DNA, Fungal, Genotyping, Aged, Aged, 80 and over, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, 030306 microbiology, Pneumonia, Pneumocystis, exhalation, Fungal genetics, Exhalation, General Medicine, Sequence Analysis, DNA, Middle Aged, medicine.disease, biology.organism_classification, colonization, 3. Good health, [SDV] Life Sciences [q-bio], Pneumonia, Infectious Diseases, RNA, Ribosomal, Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; In this study, Pneumocystis jirovecii was detected and characterized in the air surrounding patients with Pneumocystis pulmonary colonization. Air samples were collected in the rooms of 10 colonized patients using Coriolis® μ air sampler at 1m and 5m from the patient's head. P. jirovecii DNA was amplified and genotyped in pulmonary and air samples at the mitochondrial large subunit ribosomal RNA gene. P. jirovecii DNA was detected in 5 of the 10 air samples collected at 1m and in 5 of the 10 other air samples collected at 5m. P. jirovecii genotyping was successful in 4 pairs or triplets of air and pulmonary samples. Full genotype matches were observed in 3 of the 4 pairs or triplets of air and pulmonary samples. These results provide original data supporting P. jirovecii exhalation from colonized patients and emphasize the risk of P. jirovecii nosocomial transmission from this patient population.

Published
2014
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11. A Conservative Assessment of the Major Genetic Causes of Idiopathic Chronic Pancreatitis: Data from a Comprehensive Analysis of PRSS1, SPINK1, CTRC and CFTR Genes in 253 Young French Patients

Author

David Neil Cooper, Emmanuelle Masson, Marie-Pierre Audrézet, Claude Férec, Jian-Min Chen, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Génétique Moléculaire et d'Histocompatibilité [Brest], Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Etablissement Français du Sang Bretagne, EFS, School of Medicine [Cardiff], and Cardiff University-Institute of Medical Genetics [Cardiff]

Subjects
Adult, Male, Genotype, [SDV]Life Sciences [q-bio], lcsh:Medicine, Cystic Fibrosis Transmembrane Conductance Regulator, Disease, Biology, Bioinformatics, Cohort Studies, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Human genetics, Pancreatitis, Chronic, Genetic predisposition, medicine, Chymotrypsin, Humans, Trypsin, Variant genotypes, Allele, lcsh:Science, French people, Genetics of disease, Allele frequency, Alleles, 030304 developmental biology, Genetics, 0303 health sciences, Multidisciplinary, lcsh:R, Epistasis, Genetic, Genetic screens, medicine.disease, 3. Good health, Pancreatitis, Trypsin Inhibitor, Kazal Pancreatic, Mutation, lcsh:Q, Female, 030211 gastroenterology & hepatology, France, Carrier Proteins, Research Article, Genetic screen
Abstract

International audience; Idiopathic chronic pancreatitis (ICP) has traditionally been defined as chronic pancreatitis in the absence of any obvious precipitating factors (e.g. alcohol abuse) and family history of the disease. Studies over the past 15 years have revealed that ICP has a highly complex genetic architecture involving multiple gene loci. Here, we have attempted to provide a conservative assessment of the major genetic causes of ICP in a sample of 253 young French ICP patients. For the first time, conventional types of mutation (comprising coding sequence variants and variants at intron/exon boundaries) and gross genomic rearrangements were screened for in all four major pancreatitis genes, PRSS1, SPINK1, CTRC and CFTR. For the purposes of the study, synonymous, intronic and 5'- or 3'-untranslated region variants were excluded from the analysis except where there was persuasive evidence of functional consequences. The remaining sequence variants/genotypes were classified into causative, contributory or neutral categories by consideration of (i) their allele frequencies in patient and normal control populations, (ii) their presumed or experimentally confirmed functional effects, (iii) the relative importance of their associated genes in the pathogenesis of chronic pancreatitis and (iv) gene-gene interactions wherever applicable. Adoption of this strategy allowed us to assess the pathogenic relevance of specific variants/genotypes to their respective carriers to an unprecedented degree. The genetic cause of ICP could be assigned in 23.7% of individuals in the study group. A strong genetic susceptibility factor was also present in an additional 24.5% of cases. Taken together, up to 48.2% of the studied ICP patients were found to display evidence of a genetic basis for their pancreatitis. Whereas these particular proportions may not be extrapolable to all ICP patients, the approach employed should serve as a useful framework for acquiring a better understanding of the role of genetic factors in causing this oligogenic disease.

Published
2013
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